Search

Abstract Background Impaired hospitalizations for heart failure (HHF) and mortality are associated with tricuspid regurgitation (TR). Objectives The objective of this study was to investigate the benefit of transcatheter tricuspid valve replacement (TTVR) over guideline-directed medical therapy (GDMT) in patients with symptomatic severe TR. Methods Between May 2020 and April 2023, 88 patients with symptomatic severe TR were treated in our center. Of these, 57 patients received GDMT alone, and 31 patients underwent combined TTVR and GDMT. We collected and analyzed baseline data, and follow-up information for both groups. The primary endpoints were all-cause mortality and the combined endpoint (including all-cause mortality and HHF). Results At a median follow-up of 20 (IQR 10–29) months, significant improvements were shown in TR severity, right ventricular function, and dimensions in TTVR group (all P

Abstract Pancreatic cancer, characterized by its poor prognosis, exhibits a marked resistance to conventional chemotherapy and immunotherapy, underscoring the urgent need for more effective treatment modalities. In light of this, the present study is designed to assess the potential antineoplastic efficacy of a combined regimen involving tetrandrine, a plant-derived alkaloid, and autophagy inhibitors in the context of pancreatic cancer. Electron microscopy and immunoblots showed that tetrandrine promoted the formation of autophagosomes and the upregulation of LC3II and the downregulation of p62 expression, indicating that tetrandrine induced autophagy in pancreatic cancer cells. Western blot revealed that tetrandrine inhibited the phosphorylation of AKT and mTOR, as well as the expression of Bcl-2, while upregulating Beclin-1 expression. Moreover, tetrandrine promoted the transcription and protein expression of ATG7. Following the combination of autophagy inhibitors and tetrandrine, the apoptotic rate and cell death significantly increased in pancreatic cancer cells. Consistent results were obtained when ATG7 was silenced. Additionally, tetrandrine induced the generation of ROS, which was involved in the activation of autophagy and apoptosis. Further investigation revealed that upon autophagy inhibition, ROS accumulated in pancreatic cancer cells, resulting in decreased mitochondrial membrane potential and further induction of apoptosis. The results of treating subcutaneous xenograft tumors with a combination of tetrandrine and chloroquine validated that autophagy inhibition enhances the toxicity of tetrandrine against pancreatic cancer in vivo. Altogether, our study demonstrates that tetrandrine induces cytoprotective autophagy in pancreatic cancer cells. Inhibiting tetrandrine-induced autophagy promotes the accumulation of ROS and enhances its toxicity against pancreatic cancer.

6:2 fluorotelomer carboxylic acid (6:2 FTCA) is a perfluorooctanoic acid (PFOA) substitute, which is supposedly less accumulative and toxic than PFOA. However, 6:2 FTCA is structurally similar to PFOA, and there had already been reports about its toxicities comparable to PFOA. The aim of the current study is to assess potential effects of developmental exposure to 6:2 FTCA on the development of kidney in chicken embryo and to investigate underlying mechanism. Fertile chicken eggs were exposed to 1.25 mg/kg, 2.5 mg/kg or 5 mg/kg doses of 6:2 FTCA, or 2 mg/kg PFOA, then incubated to hatch. Serum and kidney of hatchling chickens were collected. Blood urea nitrogen (BUN) and creatinine (Cre) levels were measured with commercially available kits. Morphology of kidney was assessed with histopathology. To further reveal molecular mechanism of observed endpoints, IGF signaling molecules were assessed in the kidney samples with qRT-PCR, results indicated that IGFBP3 is a potentially crucial molecule. Lentiviruses overexpressing or silencing IGFBP3 were designed and applied to enhance/suppress the expression of IGFBP3 in developing chicken embryo for further verification of its role in the observed effects. Disrupted nephron formation, in the manifestation of decreased glomeruli number/area and increased serum BUN/Cre levels, was observed in the animals developmentally exposed to 6:2 FTCA. Correspondingly, IGF signaling molecules (IGF1, IGF1R and IGFBP3) were affected by 6:2 FTCA exposure. Meanwhile, overexpression of IGFBP3 effectively alleviated such changes, while silencing of IGFBP3 mimicked observed effects. In conclusion, developmental exposure to 6:2 FTCA is associated with disrupted chicken embryo renal development, in which IGFBP3 seems to be a remarkable contributor, suggesting potential health risks for human and other species. Further risk assessments and mechanistic works are necessary.

Anaerobic digestion (AD) plays a significant role in renewable energy recovery. Upgrading AD from thermophilic (50–57 °C) to mesophilic (30–38 °C) conditions to enhance process stability and reduce energy input remains challenging due to the high sensitivity of thermophilic microbiomes to temperature fluctuations. Here we compare the effects of two decreasing-temperature modes from 55 to 35 °C on cell viability, microbial dynamics, and interspecies interactions. A sharp transition (ST) is a one-step transition by 20 °C d−1, while a mild transition (MT) is a stepwise transition by 1 °C d−1. We find a greater decrease in methane production with ST (88.8%) compared to MT (38.9%) during the transition period. ST mode overproduced reactive oxygen species by 1.6-fold, increased membrane permeability by 2.2-fold, and downregulated microbial energy metabolism by 25.1%, leading to increased apoptosis of anaerobes by 1.9-fold and release of intracellular substances by 2.9-fold, further constraining methanogenesis. The higher (1.6 vs. 1.1 copies per gyrA) metabolic activity of acetate-dependent methanogenesis implied more efficient methane production in a steady mesophilic, MT-mediated system. Metagenomic binning and network analyses indicated that ST induced dysbiosis in keystone species and greatly enhanced microbial functional redundancy, causing loss of microbial syntrophic interactions and redundant metabolic pathways. In contrast, the greater microbial interconnections (average degrees 44.9 vs. 22.1) in MT at a steady mesophilic state suggested that MT could better maintain necessary system functionality and stability through microbial syntrophy or specialized pathways. Adopting MT to transform thermophilic digesters into mesophilic digesters is feasible and could potentially enhance the further optimization and broader application of practical anaerobic engineering.

ObjectivesTo evaluate the changes in distal vascular morphology and hemodynamics in patients with extremely severe aortic coarctation (CoA) after covered palliative (CP) stent dilation with different surgical strategies.Materials and methodsPerioperative computed tomography angiography and digital subtraction angiography were utilized to construct three aortic models with varying stenosis rates and one follow-up model in a patient with extremely severe CoA. The models included: an idealized non-stenosed model (A: 0%), a model post initial stent deployment (B: 28%), a model post balloon expansion (C: 39%), and a model 18 months after post-balloon expansion (D: 39%). Consistent boundary conditions were applied to all models, and hemodynamic simulation was conducted using the pure fluid method.ResultsThe narrowest and distal diameter of the stent increased by 34.71% and 59.29%, respectively, from model B to C. Additionally, the distal diameter of the stent increased by −13.80% and +43.68% compared to the descending aorta diameter, respectively. Furthermore, the ellipticity of the maximum cross-section of the aneurysm region in model A to D continued to increase. The oscillatory shear index at the stenosis to the region of the aneurysm were found to be higher in Models A and B, and lower in Models C and D. At the moment of maximum flow velocity, the blood flow distribution in models A and B was more uniform in the widest section of the blood vessels at the distal end of the stenosis, whereas models C and D exhibited disturbed blood flow with more than 2 eddy currents. The time-averaged wall shear stress (TAWSS) decreased in the distal and basal aneurysms, while it significantly increased at the step position. The aneurysmal region exhibited an endothelial cell activation potential value lower than 0.4 Pa−1.ConclusionIn patients with extremely severe CoA, it is crucial to ensure that the expanded diameter at both ends of the CP stent does not exceed the native vascular diameter during deployment. Our simulation results demonstrate that overdilation leads to a decrease in the TAWSS above the injured vessel, creating an abnormal hemodynamic environment that may contribute to the development and enlargement of false aneurysms in the early postoperative period. Clinical Trial RegistrationClinicalTrials.gov, (NCT02917980).

Abstract The “Eight Scenic Views Paintings” represent crucial visual materials for investigating the history of cultural landscapes. However, traditional methods of interpreting materials struggle to discern the inherent connections between different landscape elements. This study proposes an approach for deconstructing historical images, taking the example of the Forty Scenic Views in the Late Ming Dynasty in Nanjing, China. To explore the co-occurrence structure, hierarchical clustering, and correlation features among various elements, various digital humanities quantification methods were applied, including spatial analysis of ArcGIS, co-occurrence and clustering of KH Coder, and correlation analysis of SPSS. This study reveals the characteristics of the landscape construction of Nanjing in the Late Ming: natural landscape as the foundation, artificial landscape as the core, and advocating tradition as the fashion. It also uncovers the landscape order: mountains, waters, and scenic views interweaved and coexisted, as well as nature and culture intertwined and clustered. In addition, multiple information graphs of the subordinate and co-occurrence relationships of 20 landscape elements were constructed, 5 landscape paradigms were extracted, and 36 pairs of related relationships were discovered, deepening the historical understanding of the urban landscape construction of Nanjing in the Late Ming. This paper puts forward the idea of analyzing historical images by digital method, which provides some essential and detailed historical basis for explaining the value of cultural landscape heritage and shaping contemporary urban landscape.

Abstract Recurrent tricuspid regurgitation after failed ring annuloplasty is associated with high mortality rates and unfavourable clinical outcomes. Transcatheter tricuspid valve‐in‐ring (TVIR) replacement offers an alternative to high‐risk surgical reoperation, but challenges remain. We present a case of a 67‐year‐old male who underwent tricuspid annuloplasty 3 years ago and developed severe recurrent tricuspid regurgitation (regurgitation volume = 36 mL) 6 months ago. To avoid a high‐risk thoracotomy, we finally performed TVIR replacement using the novel device, LuX‐Valve Plus system, via the transjugular approach. Cardiovascular three‐dimensional printing technology was utilized to investigate the distinct advantages offered by the new device in this specific intervention, as well as to simulate the procedure. Successful TVIR replacement resulted in significant symptomatic improvement. TVIR replacement with the LuX‐Valve Plus system is feasible for failed annuloplasty ring cases. Patient‐specific three‐dimensional printed models enable personalized procedural planning, enhancing safety and precision.

We consider a quasi-one-dimensional Poisson-Nernst-Planck model with two cations having the same valances and one anion. Bikerman's local hard-sphere potential is included to account for ion size effects. Under some further restrictions on the boundary conditions of the two cations, we obtain approximations of the I-V (current-voltage) relations by treating the ion sizes as small parameters. Critical potentials are identified, which play critical roles in characterizing finite ion size effects on ionic flows. Nonlinear interplays between system parameters, such as boundary concentrations and diffusion coefficients, are analyzed. To provide more intuitive illustrations of our analytical results and better understanding of the dynamics of ionic flows through membrane channels, numerical simulations are performed.

The resection of malignant osteosarcoma often results in large segmental bone defects, and the residual cells can facilitate recurrence. Consequently, the treatment of osteosarcoma is a major challenge in clinical practice. The ideal goal of treatment for osteosarcoma is to eliminate it thoroughly, and repair the resultant bone defects as well as avoid bacterial infections. Herein, we fabricated a selenium/strontium/zinc-doped hydroxyapatite (Se/Sr/Zn-HA) powder by hydrothermal method, and then employed it with polycaprolactone (PCL) as ink to construct composite scaffolds through 3D printing, and finally introduced them in bone defect repair induced by malignant osteosarcoma. The resultant composite scaffolds integrated multiple functions involving anti-tumor, osteogenic, and antibacterial potentials, mainly attributed to the anti-tumor effects of SeO32−, osteogenic effects of Sr2+ and Zn2+, and antibacterial effects of SeO32− and Zn2+. In vitro studies confirmed that Se/Sr/Zn-HA leaching solution could induce apoptosis of osteosarcoma cells, differentiation of MSCs, and proliferation of MC3T3-E1 while showing excellent antibacterial properties. In vivo tests demonstrated that Se/Sr/Zn-HA could significantly suppress tumors after 8 days of injection, and the Se/Sr/Zn-HA-PCLs scaffold repaired femoral defects effectively after 3 months of implantation. Summarily, the Se/Sr/Zn-HA-PCLs composite scaffolds developed in this study were effective for tumor treatment, bone defect repair, and post-operative anti-infection, which provided a great potential to be a facile therapeutic material for osteosarcoma resection.

AbstractPurpose To evaluate the role of M2 macrophages in subconjunctival fibrosis after silicone implantation (SI) and investigate the underlying mechanisms.Materials and methods A model of subconjunctival fibrosis was established by SI surgery in rabbit eyes. M2 distribution and collagen deposition were evaluated by histopathology. The effects of M2 cells on the migration (using wound-scratch assay) and activation (by immunofluorescence and western blotting) of human Tenon’s fibroblasts (HTFs) were investigated.Results There were more M2 macrophages (CD68+/CD206+ cells) occurring in tissue samples around silicone implant at 2 weeks postoperatively. Dense collagen deposition was observed at 8 weeks after SI. In vitro experiment showed M2 expressed high level of CD206 and transforming growth factor-β1 (TGF-β1). The M2-conditioned medium promoted HTFs migration and the synthesis of collagen I and fibronectin. Meanwhile, M2-conditioned medium increased the protein levels of TGF-β1, TGF-βR II, p-Smad2/3, yes-associated protein (YAP), and transcriptional coactivator with PDZ-binding motif (TAZ). Verteporfin, a YAP inhibitor, suppressedTGF-β1/Smad2/3-YAP/TAZ pathway and attenuated M2-induced extracellular matrix deposition by HTFs.Conclusions TGF-β1/Smad2/3-YAP/TAZ signalling may be involved in M2-induced fibrotic activities in HTFs. M2 plays a key role in promoting subconjunctival fibrosis and can serve as an attractive target for anti-fibrotic therapeutics.

Thrombocytopenia caused by long-term radiotherapy and chemotherapy exists in cancer treatment. Previous research demonstrates that 5-Hydroxtrayptamine (5-HT) and its receptors induce the formation of megakaryocytes (MKs) and platelets. However, the relationships between 5-HT1A receptor (5-HTR1A) and MKs is unclear so far. We screened and investigated the mechanism of vilazodone as a 5-HTR1A partial agonist in promoting MK differentiation and evaluated its therapeutic effect in thrombocytopenia. We employed a drug screening model based on machine learning (ML) to screen the megakaryocytopoiesis activity of Vilazodone (VLZ). The effects of VLZ on megakaryocytopoiesis were verified in HEL and Meg-01 cells. Tg (itga2b: eGFP) zebrafish was performed to analyze the alterations in thrombopoiesis. Moreover, we established a thrombocytopenia mice model to investigate how VLZ administration accelerates platelet recovery and function. We carried out network pharmacology, Western blot, and immunofluorescence to demonstrate the potential targets and pathway of VLZ. VLZ has been predicted to have a potential biological action. Meanwhile, VLZ administration promotes MK differentiation and thrombopoiesis in cells and zebrafish models. Progressive experiments showed that VLZ has a potential therapeutic effect on radiation-induced thrombocytopenia in vivo. The network pharmacology and associated mechanism study indicated that SRC and MAPK signaling are both involved in the processes of megakaryopoiesis facilitated by VLZ. Furthermore, the expression of 5-HTR1A during megakaryocyte differentiation is closely related to the activation of SRC and MAPK. Our findings demonstrated that the expression of 5-HTR1A on MK, VLZ could bind to the 5-HTR1A receptor and further regulate the SRC/MAPK signaling pathway to facilitate megakaryocyte differentiation and platelet production, which provides new insights into the alternative therapeutic options for thrombocytopenia.

Abstract Background Schizophrenia patients have a high risk of suicide, and their cognition function is impaired with increasing age. The association between neurocognitive and suicidality in schizophrenia patients are heterogeneous. We aimed to explore the relationship between neurocognitive function and suicidal ideation in schizophrenia patients across age groups. Methods A total of 587 patients with schizophrenia were enrolled in this study. The schizophrenia patients were divided into young group (aged 18–44) and middle-aged and elderly group (aged 45–70). The schizophrenia patients were divided into suicidal ideation group and non-suicidal ideation group according to the evaluation results of the Beck Scale for Suicide Ideation. Insomnia symptoms were measured by the Insomnia Severity Index (ISI). Psychotic symptoms were measured by the Positive and Negative Syndrome Scale (PANSS), and cognitive function was measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Results There was a negative correlation between the age and attention scores of RBANS (P = 0.018). The young schizophrenia patients had higher risk of suicidality than middle-aged and elderly schizophrenia patients (P = 0.001). In the logistic regression analysis, the scores of ISI and positive symptoms scores of PANSS were associated with suicidal ideation among young schizophrenia patients (All P

Highlights The flower-like δ-MnO2 nanostructures with controlled oxygen vacancies as an extraordinary ZIBs cathode are innovatively developed. The cathode can present large capacity and high-rate zinc-ion storage. DFT analysis substantially unveils the effects of various vacancy concentrations on their electrochemical performances.

The in vitro maturation efficiency of porcine oocytes is relatively low, and this limits the production of in vitro porcine embryos. Since melatonin is involved in mammalian reproductive physiology, in this study, we have explored whether endogenously produced melatonin can help in porcine oocyte in vitro maturation. We have found, for the first time in the literature, that mitochondria are the major sites for melatonin biosynthesis in porcine oocytes. This mitochondrially originated melatonin reduces ROS production and increases the activity of the mitochondrial respiratory electron transport chain, mitochondrial biogenesis, mitochondrial membrane potential, and ATP production. Therefore, melatonin improves the quality of oocytes and their in vitro maturation. In contrast, the reduced melatonin level caused by siRNA to knockdown AANAT (siAANAT) is associated with the abnormal distribution of mitochondria, decreasing the ATP level of porcine oocytes and inhibiting their in vitro maturation. These abnormalities can be rescued by melatonin supplementation. In addition, we found that siAANAT switches the mitochondrial oxidative phosphorylation to glycolysis, a Warburg effect. This metabolic alteration can also be corrected by melatonin supplementation. All these activities of melatonin appear to be mediated by its membrane receptors since the non-selective melatonin receptor antagonist Luzindole can blunt the effects of melatonin. Taken together, the mitochondria of porcine oocytes can synthesize melatonin and improve the quality of oocyte maturation. These results provide an insight from a novel aspect to study oocyte maturation under in vitro conditions.

Abstract Urbanization is a leading cause of global biodiversity loss, yet cities can provide resources required by many species throughout the year. In recognition of this, cities around the world are adopting strategies to increase biodiversity. These efforts would benefit from a robust understanding of how natural and enhanced features in urbanized areas influence various taxa. We explored seasonal and spatial patterns in occupancy and taxonomic richness of birds and pollinators among office parks in Santa Clara County, California, USA, where natural features and commercial landscaping have generated variation in conditions across scales. We surveyed birds and insect pollinators, estimated multi‐species occupancy and species richness, and found that spatial scale (local, neighborhood, and landscape scale), season, and urban sensitivity were all important for understanding how communities occupied sites. Features at the landscape (distance to streams or baylands) and local scale (tree canopy, shrub, or impervious cover) were the strongest predictors of avian occupancy in all seasons. Pollinator richness was influenced by local tree canopy and impervious cover in spring, and distance to baylands in early and late summer. We then predicted the relative contributions of different spatial scales to annual bird species richness by simulating “good” and “poor” quality sites based on influential covariates returned by the previous models. Shifting from poor to good quality conditions locally increased annual avian richness by up to 6.8 species with no predicted effect on the quality of the neighborhood. Conversely, sites of poor local and neighborhood scale quality in good‐quality landscapes were predicted to harbor 11.5 more species than sites of good local‐ and neighborhood‐scale quality in poor‐quality landscapes. Finally, more urban‐sensitive bird species were gained at good quality sites relative to urban tolerant species, suggesting that urban natural features at the local and landscape scales disproportionately benefited them.

Multi-scale system remains a classical scientific problem in fluid dynamics, biology, etc. In the present study, a scheme of multi-scale Physics-informed neural networks is proposed to solve the boundary layer flow at high Reynolds numbers without any data. The flow is divided into several regions with different scales based on Prandtl’s boundary theory. Different regions are solved with governing equations in different scales. The method of matched asymptotic expansions is used to make the flow field continuously. A flow on a semi infinite flat plate at a high Reynolds number is considered a multi-scale problem because the boundary layer scale is much smaller than the outer flow scale. The results are compared with the reference numerical solutions, which show that the msPINNs can solve the multi-scale problem of the boundary layer in high Reynolds number flows. This scheme can be developed for more multi-scale problems in the future.

Abstract Background Though programmed cell death‐ligand 1 (PD‐L1) has been used in predicting the efficacy of immune checkpoint blockade (ICB), it is insufficient as a single biomarker. As a key effector of an intrinsically mutagenic microhomology‐mediated end joining (MMEJ) pathway, DNA polymerase theta (POLQ) was overexpressed in various malignancies, whose expression might have an influence on genomic stability, therefore altering the sensitivity to chemotherapy and immunotherapy. Methods A total of 1304 patients with muscle‐invasive bladder cancer (MIBC) from six independent cohorts were included in this study. The Zhongshan Hospital (ZSHS) cohort (n = 134), The Cancer Genome Atlas (TCGA) cohort (n = 391), and the Neo‐cohort (n = 148) were included for the investigation of chemotherapeutic response. The IMvigor210 cohort (n = 234) and the UNC‐108 cohort (n = 89) were used for the assessment of immunotherapeutic response. In addition, the relationship between POLQ and the immune microenvironment was assessed, and GSE32894 (n = 308) was used only for the evaluation of the immune microenvironment. Results We identified POLQhigh PD‐L1high patients could benefit more from immunotherapy and platinum‐based chemotherapy. Further analysis revealed that high POLQ expression was linked to chromosome instability and higher tumor mutational burden (TMB), which might elicit the production of neoantigens. Further, high POLQ expression was associated with an active tumor immune microenvironment with abundant infiltration of immune effector cells and molecules. Conclusions The study demonstrated that high POLQ expression was correlated with chromosome instability and antitumor immune microenvironment in MIBC, and the combination of POLQ and PD‐L1 could be used as a superior companion biomarker for predicting the efficacy of immunotherapy.

BackgroundUlcerative colitis (UC) is a lifelong inflammatory disease affecting the rectum and colon with numerous treatment options that require an individualized treatment plan. Histone modifications regulate chromosome structure and gene expression, resulting in effects on inflammatory and immune responses. However, the relationship between histone modification-related genes and UC remains unclear.MethodsTranscriptomic data from GSE59071 and GSE66407 were obtained from the Gene Expression Omnibus (GEO), encompassing colonic biopsy expression profiles of UC patients in inflamed and non-inflamed status. Differentially expressed gene (DEG) analyses, functional enrichment analyses, weighted gene co-expression network analysis (WGCNA), and random forest were performed to identify histone modification-related core genes associated with UC inflammation. Features were screened through the least absolute shrinkage and selection operator (LASSO) and support vector machine‐recursive feature elimination (SVM‐RFE), establishing a molecular inflammatory predictive model using logistic regression. The model was validated in the GSE107499 dataset, and the performance of the features was assessed using receiver operating characteristic (ROC) and calibration curves. Immunohistochemistry (IHC) staining of colonic biopsy tissues from UC patients treated with infliximab was used to further confirm the clinical application value. Univariate logistic regression on GSE14580 highlighted features linked to infliximab response.ResultsA total of 253 histone modification-related DEGs were identified between inflammatory and non-inflammatory patients with UC. Seven key genes (IL-1β, MSL3, HDAC7, IRF4, CAMK2D, AUTS2, and PADI2) were selected using WGCNA and random forest. Through univariate logistic regression, three core genes (CAMK2D, AUTS2, and IL-1β) were further incorporated to construct the molecular inflammatory predictive model. The area under the curve (AUC) of the model was 0.943 in the independent validation dataset. A significant association between CAMK2D protein expression and infliximab response was observed, which was validated in another independent verification set of GSE14580 from the GEO database.ConclusionThe molecular inflammatory predictive model based on CAMK2D, AUTS2, and IL-1β could reliably distinguish the mucosal inflammatory status of UC patients. We further revealed that CAMK2D was a predictive marker of infliximab response. These findings are expected to provide a new evidence base for personalized treatment and management strategies for UC patients.

ABSTRACT: Table eggs with color-uniformity shell are visually attractive for consumers. Lueyang black-boned chicken (LBC) lays colorful eggs, which is undesirable for sale of table eggs, but provides a segregating population for mapping functional variants affecting eggshell color. SLCO1B3 was identified as the causative gene for blue eggs in the Dongxiang and Araucana chickens. The aim of this study is to map functional variants associated with chicken eggshell color in the SLCO1B3. Eggshell color of LBC (n = 383) was measured using the L*a*b color space. SLCO1B3 was resequencing using a subset (n = 30) of 383 samples. Linkage disequilibrium among 139 SNP was analyzed. Association of 16 SNP in the SLCO1B3 and 8 in CPOX, ALAS1, and ABCG2 genes with L*a*b were tested by a polygenic model (LMM) and a polygenic/oligogenic mixed model (BSLMM). Chromatin state annotations were retrieved from the UCSC database. Effect of SLCO1B3 variants distributed in mapping and upstream 1.6-kb regions on promoter activities were analyzed using dual-luciferase reporter assay. One hundred and thirty-nine variants maintained low linkage disequilibrium with 80% of r2 less than 0.226. Fifteen SLCO1B3 variants were significantly associated with a*, of which 1B3_SNP108 was showed the strongest association and the largest effect on a*. In the BSLMM, 1B3_SNP108 alone appeared in the Markov chain Monte Carlo as major variants in 100% of posterior inclusion probability. None of variants in CPOX, ALAS1, and ABCG2 were significantly associated with color indexes except that 2 ALAS1 variants were associated with L*. 1B3_SNP108 distributes in the Intron4 where 6 active enhancers and 1 ATAC island were enriched. However, 1B3_SNP108-containing constructs showed negligible activities in the reporter assay. No significant differences of activities between haplotypes were found for five 5′-deleted promoter constructs. The data recognizes 1B3_SNP108 as a valuable marker for breeding of eggshell color. Functional variants are localized in the region adjacent to the 1B3_SNP108 due to low linkage disequilibrium in the LBC. Our findings extend the role of SLCO1B3 from a causative gene for blue eggs to a major regulator driving continuous variation of LBC eggshell color.

Abstract Background The human gut microbiome (HGM), consisting of trillions of microorganisms, is crucial to human health. Adverse drug use is one of the most important causes of HGM disorder. Thus, it is necessary to identify drugs or compounds with anti-commensal effects on HGM in the early drug discovery stage. This study proposes a novel anti-commensal effects classification using a machine learning method and optimal molecular features. To improve the prediction performance, we explored combinations of six fingerprints and three descriptors to filter the best characterization as molecular features. Results The final consensus model based on optimal features yielded the F1-score of 0.725 ± 0.014, ACC of 82.9 ± 0.7%, and AUC of 0.791 ± 0.009 for five-fold cross-validation. In addition, this novel model outperformed the prior studies by using the same algorithm. Furthermore, the important chemical descriptors and misclassified anti-commensal compounds are analyzed to better understand and interpret the model. Finally, seven structural alerts responsible for the chemical anti-commensal effect are identified, implying valuable information for drug design. Conclusion Our study would be a promising tool for screening anti-commensal compounds in the early stage of drug discovery and assessing the potential risks of these drugs in vivo.

Chronic inflammation is critical in the onset and progression of atherosclerosis (AS). The lipopolysaccharide (LPS) level in the circulation system is elevated in AS patients and animal models, which is correlated with the severity of AS. Inspired by the underlying mechanism that LPS could drive the polarization of macrophages toward the M1 phenotype, aggravate inflammation, and ultimately contribute to the exacerbation of AS, LPS in the circulation system was supposed to be the therapeutic target for AS treatment. In the present study, polymyxin (PMB) covalently conjugated to PEGylated liposomes (PLPs) were formulated to adsorb LPS through specific interactions between PMB and LPS. In vitro, the experiments demonstrated that PLPs could adsorb LPS, reduce the polarization of macrophages to M1 phenotype and inhibit the formation of foam cells. In vivo, the study revealed that PLPs treatment reduced the serum levels of LPS and pro-inflammatory cytokines, decreased the proportion of M1-type macrophages in AS plaque, stabilized AS plaque, and downsized the plaque burdens in arteries, which eventually attenuated the progression of AS. Our study highlighted LPS in the circulation system as the therapeutic target for AS and provided an alternative strategy for AS treatment.

Abstract Many different types of stem cells utilize asymmetric cell division (ACD) to produce two daughter cells with distinct fates. Haspin-catalyzed phosphorylation of histone H3 at Thr3 (H3T3ph) plays important roles during mitosis, including ACD in stem cells. However, whether and how Haspin functions in ACD regulation remains unclear. Here, we report that Haspin knockout (Haspin-KO) mouse embryonic stem cells (mESCs) had increased ratio of ACD, which cumulatively regulates cell fate decisions. Furthermore, Wnt5a is significantly downregulated due to decreased Pax2 in Haspin-KO mESCs. Wnt5a knockdown mESCs phenocopied Haspin-KO cells while overexpression of Wnt5a in Haspin-KO cells rescued disproportionated ACD. Collectively, Haspin is indispensable for mESCs to maintain a balanced ratio of ACD, which is essential for normal development and homeostasis.

Abstract Background Umbelliprenin is a sesquiterpene coumarin isolated from Artemisia absinthium L. and shows antitumor effects in various cancers by inducing apoptosis. However, the antitumor effect of umbelliprenin in human pancreatic cancer has not been clarified. Methods The antitumor effects were determined by MTT and AnnexinV/PI double staining assay in vitro and xenograft mice in vivo. Autophagy was determined via immunofluorescence analysis. Apoptotic or autophagic related proteins were measured by immunoblotting. The pancreatic cancer cell stemness were determined by mammosphere formation and ALDEFLUOR assay. Results It revealed that umbelliprenin inhibited pancreatic cancer cell proliferation in vitro and pancreatic cancer tumor growth in vivo. Moreover, umbelliprenin induced pancreatic cancer cell BxPC3 apoptosis and autophagy as evidenced by upregulated apoptosis and autophagy‐ related protein expression (p

Abstract Background V domain Immunoglobulin suppressor of T cell activation (VISTA) has been proved to be a novel immune checkpoint molecule that positively regulates T cell infiltration in several malignancies. However, the clinical impact of VISTA on muscle-invasive bladder cancer (MIBC) patients remains relatively obscure. Methods This study enrolled 135 MIBC patients from Zhongshan Hospital (ZSHS) and 391 patients from The Cancer Genome Atlas (TCGA) to examine the VISTA expression and immune contexture based on immunohistochemistry (IHC) staining and CIBERSORT algorithm. Additionally, IMvigor210 Cohort included 195 bladder-derived urothelial carcinoma patients to evaluate the efficacy of immunotherapy. Kaplan-Meier curve and Cox regression analyses were conducted to assess clinical outcomes. Results MIBC patients with high VISTA+ immune cells (ICs) possessed poor overall survival and inferior therapeutic responsiveness to adjuvant chemotherapy (ACT), but superior responsiveness to PD-L1 inhibitor. VISTA+ ICs infiltration shaped an immunoevasive context featured by regulatory T cells (Tregs), M2 macrophages, mast cells and exhausted CD8+ T cells infiltration, with increased interleukin 10 (IL-10), transforming growth factor-β (TGF-β) and interferon-γ (IFN-γ), but also elevated T-cell immunoglobulin mucin-3 (TIM-3), lymphocyte activation gene 3 (LAG-3) and T-cell immunoglobulin and ITIM domain (TIGIT), which was also mainly presented in basal-squamous and luminal-infiltrated subtypes of MIBC. Conclusion VISTA+ ICs infiltration could be an independent predictor to identify poor prognosis and therapeutic responses (PD-L1 blockade and ACT) in MIBC patients, which was associated with immunoevasive contexture. The novel immune checkpoint VISTA might be utilized as a candidate treatment biomarker in MIBC patients.

Polyimide (PI) is widely used in aerospace applications due to its excellent properties. However, the high concentration of atomic oxygen (AO) in low-earth orbit (LEO) significantly degrades its performance. This study employs reactive molecular dynamics (MD) simulations to analyze the AO erosion resistance of fluorinated polyimide (FPI) and polyhedral oligomeric silsesquioxane (POSS) composite polyimide models. The 35 ps simulation results indicate that the PI/POSS composite exhibits the best protective performance. The protection mechanism involves the formation of an SiO2 carbonized layer that prevents the transmission of AO and heat to the polyimide matrix, resulting in a normalized mass of 84.1% after erosion. The FPI model shows the second-best protective effect, where the introduction of -CF3 groups enhances the thermal stability of the polyimide matrix, resulting in a normalized mass of 80.7% after erosion. This study explores the protective effects and mechanisms of different polyimide protection methods at the molecular level, providing new insights for the design of AO erosion protection systems.

Abstract A real‐aperture high‐resolution imaging method utilising a multiple‐input multiple‐output (MIMO) sonar with two‐dimensional (2‐D) deconvolution processing is proposed. Via derivation, the authors show that the conventional beamformer (CBF) output of the MIMO sonar can be approximately expressed as the 2‐D convolution between the original angular and range distributions of scatterers and a 2‐D point spread function (PSF). Hence, to improve the imaging performance degraded by the convolution effect, the 2‐D Richardson‐Lucy (R‐L) algorithm is used to deconvolve the CBF output of the MIMO sonar. Specifically, the authors give the iteration formula of the 2‐D R‐L algorithm attached to the MIMO sonar, and take the absolute values of the CBF outputs of the virtual array as the deconvolution inputs. The analytical expression of the 2‐D PSF is also given, which is designed as the angular‐ and range‐domain (amplitude) responses of a far‐field ideal scatterer located in the normal direction of the virtual array. Meanwhile, the authors point out that the mismatch made by the approximation may degrade the imaging performance, and suggest that a small number of iterations in the 2‐D R‐L algorithm can be used to alleviate the mismatch problem. Via numerical simulations and a tank experiment, the authors show that the proposed method can simultaneously increase the angular and range resolutions and suppress the sidelobes, when compared to the existing MIMO sonar imaging method.

Abstract Background Respiratory diseases are the 2nd leading cause of death globally. The current treatments for chronic lung diseases are only supportive. Very few new classes of therapeutics have been introduced for lung diseases in the last 40 years, due to the lack of reliable lung models that enable rapid, cost-effective, and high-throughput testing. To accelerate the development of new therapeutics for lung diseases, we established two classes of lung-mimicking models: (i) healthy, and (ii) diseased lungs – COPD. Methods To establish models that mimic the lung complexity to different extents, we used five design components: (i) cell type, (ii) membrane structure/constitution, (iii) environmental conditions, (iv) cellular arrangement, (v) substrate, matrix structure and composition. To determine whether the lung models are reproducible and reliable, we developed a quality control (QC) strategy, which integrated the real-time and end-point quantitative and qualitative measurements of cellular barrier function, permeability, tight junctions, tissue structure, tissue composition, and cytokine secretion. Results The healthy model is characterised by (i) continuous tight junctions, (ii) physiological cellular barrier function, (iii) a full thickness epithelium composed of multiple cell layers, and (iv) the presence of ciliated cells and goblet cells. Meanwhile, the disease model emulates human COPD disease: (i) dysfunctional cellular barrier function, (ii) depletion of ciliated cells, and (ii) overproduction of goblet cells. The models developed here have multiple competitive advantages when compared with existing in vitro lung models: (i) the macroscale enables multimodal and correlative characterisation of the same model system, (ii) the use of cells derived from patients that enables the creation of individual models for each patient for personalised medicine, (iii) the use of an extracellular matrix proteins interface, which promotes physiological cell adhesion and differentiation, (iv) media microcirculation that mimics the dynamic conditions in human lungs. Conclusion Our model can be utilised to test safety, efficacy, and superiority of new therapeutics as well as to test toxicity and injury induced by inhaled pollution or pathogens. It is envisaged that these models can also be used to test the protective function of new therapeutics for high-risk patients or workers exposed to occupational hazards. Graphical Abstract

Abstract We present a study of top quark mass measurements at the $$t\bar{t}$$ t t ¯ threshold based on CEPC. A centre-of-mass energy scan near two times of the top quark mass is performed and the measurement precision of top quark mass, width and $$\alpha _S$$ α S are evaluated using the $$t\bar{t}$$ t t ¯ production rates. Realistic scan strategies at the threshold are discussed to maximise the sensitivity to the measurements individually and simultaneously in the CEPC scenarios assuming a total luminosity limited to 100 fb $$^{-1}$$ - 1 . With the optimal scan for individual property measurements, the top quark mass precision is expected to be 9 MeV, the top quark width precision is expected to be 26 MeV, and $$\alpha _S$$ α S can be measured at a precision of 0.00039, considering only the statistical uncertainty. Taking into account the systematic uncertainties from theory, width, $$\alpha _S$$ α S , experimental efficiency, background subtraction, beam energy and luminosity spectrum, the top quark mass can be measured at a precision of 25 MeV optimistically and 59 MeV conservatively at CEPC.

Objective: To explore the efficacy, safety, and feasibility of holmium laser flexible ureteroscopic intrapelvic drainage in the treatment of parapelvic renal cysts. Methods: From September 2012 to February 2019, a total of 18 patients, aged from 28 to 62 (mean±standard deviation [SD]: 46.50±9.14) years, were diagnosed with parapelvic renal cysts and treated by holmium laser flexible ureteroscopic intrapelvic drainage. There were 10 males and eight females. All of the parapelvic renal cysts were unilateral, and two cases were complicated with pyelolithiasis. The diameters of the cysts ranged from 4.1 cm to 8.2 cm. Results: All the patients completed the operation successfully in one stage without conversion to open surgery; in two cases, it was difficult to find the cysts during the operation, and the localization was completed by B-ultrasound and percutaneous injection of methylene blue. The mean operative time was 33.89 (SD: 9.68; range: 22–54) min, and the mean hospitalization time was 2.67 (SD: 0.91; range: 2–5) days. Three months and 6 months of follow-up were performed after surgery. The cysts disappeared in 13 (72%) cases, and the diameter of the cysts in five (28%) cases decreased by more than 50%. Conclusion: Holmium laser flexible ureteroscopic intrapelvic drainage in the treatment of parapelvic renal cysts is simple, safe, and effective, and can be used as the first choice for the treatment of parapelvic renal cysts.

Objective KDM6A, a representative tumour suppressor gene with sex bias, is frequently altered in urothelial carcinoma (UC). The specific impacts of KDM6A mutations on gender-based clinical outcomes in UC remain poorly understood.Methods and analysis We enrolled 2438 patients with UC from seven independent real-world cohorts possessing comprehensive clinical and genomic data. Point mutations and homozygous deletions of KDM6A are categorised as KDM6AMut. We assessed the correlation between gender disparities in relation to KDM6A status and clinical outcomes, as well as genomic and immunological profiles.Results KDM6A mutations were identified in 679 of the 2306 patients with UC (29.4%), with 505 of 1768 (28.6%) in men and 174 of 538 (32.3%) in women. KDM6A mutations correlated with enhanced overall survival exclusively in male patients but were linked to improved outcomes following adjuvant chemotherapy only in female patients. Concerning immunotherapeutic responses, KDM6AMut male patients displayed the most favourable clinical outcomes, whereas KDM6AMut female patients demonstrated the least favourable outcomes. Independent of gender variations, KDM6AMut patients exhibited heightened androgen receptor and diminished oestrogen receptor 1 filtered regulon activity. Additionally, KDM6AMut male patients showed increased infiltration of T cells, cytotoxic T cells and NK cells with enriched neoantigens, in contrast to KDM6AMut female patients who manifested a more pronounced angiogenesis signature.Conclusion Our findings offer preliminary clinical evidence accentuating KDM6A alterations as a promising prognostic and predictive biomarker while elucidating the gender disparities observed in patients with UC.

ABSTRACT Objective: To explore the diagnostic value of the TUIAS (SW_TH01/II) computer-aided diagnosis (CAD) software system for the ultrasound Thyroid Imaging Reporting and Data System (TI-RADS) features in thyroid nodules. Materials and methods: This retrospective study enrolled patients with thyroid nodules in Shanghai East Hospital between January 2017 and October 2021. The novel CAD software (SW_TH01/II) and three sonographers performed a qualitative analysis of the ultrasound TI-RADS features in aspect ratio, margin irregularity, margin smoothness, calcification, and echogenicity of the thyroid nodules. Results: A total of 225 patients were enrolled. The accuracy, sensitivity, and specificity of the CAD software in “aspect ratio” were 95.6%, 96.2%, and 95.4%, in “margin irregularity” were 90.7%, 90.5%, and 90.9%, in “margin smoothness” were 85.8%, 88.5%, and 83.0%, in “calcification” were 83.6%, 81.7%, and 82.0%, in “homogeneity” were 88.9%, 90.6%, and 82.2%, in “major echo” were 85.3%, 88.0%, and 85.4%, and in “contains very hypoechoic echo” were 92.0%, 90.0%, and 92.4%. The analysis time of the CAD software was significantly shorter than for the sonographers (2.7 ± 1.6 vs. 29.7 ± 12.7 s, P < 0.001). Conclusion: The CAD system achieved high accuracy in describing thyroid nodule features. It might assist in clinical thyroid nodule analysis.

Summary: Immune checkpoint blockade therapies are still ineffective for most patients with colorectal cancer (CRC). Immunogenic cell death (ICD) enables the release of key immunostimulatory signals to drive efficient anti-tumor immunity, which could be used to potentiate the effects of immune checkpoint inhibitors. Here, we showed that inhibition of valosin-containing protein (VCP) elicits ICD in CRC. Meanwhile, VCP inhibitor upregulates PD-L1 expression and compromises anti-tumor immunity in vivo. Mechanistically, VCP transcriptionally regulates PD-L1 expression in a JAK1-dependent manner. Combining VCP inhibitor with anti-PD1 remodels tumor immune microenvironment and reduces tumor growth in mouse models of CRC. Addition of oncolytic virus further augments the therapeutic activity of the combination regimen. Our study shows the molecular mechanism for regulating PD-L1 expression by VCP and suggests that inhibition of VCP has the potential to increase the efficacy of immunotherapy in CRC.

BackgroundPancreatic cancer is renowned for its elevated incidence and mortality rates on a global scale. The disease burden of pancreatic cancer is anticipated to increase, particularly in Asia, due to its vast and rapidly aging population.MethodsData from the Global Burden of Disease 2019 were analyzed for pancreatic cancer burden across 52 countries in Asia, including the incidence, mortality, and disability-adjusted life years (DALY) for pancreatic cancer, with a focus on risk factors such as high body mass index (BMI), elevated fasting plasma glucose, and smoking. We applied the Estimated Annual Percentage Change, the Age–Period–Cohort model, and decomposition analysis to evaluate incidence trends and effects.ResultsFrom 1990 to 2019, both incidence and mortality rates of pancreatic cancer in Asia significantly increased, with an average annual standardized incidence rate change of 1.73%. Males consistently exhibited higher rates than females, with smoking as a key risk factor. Central Asia reported the highest rates, and South Asia the lowest. The incidence rose with age, peaking in those aged 70~74. The disease burden increased in all age groups, particularly in populations aged 55 and above, representing 84.41% of total cases in 2019, up from 79.01% in 1990. Pancreatic cancer ranked the fifth in incidence among six major gastrointestinal tumors but presented a significant growth rate of mortality and DALY.ConclusionWith the growing, aging population in Asia, the pancreatic cancer burden is projected to escalate, bringing a significant public health challenge. Hence, comprehensive public health strategies emphasizing early detection, risk modification, and optimized treatment of pancreatic cancer are imperative.

Abstract Functional diet and food safety requirements, as well as reducing the consumption of nonrenewable resources and environmental pollution are the important development themes on food processing. The development and application of edible nanocelluloses (NCs) is an urgent need in the current food field. NCs are divided into three types, including cellulose nanofibrils, and cellulose nanocrystals from natural fibers, as well as bacterial cellulose synthesized by bacteria. In this review, recent developments in surface modification, biological properties, safety issues, and their applications in the food industry were highlighted. NCs have application limits due to native hydrophilicity, surface modification strengthens their hydrophobicity and stability in the oil phase. NCs exhibit excellent physicochemical properties and successfully be used as edible coatings, emulsion stabilizers, and functional food ingredients. In particular, NCs and modified NCs can be used as low‐calorie fat substitutes and prebiotics for improving gut microbiota. However, the biological properties and safety assessments still require more attention, as well as establishing the regulations for food applications.

Abstract Background To evaluate the safety and efficacy of gonioscopy-assisted transluminal trabeculotomy (GATT) in treating patients with open-angle glaucoma (OAG) who had failed prior incisional glaucoma surgery. Methods A consecutive case series of OAG patients aged ≥ 18 who underwent GATT with previous failed glaucoma incision surgery was retrospectively analyzed. Main outcome measures included intraocular pressure (IOP), the number of glaucoma medications, surgical success rate, and occurrence of complications. Success was defined as an IOP of ≤ 21 mmHg and a reduction of IOP by 20% or more from baseline with (qualified success) or without (complete success) glaucoma medications. For eyes with preoperative IOP of

In this paper, a method for rapid detection of cordycepin in food was established based on surface-enhanced Raman spectroscopic analysis method. The surface-enhanced Raman substrates were screened and the Raman detection conditions and sample pretreatment methods were optimized. The optimal substrate was gold nanocolloid, and the optimal detection conditions were as follows: the addition amount of gold nanocolloid was 200 μL of gold nanocolloid and the sample addition amount was 5 μL. Under the optimal conditions, the detection limit of cordycepin was 1 mg/L, and the sample pretreatment was performed by methanol extraction. Based on the established surface-enhanced Raman spectroscopy (SERS) method, cordycepin in two Cordyceps militaris was detected, which confirmed the practical application of this method.

As one of the essential nutrients for plants, nitrogen (N) has a major impact on the yield and quality of wheat worldwide. Due to chemical fertilizer pollution, it has become increasingly important to improve crop yield by increasing N use efficiency (NUE). Therefore, understanding the response mechanisms to low N (LN) stress is essential for the regulation of NUE in wheat. In this study, LN stress significantly accelerated wheat root growth, but inhibited shoot growth. Further transcriptome analysis showed that 8468 differentially expressed genes (DEGs) responded to LN stress. The roots and shoots displayed opposite response patterns, of which the majority of DEGs in roots were up-regulated (66.15%; 2955/4467), but the majority of DEGs in shoots were down-regulated (71.62%; 3274/4565). GO and KEGG analyses showed that nitrate reductase activity, nitrate assimilation, and N metabolism were significantly enriched in both the roots and shoots. Transcription factor (TF) and protein kinase analysis showed that genes such as MYB-related (38/38 genes) may function in a tissue-specific manner to respond to LN stress. Moreover, 20 out of 107 N signaling homologous genes were differentially expressed in wheat. A total of 47 transcriptome datasets were used for weighted gene co-expression network analysis (17,840 genes), and five TFs were identified as the potential hub regulatory genes involved in the response to LN stress in wheat. Our findings provide insight into the functional mechanisms in response to LN stress and five candidate regulatory genes in wheat. These results will provide a basis for further research on promoting NUE in wheat.

The effect of gravity on the self-similarity of jet shape at late stage of Worthington jet development is investigated by experiment in the study. In addition, the PIV method is introduced to analyze the development of flow field. There is a linear scaling regarding the axial velocity of the jet and the scaling coefficient increases with the Froude number.

Although the role of METTL3 has been extensively studied in many cancers, its role in isoform switching in prostate cancer (PCa) has been poorly explored. To investigate its role, we applied standard RNA-sequencing and long-read direct RNA-sequencing from Oxford Nanopore to examine how METTL3 affects alternative splicing (AS) in two PCa cell lines. By dissecting genome-wide METTL3-regulated AS events, we noted that two PCa cell lines (representing two different PCa subtypes, androgen-sensitive or resistant) behave differently in exon skipping and intron retention events following METTL3 depletion, suggesting AS heterogeneity in PCa. Moreover, we revealed that METTL3-regulated AS is dependent on N6-methyladenosine (m6A) and distinct splicing factors. Analysis of the AS landscape also revealed cell type specific AS signatures for some genes (e.g., MKNK2) involved in key functions in PCa tumorigenesis. Finally, we also validated the clinical relevance of MKNK2 AS events in PCa patients and pointed to the possible regulatory mechanism related to m6A in the exon14a/b region and SRSF1. Overall, we characterize the role of METTL3 in regulating PCa-associated AS programs, expand the role of METTL3 in tumorigenesis, and suggest that MKNK2 AS events may serve as a new potential prognostic biomarker.

The repair of growth plate injuries is a highly complex process that involves precise spatiotemporal regulation of multiple cell types. While significant progress has been made in understanding the pathological mechanisms underlying growth plate injuries, effectively regulating this process to regenerate the injured growth plate cartilage remains a challenge. Tissue engineering technology has emerged as a promising therapeutic approach for achieving tissue regeneration through the use of functional biological materials, seed cells and biological factors, and it is now widely applied to the regeneration of bone and cartilage. However, due to the unique structure and function of growth plate cartilage, distinct strategies are required for effective regeneration. Thus, this review provides an overview of current research on the application of tissue engineering to promote growth plate regeneration. It aims to elucidates the underlying mechanisms by which tissue engineering promotes growth plate regeneration and to provide novel insights and therapeutic strategies for future research on the regeneration of growth plate.

This study was conducted to evaluate the effects of different additives on the fermentation quality and bacterial community of silage prepared from fresh-cut whole-plant quinoa (WPQ). Fresh-cut WPQ without wilting process was directly ensiled with one of the following additives: (i) untreated (control); (ii) fibrolytic enzyme (E); (iii) molasses (M); (iv) LAB inoculant (L); (v) a combination of fibrolytic enzyme and LAB inoculant (EL); and (vi) a combination of molasses and LAB inoculant (ML). The fermentation quality and bacterial community after 60 days of ensiling were analysed. The results showed that control silage was dominated by enterobacteria (>50%), with high pH value (5.25), acetic acid (77.9 g/kg DM) and NH3–N production (261 g/kg TN). Adding E, EL and ML shifted the fermentation pattern towards increased intensity of lactic acid production, as indicated by increased lactic acid content (>62.4 g/kg DM), lactic/acetic acid ratio (>1.12) and relative abundance of Lactobacillus (>62.0%), and decreased pH value (

During the postoperative management of urinary diseases, oral or intravenous administration of drugs and implanting ureteral stents are usually required, making localized drug delivery by ureteral stent a precise and effective medication strategy. In the traditional drug loading method, the drug was premixed in the implants in production lines and the versatility of drugs was restricted. However, the complex situation in the urinary system fails the possibility of finding a “one fits all” medication plan, and the intraoperative drug-loading of implants is highly desired to support customized therapy. Here, we designed an ultrathin (8 μm), elastic, and self-adhesive nanofiber bio-tape (NFBT) that can easily encapsulate drugs on the stent surface for controllable localized drug delivery. The NFBT exhibited high binding strength to a ureteral stent, a sustained release over 7 d in PBS for hydrophilic drug, and a zero-order release curve over 28 days for the hydrophobic drug nitrofurantoin (NFT). Further in vivo experiments using a porcine ureteral tract infection model demonstrated that NFBT loaded with NFT could significantly reduce the bacterial concentration in urine. The total amount of NFT delivered by the NFBT was about 2.68 wt% of the recommended dose for the systemic administration.

Abstract Background Thyroid carcinoma (THCA) is the most prevalent type of tumor in endocrine system. NKD2 has been increasingly evidenced to play crucial roles in many cancers, except for THCA. We herein aimed to explore the potential role of NKD2 in THCA. Methods Totally 502 THCA patient data were downloaded from TCGA (The Cancer Genome Atlas) database. Overall survival was estimated by Kaplan–Meier method. Gene set enrichment analysis was conducted to obtain significant functional pathways. Wilcoxon rank sum test was used to determine the NKD2 expression differences among various groups. The NKD2 expression was validated in cell lines and tissue microarray. Results Significantly higher NKD2 expression was observed in THCA samples compared with adjacent samples, which were successfully verified in cell lines and tissue microarray. Moreover, NKD2 expression gradually elevated along with the increase of TNM Stage, and NKD2 expression was significantly higher in elder THCA patients compared with young patients. NKD2 highly expressed THCA patients had worse prognosis compared with NKD2 low-expressed patients. Furthermore, 53 pathways were significantly activated in the high NKD2 expression patients compared with low NKD2 expression THCA patients. Conclusions In summary, high NKD2 expression was probably related to the progression and poor prognosis of THCA. NKD2 is a promising prognostic biomarker and pathogenic target of THCA.

Abstract Pelvic injuries refer to the disruption of the inherent structural and mechanical integrity of the pelvic ring. Sacroiliac screw fixation technique is often applied for the treatment of posterior pelvic ring injury, which is prone to the iatrogenic injury. This study will compare the intraoperative and postoperative variables of patients underwent sacroiliac screw fixation with intraoperative CT and conventional imaging to evaluate the effect. Thirty-two patients with posterior pelvic ring injury treated by sacroiliac screw fixation from January 2019 to December 2020 were enrolled in this retrospective study. All patients were divided into two groups according to the different assistance of intraoperative imaging. Subsequently, the correlative data were compared and analysed statistically. Twelves cases were assigned to intraoperative CT group, and the remaining twenty cases were assigned to conventional group. There was no significant difference in duration of surgery, fracture healing time, time to ambulation, complications, and Matta radiological score. There was statistically significant difference (p

In order to study the change of gas leakage behavior caused by hydrogen mixing and rapidly realize the leakage detection of hydrogen-mixed gas, a plane leakage model for specific semi-closed places was established with the Fluent software, and thereby, the diffusion of hydrogen-mixed natural gas at different wind speeds and the dynamic development law at different volume fraction of mixed hydrogen were explored. The research results show that: the increase of wind speed will prevent the hydrogen-mixed natural gas from upward diffusion and accelerate the gas accumulation in the horizontal direction, while the increasing volume fraction of mixed hydrogen will reduce the gas diffusion height and slow down the growth of diffusion height. According to the relevant standards and the simulation results of height at which natural gas with different volume fractions of mixed hydrogen diffuses to its lower limit of explosion, the layout plan of flammable gas detectors of hydrogen-mixed natural gas pipeline in the semi-closed space scenario was proposed to ensure that emergent response could be provided immediately after leakage, thus assuring the safe operation of pipelines.

Abstract A three‐phase to single‐phase direct AC power generation system based on the open‐winding permanent magnet synchronous generator (PMSG) with the dual‐inverter is proposed in this study for the standalone power system. The negative DC terminals of the dual‐inverter are commonly connected, and the positive DC terminals are reconstructed as the output port of the single‐phase AC power; the three‐phase AC power generated by PMSG could be converted to be the high power quality single‐phase AC power directly without any LC filters. Different from the traditional OW‐PMSG system, zero‐sequence current is employed to achieve adjustable frequency and voltage of the single‐phase AC power, and the corresponding dual voltage‐loop control strategy with the separate positive‐sequence and zero‐sequence currents regulation of PMSG is given to achieve high output performance. The effectiveness of the proposed control strategy and the output characteristics have been verified by simulation and the experiment of the prototype, and the results show that the high‐quality single‐phase AC power can be obtained at a wide speed range and at different load operating conditions.

Abstract Resolving inflammation and promoting intestinal tissue regeneration are critical for inflammatory bowel disease (IBD) treatment. Bioactive glass (BG) is a clinically approved bone graft material and has been shown to modulate inflammatory response, but it is unknown whether BG can be applied to treat IBD. Here, it is reported that BG attenuates pro‐inflammatory response of lipopolysaccharide (LPS)‐stimulated macrophages and hence reduces inflammatory damage to intestinal organoids in vitro. In addition, zein/sodium alginate‐based core–shell microspheres (Zein/SA/BG) are developed for oral delivery of BG, which helps prevent premature dissolution of BG in the stomach. The results show that Zein/SA/BG protects BG from a gastric‐simulated environment while dissolved in an intestinal‐simulated environment. When administered to acute and chronic colitis mice model, Zein/SA/BG significantly reduces intestinal inflammation, promotes epithelial tissue regeneration, and partially restores microbiota homeostasis. These findings are the first to reveal the therapeutic efficacy of BG against IBD, which may provide a new therapeutic approach at low cost for effective IBD treatment.

Introduction: Growth plate injury is a significant challenge in clinical practice, as it could severely affect the limb development of children, leading to limb deformity. Tissue engineering and 3D bioprinting technology have great potential in the repair and regeneration of injured growth plate, but there are still challenges associated with achieving successful repair outcomes.Methods: In this study, GelMA hydrogel containing PLGA microspheres loaded with chondrogenic factor PTH(1–34) was combined with BMSCs and Polycaprolactone (PCL) to develop the PTH(1–34)@PLGA/BMSCs/GelMA-PCL scaffold using bio-3D printing technology.Results: The scaffold exhibited a three-dimensional interconnected porous network structure, good mechanical properties, biocompatibility, and was suitable for cellchondrogenic differentiation. And a rabbit model of growth plate injury was appliedto validate the effect of scaffold on the repair of injured growth plate. The resultsshowed that the scaffold was more effective than injectable hydrogel in promotingcartilage regeneration and reducing bone bridge formation. Moreover, the addition ofPCL to the scaffold provided good mechanical support, significantly reducing limbdeformities after growth plate injury compared with directly injected hydrogel.Discussion: Accordingly, our study demonstrates the feasibility of using 3D printed scaffolds for treating growth plate injuries and could offer a new strategy for the development of growth plate tissue engineering therapy.

Introduction: The repair and regeneration of growth plate injuries using tissue engineering techniques remains a challenge due to large bone bridge formation and low chondrogenic efficiency.Methods: In this study, a bilayer drug-loaded microspheres was developed that contains the vascular endothelial growth factor (VEGF) inhibitor, Bevacizumab, on the outer layer and insulin-like growth factor-1 (IGF-1), a cartilage repair factor, on the inner layer. The microspheres were then combined with bone marrow mesenchymal stem cells (BMSCs) in the gelatin methacryloyl (GelMA) hydrogel to create a composite hydrogel with good injectability and biocompatibility.Results: The in vitro drug-release profile of bilayer microspheres showed a sequential release, with Bevacizumab released first followed by IGF-1. And this hydrogel simultaneously inhibited angiogenesis and promoted cartilage regeneration. Finally, in vivo studies indicated that the composite hydrogel reduced bone bridge formation and improved cartilage regeneration in the rabbit model of proximal tibial growth plate injury.Conclusion: This bilayer microsphere-based composite hydrogel with sequential controlled release of Bevacizumab and IGF-1 has promising potential for growth plate injury repair.