A Janus Platinum/Tin Oxide Heterostructure for Durable Oxygen Reduction Reaction.

Designing efficient and durable electrocatalysts for oxygen reduction reaction (ORR) is essential for proton exchange membrane fuel cells (PEMFCs). Platinum-based catalysts are considered efficient ORR catalysts due to their high activity. However, the degradation of Pt species leads to poor durability of catalysts, limiting their applications in PEMFCs. Herein, a Janus heterostructure is designed for high durability ORR in acidic media. The Janus heterostructure composes of crystalline platinum and cassiterite tin oxide nanoparticles with carbon support (J-Pt@SnO2/C). Based on the synchrotron fine structure analysis and electrochemical investigation, the crystalline reconstruction and charge redistribution at the interface of Janus structure are revealed. The tightly coupled interface could optimize the valance states of Pt and the adsorption/desorption of oxygenated intermediates. As a result, the J-Pt@SnO2/C catalyst possesses distinguishing long-term stability during the accelerated durability test without obvious degradation after 40 000 cycles and keeps the majority of activity after 70 000 cycles. Meanwhile, the catalyst exhibits outstanding activity with half-wave potential at 0.905 V and a mass activity of 0.355 A mgPt -1 (2.7 times higher than Pt/C). The approach of the Janus catalyst paves an avenue for designing highly efficient and stable Pt-based ORR catalyst in the future implementation.

Feasibility and tolerability of anlotinib plus PD-1 blockades as rechallenge immunotherapy in previously treated advanced ESCC: a retrospective study.

BACKGROUND: Rechallenge with immune checkpoint inhibitor (ICI) seemed favorable in several tumors, but clinical experience on esophageal squamous cell carcinoma (ESCC) was scanty. This real-world study aimed to assess the feasibility and safety of anlotinib plus ICI for patients with previously ICI-treated advanced ESCC. MATERIALS AND METHODS: We retrospectively identified advanced ESCC patients who received anlotinib plus ICI in the rechallenge setting for evaluation of clinical outcomes and safety. Totally 110 ICI-pretreated patients, of which 89 (80.9%) received prior first- or second-line treatment, were included from September 9, 2019, to November 30, 2022. Most patients (63.6%) discontinued initial ICI due to disease progression. RESULTS: After rechallenge, median overall survival (OS) and progression-free survival (PFS) were 11.1 (95% CI, 8.6-13.7) and 5.6 (95% CI, 4.4-6.8) months, respectively; estimated OS and PFS rates at 12 months were 47.6% (95% CI, 36.8%-57.7%) and 21.4% (95% CI, 10.9%-34.2%), respectively. No complete response was reported and 21 (19.1%) patients attained partial response; the objective response rate was 19.1%. Fifty-five (50.0%) had stable disease for a disease control rate of 69.1%. Of the 21 responders, median duration of response was 6.4 months. Tendencies for longer OS were observed in patients with Eastern Cooperative Oncology Group Performance of 0 (P = .056). The incidence of grade 3 or higher treatment-related adverse events was 10.0%. CONCLUSION: Anlotinib plus ICI in the rechallenge setting was promising and resulted in encouraging benefits for patients with previously ICI-treated advanced ESCC. Our findings provided preliminary but unique evidence to help select ESCC patients benefiting from this strategy. TRIAL REGISTRATION: chictr.org.cn; number ChiCTR2300070777.

DNA damage response in breast cancer and its significant role in guiding novel precise therapies.

DNA damage response (DDR) deficiency has been one of the emerging targets in treating breast cancer in recent years. On the one hand, DDR coordinates cell cycle and signal transduction, whose dysfunction may lead to cell apoptosis, genomic instability, and tumor development. Conversely, DDR deficiency is an intrinsic feature of tumors that underlies their response to treatments that inflict DNA damage. In this review, we systematically explore various mechanisms of DDR, the rationale and research advances in DDR-targeted drugs in breast cancer, and discuss the challenges in its clinical applications. Notably, poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated favorable efficacy and safety in breast cancer with high homogenous recombination deficiency (HRD) status in a series of clinical trials. Moreover, several studies on novel DDR-related molecules are actively exploring to target tumors that become resistant to PARP inhibition. Before further clinical application of new regimens or drugs, novel and standardized biomarkers are needed to develop for accurately characterizing the benefit population and predicting efficacy. Despite the promising efficacy of DDR-related treatments, challenges of off-target toxicity and drug resistance need to be addressed. Strategies to overcome drug resistance await further exploration on DDR mechanisms, and combined targeted drugs or immunotherapy will hopefully provide more precise or combined strategies and expand potential responsive populations.

Novel insights into the mechanisms of seasonal cyclicity of testicles by proteomics and transcriptomics analyses in goose breeder lines.

Spermatogenesis is a crucial indicator of geese reproduction performance and production. The testis is the main organ responsible for sperm production, and the egg-laying cycle in geese is a complex physiological process that demands precise orchestration of hormonal cues and cellular events within the testes, however, the seasonal changes in the transcriptomic and proteomic profiles of goose testicles remain unclear. To explore various aspects of the mechanisms of the seasonal cyclicity of testicles in different goose breeds, in this study, we used an integrative transcriptomic and proteomic approach to screen the key genes and proteins in the testes of 2 goose males, the Hungarian white goose and the Wanxi white goose, at 3 different periods of the laying cycle: beginning of laying cycle (BLC), peak of laying cycle (PLC), and end of laying cycle (ELC). The results showed that a total of 9,273 differentially expressed genes and 4,543 differentially expressed proteins were identified in the geese testicles among the comparison groups. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis suggested that the DEGs, in the comparison groups, were mainly enrichment in metabolic pathways, neuroactive ligand-receptor interaction, cyctokine-cyctokine receptor interaction, calcium signaling pathway, apelin signaling pathway, ether lipid metabolism, cysteine, and methionine metabolism. While the DEPs, in the 3 comparison groups, were mainly involved in the ribosome, metabolic pathways, carbon metabolism, proteasome, endocytosis, lysosome, regulation of actin cytoskeleton, oxidative phosphorylation, nucleocytoplasmic transport, and tight junction. The protein-protein interaction network analysis (PPI) indicated that selected DEPs, such as CHD1L, RAB18, FANCM, TAF5, TSC1/2, PHLDB2, DNAJA2, NCOA5, DEPTOR, TJP1, and RAPGEF2, were highly associated with male reproductive regulation. Further, the expression trends of 4 identified DEGs were validated by qRT-PCR. In conclusion, this work offers a new perspective on comprehending the molecular mechanisms and pathways involved in the seasonal cyclicity of testicles in the Hungarian white goose and the Wanxi white goose, as well as contributing to improving goose reproductive performance.

Construction and validation of a ubiquitination-related prognostic risk score signature in breast cancer.

Background: Breast cancer (BC) is a highly common form of cancer that occurs in many parts of the world. However, early -stage BC is curable. Many patients with BC have poor prognostic outcomes owing to ineffective diagnostic and therapeutic tools. The ubiquitination system and associated proteins were found influencing the outcome of individuals with cancer. Therefore, developing a biomarker associated with ubiquitination genes to forecast BC patient outcomes is a feasible strategy. Objective: The primary goal of this work was to develop a novel risk score signature capable of accurately estimate the future outcome of patients with BC by targeting ubiquitinated genes. Methods: Univariate Cox regression analysis was conducted utilizing the E1, E2, and E3 ubiquitination-related genes in the GSE20685 dataset. Genes with p < 0.01 were screened again using the Non-negative Matrix Factorization (NMF) algorithm, and the resulting hub genes were composed of a risk score signature. Patients were categorized into two risk groups, and the predictive effect was tested using Kaplan-Meier (KM) and Receiver Operating Characteristic (ROC) curves. This risk score signature was later validated using multiple external datasets, namely TCGA-BRAC, GSE1456, GSE16446, GSE20711, GSE58812 and GSE96058. Immuno-microenvironmental, single-cell, and microbial analyses were also performed. Results: The selected gene signature comprising six ubiquitination-related genes (ATG5, FBXL20, DTX4, BIRC3, TRIM45, and WDR78) showed good prognostic power in patients with BC. It was validated using multiple externally validated datasets, with KM curves showing significant differences in survival (p < 0.05). The KM curves also demonstrated superior predictive ability compared to traditional clinical indicators. Single-cell analysis revealed that Vd2 gd T cells were less abundantin the low-risk group, whereas patients in the high-risk group lacked myeloid dendritic cells. Tumor microbiological analysis revealed a notable variation in microorganism diversity between the high- and low-risk groups. Conclusion: This study established an risk score signature consisting of six ubiquitination genes, that can accurately forecast the outcome of patients with BC using multiple datasets. It can provide personalized and targeted assistance to provide the evaluation and therapy of individuals having BC.

G-CSF promotes the development of hepatocellular carcinoma by activating the PI3K/AKT/mTOR pathway in TAM.

OBJECTIVE: This investigation seeks to elucidate the role of the Granulocyte Colony-Stimulating Factor (G-CSF) in the progression of hepatocellular carcinoma (HCC), as well as the impact of the substance on related signaling pathways within the disease matrix. METHODS: Nude mouse tumor-bearing assay was used to detect tumor progression. Levels of Mannose/CD68 and CD34/Mannose within these samples and the concentrations of Mannose and inducible Nitric Oxide Synthase (iNOS) in macrophages were quantified using immunofluorescence techniques. The angiogenic capability was assessed via tube formation assays, and protein expressions of G-CSF, Vascular Endothelial Growth Factor (VEGF), Transforming Growth Factor-beta (TGF-ß), Matrix Metalloproteinases 2 and 9 (MMP2/9), SH2-containing protein tyrosine phosphatase-2 (SHP-2), phosphorylated PI3K/total PI3K (P-PI3K/t-PI3K), phosphorylated AKT/total AKT (P-AKT/t-AKT), and phosphorylated mTOR/total mTOR (P-mTOR/t-mTOR) were measured through Western Blot analysis in both tumor tissues and macrophages. RESULTS: Administration of G-CSF resulted in a marked augmentation of tumor volume. Macrophage Mannose expression was significantly elevated upon G-CSF treatment, while iNOS levels were conspicuously diminished. G-CSF substantially enhanced the secretion of VEGF, TGF-ß, and MMPs in tumor tissues. Macrophage parameters, following incubation in G-CSF pre-treated conditioned medium, indicated enhanced tube-forming capabilities relative to the control, an effect mitigated by the introduction of specific inhibitors. Furthermore, the G-CSF group exhibited a notable reduction in SHP-2 expression, alongside a substantial elevation in the phosphorylation levels of the PI3K/AKT/mTOR pathway proteins across all tumor-bearing paradigms. CONCLUSION: G-CSF ostensibly facilitates the advancement of hepatocellular carcinoma by activating the PI3K/AKT/mTOR signaling cascade within Tumor-Associated Macrophages (TAM).

Early identification of macrophage activation syndrome secondary to systemic lupus erythematosus with machine learning.

OBJECTIVE: The macrophage activation syndrome (MAS) secondary to systemic lupus erythematosus (SLE) is a severe and life-threatening complication. Early diagnosis of MAS is particularly challenging. In this study, machine learning models and diagnostic scoring card were developed to aid in clinical decision-making using clinical characteristics. METHODS: We retrospectively collected clinical data from 188 patients with either SLE or the MAS secondary to SLE. 13 significant clinical predictor variables were filtered out using the Least Absolute Shrinkage and Selection Operator (LASSO). These variables were subsequently utilized as inputs in five machine learning models. The performance of the models was evaluated using the area under the receiver operating characteristic curve (ROC-AUC), F1 score, and F2 score. To enhance clinical usability, we developed a diagnostic scoring card based on logistic regression (LR) analysis and Chi-Square binning, establishing probability thresholds and stratification for the card. Additionally, this study collected data from four other domestic hospitals for external validation. RESULTS: Among all the machine learning models, the LR model demonstrates the highest level of performance in internal validation, achieving a ROC-AUC of 0.998, an F1 score of 0.96, and an F2 score of 0.952. The score card we constructed identifies the probability threshold at a score of 49, achieving a ROC-AUC of 0.994 and an F2 score of 0.936. The score results were categorized into five groups based on diagnostic probability: extremely low (below 5%), low (5-25%), normal (25-75%), high (75-95%), and extremely high (above 95%). During external validation, the performance evaluation revealed that the Support Vector Machine (SVM) model outperformed other models with an AUC value of 0.947, and the scorecard model has an AUC of 0.915. Additionally, we have established an online assessment system for early identification of MAS secondary to SLE. CONCLUSION: Machine learning models can significantly improve the diagnostic accuracy of MAS secondary to SLE, and the diagnostic scorecard model can facilitate personalized probabilistic predictions of disease occurrence in clinical environments.

Terminal trajectory of HbA1c for 10 years supports the HbA1c paradox: a longitudinal study using Health and Retirement Study data.

Objectives: We aimed to assess the potential time-varying associations between HbA1c and mortality, as well as the terminal trajectory of HbA1c in the elderly to reveal the underlying mechanisms. Design: The design is a longitudinal study using data from the Health and Retirement Study. Setting and participants: Data were from the Health and Retirement Study. A total of 10,408 participants aged ≥50 years with available HbA1c measurements at baseline (2006/2008) were included. Methods: Longitudinal HbA1c measured at 2010/2012 and 2014/2016 were collected. HbA1c values measured three times for their associations with all-cause mortality were assessed using Cox regression and restricted cubic splines. HbA1c terminal trajectories over 10 years before death were analyzed using linear mixed-effect models with a backward time scale. Results: Women constitute 59.6% of the participants with a mean age of 69 years, with 3,070 decedents during the follow-up (8.9 years). The mortality rate during follow-up was 29.5%. Increased mortality risk became insignificant for the highest quartile of HbA1c compared to the third quartile (aHR 1.148, 1.302, and 1.069 for a follow-up of 8.9, 6.5, and 3.2 years, respectively) with a shorter follow-up, while it became higher for the lowest quartile of HbA1c (aHR 0.986, 1.068, and 1.439 for a follow-up of 8.9, 6.5, and 3.2 years, respectively). Accordingly, for both decedents with and without diabetes, an initial increase in HbA1c was followed by an accelerating terminal decline starting 5-6 years before death. Conclusions and implications: The time-varying association between HbA1c and mortality mapped to the terminal trajectory in HbA1c. High and low HbA1c may have different clinical relationships with mortality. The HbA1c paradox may be partially explained by reverse causation, namely, early manifestation of death.

Effect of dietary supplementation with recombinant human lysozyme on growth performance, antioxidative characteristics, and intestinal health in broiler chickens.

Lysozyme is often used as a feed additive to act as an antibacterial protein that boosts the immune system of livestock and poultry while protecting against pathogens. To investigate the effects of recombinant human lysozyme (rhLYZ) from Pichia pastoris and chlortetracycline on broiler chicken's production performance, antioxidant characteristics, and intestinal microbiota, a total of 200, 1-d-old male Arbor Acres broiler chickens (46.53 ±â€…0.42 g) were selected for a 42-d experiment. Dietary treatments included a basal diet of corn-soybean meal supplemented with either 0 mg/kg (CON), 50 mg/kg aureomycin (ANT), 20 mg/kg rhLYZ (LOW), 60 mg/kg rhLYZ (MEDIUM), or 180 mg/kg rhLYZ (HIGH). Compared with CON, MEDIUM diet increased (P < 0.05) average daily gain (67.40 g) of broilers from day 22 to 42. In the early (1.29) and overall phases (1.69), MEDIUM led to a reduction (P < 0.05) in the feed conversion ratio of broiler chickens. Furthermore, in comparison to the CON and ANT, MEDIUM exhibited reduced (P < 0.05) levels of INF-γ and tumor necrosis factor-α in the serum. In the cecum, the abundance of Monoglobus and Family_XIII_AD3011_group was lower (P < 0.05) in the MEDIUM treatment compared to CON. Overall, supplementation of 60 mg/kg of rhLYZ improved growth performance, nutrient utilization efficiency, and serum immune function, while also influencing the composition of intestinal microbiota. This suggests lysozyme's potential to replace antibiotic additives in feed.

The aim of this study was to explore the effects of recombinant human lysozyme (rhLYZ) produced from Pichia pastoris and chlortetracycline on broiler chicken performance, antioxidant properties, and gut microbiota. A 42-d experiment was conducted, involving 200 1-d-old male Arbor Acres broiler chickens. We provided different diets: a standard diet (CON), a diet with 50 mg/kg aureomycin (ANT), a diet with 20 mg/kg rhLYZ (LOW), a diet with 60 mg/kg rhLYZ (MEDIUM), or a diet with 180 mg/kg rhLYZ (HIGH). The results showed that, compared to the control group, the MEDIUM group significantly increased the average daily gain of broilers to 67.40 g from day 22 to 42. Additionally, the MEDIUM group exhibited a reduced feed conversion ratio during both the early and overall growth stages of the chickens. Furthermore, serum levels of INF-γ and tumor necrosis factor-α were lower in the MEDIUM group compared to both the CON and ANT groups. In the cecum, the abundance of Monoglobus and Family_XIII_AD3011_group was also lower in the MEDIUM treatment compared to the CON group. Overall, supplementation with 60 mg/kg of rhLYZ improved growth performance, nutrient utilization efficiency, and serum immune function in broiler chickens while also influencing the composition of their intestinal microbiota. This suggests the potential of lysozyme as a replacement for antibiotic additives in feed.

Identification of relevant differential genes to the divergent development of pectoral muscle in ducks by transcriptomic analysis.

OBJECTIVE: The objective of this study was to identify candidate genes that play important roles in skeletal muscle development in ducks. METHODS: In this study, we investigated the transcriptional sequencing of embryonic pectoral muscles from two specialized lines: Liancheng white ducks (female) and Cherry valley ducks (male) hybrid Line A (LCA) and Line C (LCC) ducks. In addition, prediction of target genes for the differentially expressed mRNAs was conducted and the enriched gene ontology (GO) terms and Kyoto encyclopedia of genes and genomes signaling pathways were further analyzed. Finally, a protein-to-protein interaction network was analyzed by using the target genes to gain insights into their potential functional association. RESULTS: A total of 1,428 differentially expressed genes (DEGs) with 762 being up-regulated genes and 666 being down-regulated genes in pectoral muscle of LCA and LCC ducks identified by RNA-seq (p<0.05). Meanwhile, 23 GO terms in the down-regulated genes and 75 GO terms in up-regulated genes were significantly enriched (p<0.05). Furthermore, the top 5 most enriched pathways were ECM-receptor interaction, fatty acid degradation, pyruvate degradation, PPAR signaling pathway, and glycolysis/gluconeogenesis. Finally, the candidate genes including integrin b3 (Itgb3), pyruvate kinase M1/2 (Pkm), insulinlike growth factor 1 (Igf1), glucose-6-phosphate isomerase (Gpi), GABA type A receptorassociated protein-like 1 (Gabarapl1), and thyroid hormone receptor beta (Thrb) showed the most expression difference, and then were selected to verification by quantitative realtime polymerase chain reaction (qRT-PCR). The result of qRT-PCR was consistent with that of transcriptome sequencing. CONCLUSION: This study provided information of molecular mechanisms underlying the developmental differences in skeletal muscles between specialized duck lines.

Construction of an Electron Capture and Transfer Center for Highly Efficient and Selective Solar-Light-Driven CO2 Conversion.

Exploring high-efficiency photocatalysts for selective CO2 reduction is still challenging because of the limited charge separation and surface reactions. In this study, a noble-metal-free metallic VSe2 nanosheet was incorporated on g-C3N4 to serve as an electron capture and transfer center, activating surface active sites for highly efficient and selective CO2 photoreduction. Quasi in situ X-ray photoelectron spectroscopy (XPS), soft X-ray absorption spectroscopy (sXAS), and femtosecond transient absorption spectroscopy (fs-TAS) unveiled that VSe2 could capture electrons, which are further transferred to the surface for activating active sites. In situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) and density functional theory (DFT) calculations revealed a kinetically feasible process for the formation of a key intermediate and confirmed the favorable production of CO on the VSe2/PCN (protonated C3N4) photocatalyst. As an outcome, the optimized VSe2/PCN composite achieved 97% selectivity for solar-light-driven CO2 conversion to CO with a high rate of 16.3 µmol·g-1·h-1, without any sacrificial reagent or photosensitizer. This work offers new insights into the photocatalyst design toward highly efficient and selective CO2 conversion.

Analysis of carcass traits, meat quality, amino acid and fatty acid profiles between different duck lines.

To investigate the effect of genetic selection on meat quality in ducks, twenty of each fast growth ducks (LCA) and slow growth ducks (LCC) selected from F6 generation of Cherry Valley ducks (♂) x Liancheng white ducks (♀) were analyzed for carcass characteristics, meat quality (physicochemical and textural characteristics), amino acid and fatty acid profiles at 7 wk. Results showed that live body weight, slaughter weight, eviscerated yield and abdominal fat percentage of LCA were significantly higher than those in LCC ducks (P < 0.01). Moreover, the average area and diameter of myofiber were larger in LCA than LCC ducks (P < 0.01). The breast and thigh muscles of LCA exhibited significantly lower water holding capacity and thermal loss compared with LCC ducks (P < 0.01). In addition, the content of nonessential amino acids (Glu, Asp, and Arg) in breast muscles and Asp, Ser, Thr, and Met in thigh muscles was higher in LCC than LCA ducks (P < 0.05). The proportion of polyunsaturated fatty acids (PUFA) in breast muscles of LCC was higher than LCA ducks (P < 0.05). However, the content of saturated fatty acids (SFA) in breast and thigh muscles of LCA was higher compared with LCC ducks (P < 0.05). The proportion of monounsaturated fatty acids (MUFA) in thigh muscles was significantly higher in LCC compared with LCA ducks (P < 0.01). Finally, multiple traits were evaluated by applying principal component analysis (PCA) and the results indicated that PUFA and SFA in breast muscles of LCA played important roles in meat quality, followed by Warner-Bratzler shear force (WBSF) and MUFA. However, water holding capacity (WHC) had a dominant effect in meat quality of thigh muscles in both LCA and LCC ducks.

Neighbouring Synergy in High-Density Single Ir Atoms on CoGaOOH for Efficient Alkaline Electrocatalytic Oxygen Evolution.

The catalytic performance of single-atom catalysts was strictly limited by isolated single-atom sites. Fabricating high-density single atoms to realize the synergetic interaction in neighbouring single atoms could optimize the adsorption behaviors of reaction intermediates, which exhibited great potential to break performance limitations and deepen mechanistic understanding of electrocatalysis. However, the catalytic behavior governed by neighbouring single atoms is particularly elusive and has yet to be understood. Herein, we revealed that the synergetic interaction in neighbouring single atoms contributes to superior performance for oxygen evolution relative to isolated Ir single atoms. Neighbouring single atoms was achieved by fabricating high-density single atoms to narrow the distance between single atoms. Electrochemical measurements demonstrated that the Nei-Ir1/CoGaOOH with neighbouring Ir single atoms exhibited a low overpotential of 170 mV at a current density of 10 mA cm-2, and long-durable stability over 2000 h for oxygen evolution. Mechanistic studies revealed that neighbouring single atoms synergetic stabilized the *OOH intermediates via extra hydrogen bonding interactions, thus significantly reducing the reaction energy barriers, as compared to isolated Ir single atoms. The discovery of the synergetic interaction in neighbouring single atoms could offer guidance for the development of efficient electrocatalysts, thus accelerating the world's transition to sustainable energy.

An externally validated clinical-laboratory nomogram for myocardial involvement in adult idiopathic-inflammatory-myopathy patients.

OBJECTIVES: This study aimed at identifying clinical and laboratory risk factors for myocardial involvement (MI) in idiopathic inflammatory myopathies (IIMs) patients as well as constructing a risk-predicted nomogram for prediction and early identification of MI. METHODS: An IIMs cohort in southeastern China was constructed, including 504 adult IIMs patients who met the inclusion and exclusion criteria, and were hospitalized at four divisions of the First Affiliated Hospital, Zhejiang University School of Medicine from January 1st 2018 to April 30st 2022. After dividing patients into the training cohort and the validation cohort, risk factors for MI were identified through least absolute shrinkage and selection operator regression and multivariate logistic regression. A risk-predicted nomogram was established and validated internally and externally for discrimination, calibration and practicability. RESULTS: In this cohort, 17.7% of patients developed MI and the survival was significantly inferior to that of IIMs patients without MI (P < 0.001). In the training cohort, age > 55 years old (P < 0.001), disease activity > 10 points (P < 0.001), interleukin-17A (IL-17A) > 7.5 pg/ml (P < 0.001), lactic dehydrogenase (LDH) > 425 U/L (P < 0.001), anti-mitochondrial antibodies (AMAs, P = 0.017), and anti-MDA5 antibody (P = 0.037) were significantly correlated with development of MI. A nomogram was established by including the above values to predict MI and was found efficient in discrimination, calibration, and practicability through internal and external validation. CONCLUSION: This study developed and validated a nomogram model to predict the risk of MI in adult IIMs patients, which can benefit the prediction and early identification of MI as well as timely intervention in these patients.

Study on the Mechanism of Lipid Peroxidation Induced by Carbonate Radicals.

Based on the reported research, hydroxyl radicals can be rapidly transformed into carbonate radicals in the carbonate-bicarbonate buffering system in vivo. Many of the processes considered to be initiated by hydroxyl radicals may be caused by carbonate radicals, which indicates that lipid peroxidation initiated by hydroxyl radicals can also be caused by carbonate radicals. To date, theoretical research on reactions of hydrogen abstraction from and radical addition to polyunsaturated fatty acids (PUFAs) of carbonate radicals has not been carried out systematically. This paper employs (3Z,6Z)-nona-3,6-diene (NDE) as a model for polyunsaturated fatty acids (PUFAs). Density functional theory (DFT) with the CAM-B3LYP method at the 6-311+g(d,p) level was used to calculate the differences in reactivity of carbonate radicals abstracting hydrogen from different positions of NDE and their addition to the double bonds of NDE under lipid solvent conditions with a dielectric constant of 4.0 (CPCM model). Grimme's empirical dispersion correction was taken into account through the D3 scheme. The energy barrier, reaction rate constants, internal energy, enthalpy and Gibbs free energy changes in these reactions were calculated With zero-point vibrational energy (ZPVE) corrections. The results indicated that carbonate radicals initiate lipid peroxidation primarily through hydrogen abstraction from diallyl carbon atoms. The reaction of hydrogen abstraction from diallyl carbon atoms exhibits the highest reaction rate, with a reaction rate constant approximately 43-fold greater than the second-ranked hydrogen abstraction from allyl carbon atoms. This process has the lowest energy barrier, internal energy, enthalpy, and Gibbs free energy changes, indicating that it is also the most spontaneous process.

Ten-eleven translocation 1 mediating DNA demethylation regulates the proliferation of chicken primordial germ cells through the activation of Wnt4/ß-catenin signaling pathway.

OBJECTIVE: The objective of this study was to investigate the regulation relationship of Teneleven translocation 1 (Tet1) in DNA demethylation and the proliferation of primordial germ cells (PGCs) in chickens. METHODS: siRNA targeting Tet1 was used to transiently knockdown the expression of Tet1 in chicken PGCs, and the genomic DNA methylation status was measured. The proliferation of chicken PGCs was detected by flow cytometry analysis and cell counting kit-8 assay when activation or inhibition of Wnt4/ß-catenin signaling pathway. And the level of DNA methylation and hisotne methylation was also tested. RESULTS: Results revealed that knockdown of Tet1 inhibited the proliferation of chicken PGCs and downregulated the mRNA expression of Cyclin D1 and cyclin-dependent kinase 6 (CDK6), as well as pluripotency-associated genes (Nanog, PouV, and Sox2). Flow cytometry analysis confirmed that the population of PGCs in Tet1 knockdown group displayed a significant decrease in the proportion of S and G2 phase cells, which meant that there were less PGCs entered the mitosis process than that of control. Furthermore, Tet1 knockdown delayed the entrance to G1/S phase and this inhibition was rescued by treated with BIO. Consistent with these findings, Wnt/ß-catenin signaling was inactivated in Tet1 knockdown PGCs, leading to aberrant proliferation. Further analysis showed that the methylation of the whole genome increased significantly after Tet1 downregulation, while hydroxymethylation obviously declined. Meanwhile, the level of H3K27me3 was upregulated and H3K9me2 was downregulated in Tet1 knockdown PGCs, which was achieved by regulating Wnt/ß-catenin signaling pathway. CONCLUSION: These results suggested that the self-renewal of chicken PGCs and the maintenance of their characteristics were regulated by Tet1 mediating DNA demethylation through the activation of Wnt4/ß-catenin signaling pathway.

Release of miR-29 Target Laminin C2 Improves Skin Repair.

miRNAs are small noncoding RNAs that regulate mRNA targets in a cell-specific manner. miR-29 is expressed in murine and human skin, where it may regulate functions in skin repair. Cutaneous wound healing model in miR-29a/b1 gene knockout mice was used to identify miR-29 targets in the wound matrix, where angiogenesis and maturation of provisional granulation tissue was enhanced in response to genetic deletion of miR-29. Consistently, antisense-mediated inhibition of miR-29 promoted angiogenesis in vitro by autocrine and paracrine mechanisms. These processes are likely mediated by miR-29 target mRNAs released upon removal of miR-29 to improve cell-matrix adhesion. One of these, laminin (Lam)-c2 (also known as laminin γ2), was strongly up-regulated during skin repair in the wound matrix of knockout mice. Unexpectedly, Lamc2 was deposited in the basal membrane of endothelial cells in blood vessels forming in the granulation tissue of knockout mice. New blood vessels showed punctate interactions between Lamc2 and integrin α6 (Itga6) along the length of the proto-vessels, suggesting that greater levels of Lamc2 may contribute to the adhesion of endothelial cells, thus assisting angiogenesis within the wound. These findings may be of translational relevance, as LAMC2 was deposited at the leading edge in human wounds, where it formed a basal membrane for endothelial cells and assisted neovascularization. These results suggest a link between LAMC2, improved angiogenesis, and re-epithelialization.

Multi-copy expression of a protease-resistant xylanase with high xylan degradation ability and its application in broilers fed wheat-based diets.

The acidic thermostable xylanase (AT-xynA) has great potential in the feed industry, but its low activity is not conductive to large-scale production, and its application in poultry diets still needs to be further evaluated. In Experiment1, AT-xynA activity increased 3.10 times by constructing multi-copy strains, and the highest activity reached 10,018.29 ± 91.18 U/mL. AT-xynA showed protease resistance, high specificity for xylan substrates, xylobiose and xylotriose were the main hydrolysates. In Experiment2, 192 broilers were assigned into 3 treatments including a wheat-based diet, and the diets supplemented with AT-xynA during the entire period (XY-42) or exclusively during the early stage (XY-21). AT-xynA improved growth performance, while the performance of XY-21 and XY-42 was identical. To further clarify the mechanism underlying the particular effectiveness of AT-xynA during the early stage, 128 broilers were allotted into 2 treatments including a wheat-based diet and the diet supplemented with AT-xynA for 42 d in Experiment3. AT-xynA improved intestinal digestive function and microbiota composition, the benefits were stronger in younger broilers than older ones. Overall, the activity of AT-xynA exhibiting protease resistance and high xylan degradation ability increased by constructing multi-copy strains, and AT-xynA was particularly effective in improving broiler performance during the early stage.

SOCS3 inhibiting JAK-STAT pathway enhances oncolytic adenovirus efficacy by potentiating viral replication and T-cell activation.

Oncolytic viruses (OVs) are emerging as a potentially useful treatment for malignancies due to the capabilities of direct oncolysis and immune induction. Improving the replication of OVs is an effective approach to enhance the oncolytic effects. Here, we observed that cancer cells with deficiencies in JAK-STAT pathway showed greater sensitivity to oncolytic adenovirus (oAd), and JAK inhibitor could enhance the replication of oAd. Therefore, we constructed a novel oAd expressing SOCS3, a major negative regulator of JAK-STAT pathway, and confirmed that oAd-SOCS3 exhibited a more significant antitumor effect than oAd-Ctrl both in vitro and in vivo. Mechanistically, SOCS3 inhibited the activation of JAK-STAT pathway, resulting in stronger tumor selective replication of oAd and downregulated expression of PD-L1 on cancer cells as well. Both benefits could collectively awaken antitumor immunity. This study highlights the importance of JAK-STAT pathway in viral replication and confirms the treatment of oAd-SOCS3 in potential clinical applications.