The lysine deacetylase activity of histone deacetylases 1 and 2 is required to safeguard zygotic genome activation in mice and cattle.

The genome is transcriptionally inert at fertilization and must be activated through a remarkable developmental process called zygotic genome activation (ZGA). Epigenetic reprogramming contributes significantly to the dynamic gene expression during ZGA; however, the mechanism has yet to be resolved. Here, we find histone deacetylases 1 and 2 (HDAC1/2) can regulate ZGA through lysine deacetylase activity. Notably, in mouse embryos, overexpression of a HDAC1/2 dominant-negative mutant leads to developmental arrest at the two-cell stage. RNA-seq reveals that 64% of downregulated genes are ZGA genes and 49% of upregulated genes are developmental genes. Inhibition of the deacetylase activity of HDAC1/2 causes a failure of histone deacetylation at multiple sites, including H4K5, H4K16, H3K14, H3K18 and H3K27. ChIP-seq analysis exhibits an increase and decrease of H3K27ac enrichment at promoters of up- and downregulated genes, respectively. Moreover, HDAC1 mutants prohibit the removal of H3K4me3 by impeding expression of Kdm5 genes. Importantly, the developmental block can be greatly rescued by Kdm5b injection and by partially correcting the expression of the majority of dysregulated genes. Similar functional significance of HDAC1/2 is conserved in bovine embryos. Overall, we propose that HDAC1/2 are indispensable for ZGA by creating correct transcriptional repressive and active states in mouse and bovine embryos.

Base editing in bovine embryos reveals a species-specific role of SOX2 in regulation of pluripotency.

The emergence of the first three lineages during development is orchestrated by a network of transcription factors, which are best characterized in mice. However, the role and regulation of these factors are not completely conserved in other mammals, including human and cattle. Here, we establish a gene inactivation system with a robust efficiency by introducing premature codon with cytosine base editors in bovine early embryos. By using this approach, we have determined the functional consequences of three critical lineage-specific genes (SOX2, OCT4 and CDX2) in bovine embryos. In particular, SOX2 knockout results in a failure of the establishment of pluripotency in blastocysts. Indeed, OCT4 level is significantly reduced and NANOG barely detectable. Furthermore, the formation of primitive endoderm is compromised with few SOX17 positive cells. RNA-seq analysis of single blastocysts (day 7.5) reveals dysregulation of 2074 genes, among which 90% are up-regulated in SOX2-null blastocysts. Intriguingly, more than a dozen lineage-specific genes, including OCT4 and NANOG, are down-regulated. Moreover, SOX2 level is sustained in the trophectoderm in absence of CDX2. However, OCT4 knockout does not affect the expression of SOX2. Overall, we propose that SOX2 is indispensable for OCT4 and NANOG expression and CDX2 represses the expression of SOX2 in the trophectoderm in cattle, which are all in sharp contrast with results in mice.

Close Intimacy between PtIn Clusters and Zeolite Channels for Ultrastability toward Propane Dehydrogenation.

Propane dehydrogenation (PDH) serves as a pivotal intentional technique to produce propylene. The stability of PDH catalysts is generally restricted by the readsorption of propylene which can subsequently undergo side reactions for coke formation. Herein, we demonstrate an ultrastable PDH catalyst by encapsulating PtIn clusters within silicalite-1 which serves as an efficient promoter for olefin desorption. The mean lifetime of PtIn@S-1 (S-1, silicalite-1) was calculated as 37317 h with high propylene selectivity of >97% at 580 °C with a weight hourly space velocity (WHSV) of 4.7 h-1. With an ultrahigh WHSV of 1128 h-1, which pushed the catalyst away from the equilibrium conversion to 13.3%, PtIn@S-1 substantially outperformed other reported PDH catalysts in terms of mean lifetime (32058 h), reaction rates (3.42 molpropylene gcat-1 h-1 and 341.90 molpropylene gPt-1 h-1), and total turnover number (14387.30 kgpropylene gcat-1). The developed catalyst is likely to lead the way to scalable PDH applications.

Lysosome Targeting Chimaeras for Glut1-Facilitated Targeted Protein Degradation.

Targeted protein degradation technology holds great potential in biomedicine, particularly in treating tumors and other protein-related diseases. Research on intracellular protein degradation using molecular glues and PROTAC technology is leading, while research on the degradation of membrane proteins and extracellular proteins through the lysosomal pathway is still in the preclinical stage. The scarcity of useful targets is an immense limitation to technological advancement, making it essential to explore novel, potentially effective approaches for targeted lysosomal degradation. Here, we employed the glucose transporter Glut1 as an innovative lysosome-targeting receptor and devised the Glut1-Facilitated Lysosomal Degradation (GFLD) strategy. We synthesized potential Glut1 ligands via reversible addition-fragmentation chain transfer (RAFT) polymerization and acquired antibody-glycooligomer conjugates through bioorthogonal reactions as lysosome-targeting protein degradation molecules, utilized in the management of PD-L1 high-expressing triple-negative breast cancer. The glucose transporter Glut1 as a lysosome-targeting receptor exhibits potential for the advancement of a broader array of medications in the future.

Predictive models of recurrent implantation failure in patients receiving ART treatment based on clinical features and routine laboratory data.

STUDY QUESTION: The objective was to construct a model for predicting the probability of recurrent implantation failure (RIF) after assisted reproductive technology (ART) treatment based on the clinical characteristics and routine laboratory test data of infertile patients. A model was developed to predict RIF. The model showed high calibration in external validation, helped to identify risk factors for RIF, and improved the efficacy of ART therapy. WHAT IS KNOWN ALREADY: Research on the influencing factors of RIF has focused mainly on embryonic factors, endometrial receptivity, and immune factors. However, there are many kinds of examinations regarding these aspects, and comprehensive screening is difficult because of the limited time and economic conditions. Therefore, we should try our best to analyse the results of routine infertility screenings to make general predictions regarding the occurrence of RIF. STUDY DESIGN, SIZE, DURATION: A retrospective study was conducted with 5212 patients at the Reproductive Center of the First Affiliated Hospital of USTC from January 2018 to June 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included 462 patients in the RIF group and 4750 patients in the control group. The patients' basic characteristics, clinical treatment data, and laboratory test indices were compared. Logistic regression was used to analyse RIF-related risk factors, and the prediction model was evaluated by receiver operating characteristic (ROC) curves and the corresponding areas under the curve (AUCs). Further analysis of the influencing factors of live births in the first cycle of subsequent assisted reproduction treatment in RIF patients was performed, including the live birth subgroup (n = 116) and the no live birth subgroup (n = 200). MAIN RESULTS AND THE ROLE OF CHANCE: (1) An increased duration of infertility (1.978; 95% CI, 1.264-3.097), uterine cavity abnormalities (2.267; 95% CI, 1.185-4.336), low AMH levels (0.504; 95% CI, 0.275-0.922), insulin resistance (3.548; 95% CI, 1.931-6.519), antinuclear antibody (ANA)-positive status (3.249; 95% CI, 1.20-8.797) and anti-ß2-glycoprotein I antibody (A-ß2-GPI Ab)-positive status (5.515; 95% CI, 1.481-20.536) were associated with an increased risk of RIF. The area under the curve of the logistic regression model was 0.900 (95% CI, 0.870-0.929) for the training cohort and 0.895 (95% CI, 0.865-0.925) for the testing cohort. (2) Advanced age (1.069; 95% CI, 1.015-1.126) was a risk factor associated with no live births after the first cycle of subsequent assisted reproduction treatment in patients with RIF. Blastocyst transfer (0.365; 95% CI = 0.181-0.736) increased the probability of live birth in subsequent cycles in patients with RIF. The area under the curve of the logistic regression model was 0.673 (95% CI, 0.597-0.748). LIMITATIONS, REASONS FOR CAUTION: This was a single-centre regression study, for which the results need to be evaluated and verified by prospective large-scale randomized controlled studies. The small sample size for the analysis of factors influencing pregnancy outcomes in subsequent assisted reproduction cycles for RIF patients resulted in the inclusion of fewer covariates, and future studies with larger samples and the inclusion of more factors are needed for assessment and validation. WIDER IMPLICATIONS OF THE FINDINGS: Prediction of embryo implantation prior to transfer will facilitate the clinical management of patients and disease prediction and further improve ART treatment outcomes. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the General Project of the National Natural Science Foundation of China (Nos. 82,201,792, 82,301,871, 81,971,446, and 82,374,212) and the Natural Science Foundation of Anhui Province (No. 2208085MH206). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: This study was registered with the Chinese Clinical Trial Register (Clinical Trial Number: ChiCTR1800018298 ).

Amphiphilic Block Copolymers Containing Benzenesulfonyl Azide Groups as Visible Light-Responsive Drug Carriers for Image-Guided Delivery.

Nanoparticles (NPs) containing light-responsive polymers and imaging agents show great promise for controlled drug delivery. However, most light-responsive NPs rely on short-wavelength excitation, resulting in poor tissue penetration and potential cytotoxicity. Moreover, excessively sensitive NPs may prematurely release drugs during storage and circulation, diminishing their efficacy and causing off-target toxicity. Herein, we report visible-light-responsive NPs composed of an amphiphilic block copolymer containing responsive 4-acrylamide benzenesulfonyl azide (ABSA) and hydrophilic N,N'-dimethylacrylamide (DMA) units. The polymer pDMA-ABSA was loaded with the chemotherapy drug dasatinib and zinc tetraphenylporphyrin (ZnTPP). ZnTPP acted as an imaging reagent and a photosensitizer to reduce ABSA upon visible light irradiation, converting hydrophobic units to hydrophilic units and disrupting NPs to trigger drug release. These NPs enabled real-time fluorescence imaging in cells and exhibited synergistic chemophotodynamic therapy against multiple cancer cell lines. Our light-responsive NP platform holds great promise for controlled drug delivery and cancer theranostics, circumventing the limitations of traditional photosensitive nanosystems.

Association between the dietary antioxidant index and relative telomere length of leucocytes in the Chinese population.

Dietary antioxidant indices (DAI) may be potentially associated with relative telomere length (RTL) of leucocytes. This study aimed to investigate the relationship between DAI and RTL. A cross-sectional study involving 1656 participants was conducted. A generalised linear regression model and a restricted cubic spline model were used to assess the correlation of DAI and its components with RTL. Generalised linear regression analysis revealed that DAI (ß = 0·005, P = 0·002) and the intake of its constituents vitamin C (ß = 0·043, P = 0·027), vitamin E (ß = 0·088, P < 0·001), Se (ß = 0·075, P = 0·003), and Zn (ß = 0·075, P = 0·023) were significantly and positively correlated with RTL. Sex-stratified analysis showed that DAI (ß = 0·006, P = 0·005) and its constituents vitamin E (ß = 0·083, P = 0·012), Se (ß = 0·093, P = 0·006), and Zn (ß = 0·092, P = 0·034) were significantly and positively correlated with RTL among females. Meanwhile, among males, only vitamin E intake (ß = 0·089, P = 0·013) was significantly and positively associated with RTL. Restricted cubic spline analysis revealed linear positive associations between DAI and its constituents' (vitamin E, Se and Zn) intake and RTL in the total population. Sex-stratified analysis revealed a linear positive correlation between DAI and its constituents' (vitamin E, Se and Zn) intake and RTL in females. Our study found a significant positive correlation between DAI and RTL, with sex differences.

The clinical characteristics of subcutaneous and mediastinal emphysema in anti-melanoma differentiation-associated 5 positive dermatomyositis associated with interstitial lung disease.

OBJECTIVES: To investigate the clinical characteristics of subcutaneous emphysema (SE) and mediastinal emphysema (ME) occurring in patients with anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis associated with interstitial lung disease (anti-MDA5-positive DM-ILD). METHODS: In this retrospective study, a total of 117 anti-MDA5-positive DM-ILD patients were admitted to our hospital. All patients underwent an assessment of autoantibodies, serum ferritin levels, and lung high-resolution CT scans. RESULTS: In patients with anti-MDA5-positive DM-ILD, the incidence of SE/ME was found to be 11.1%, which was significantly higher compared to patients with anti-synthetase syndrome (p<0.01). The mortality rate among anti-MDA5-positive DM-ILD patients with SE/ME was significantly higher than those without SE/ME (p=0.0022). There was no statistically significant difference in the occurrence of SE/ME between patients with positive anti-Ro-52 antibodies and those with negative anti-Ro-52 antibodies (p=0.18). Patients with higher serum ferritin levels (1000 ng/ml ≤serum ferritin ≤1500 ng/ml) had a higher likelihood of developing SE/ME compared to patients with lower serum ferritin levels (serum ferritin <500 ng/ml) (p<0.01). Among 13 anti-MDA5-positive DM-ILD patients with SE/ME, six (46.2%) developed SE/ME within 1 month of being diagnosed and 53.8% of patients underwent positive pressure ventilation prior to the onset of SE/ME. CONCLUSIONS: We found that SE/ME is not uncommon in anti-MDA5-positive DM-ILD and is an important factor associated with poor patient prognosis. The occurrence of SE/ME is correlated with high levels of serum ferritin and is not related to anti-Ro-52 antibodies. Rheumatologists should pay close attention to SE/ME caused by positive pressure ventilation in anti-MDA5-positive DM-ILD patients.

Combined clinical significance of MRI and serum mannose-binding lectin in the prediction of spinal tuberculosis.

BACKGROUND: Spinal tuberculosis (STB) is a local manifestation of systemic infection caused by Mycobacterium tuberculosis, accounting for a significant proportion of joint tuberculosis cases. This study aimed to explore the diagnostic value of MRI combined with mannose-binding lectin (MBL) for STB. METHODS: 124 patients suspected of having STB were collected and divided into STB and non-STB groups according to their pathological diagnosis. Serum MBL levels were measured using ELISA and a Pearson analysis was constructed to determine the correlation between MBL and STB. ROC was plotted to analyze their diagnostic value for STB. All the subjects included in the study underwent an MRI. RESULTS: The sensitivity of MRI for the diagnosis of STB was 84.38% and specificity was 86.67%. The serum MBL levels of the patients in the STB group were significantly lower than the levels in the non-STB group. ROC analysis results indicated that serum MBL's area under the curve (AUC) for diagnosis of STB was 0.836, with a sensitivity of 82.3% and a specificity was 77.4%. The sensitivity of MRI combined with MBL diagnosis was 96.61%, and the specificity was 92.31%, indicating that combining the two diagnostic methods was more effective than using either one alone. CONCLUSIONS: Both MRI and MBL had certain diagnostic values for STB, but their combined use resulted in a diagnostic accuracy than either one alone.

Predicting the incidence of infectious diarrhea with symptom surveillance data using a stacking-based ensembled model.

BACKGROUND: Infectious diarrhea remains a major public health problem worldwide. This study used stacking ensemble to developed a predictive model for the incidence of infectious diarrhea, aiming to achieve better prediction performance. METHODS: Based on the surveillance data of infectious diarrhea cases, relevant symptoms and meteorological factors of Guangzhou from 2016 to 2021, we developed four base prediction models using artificial neural networks (ANN), Long Short-Term Memory networks (LSTM), support vector regression (SVR) and extreme gradient boosting regression trees (XGBoost), which were then ensembled using stacking to obtain the final prediction model. All the models were evaluated with three metrics: mean absolute percentage error (MAPE), root mean square error (RMSE), and mean absolute error (MAE). RESULTS: Base models that incorporated symptom surveillance data and weekly number of infectious diarrhea cases were able to achieve lower RMSEs, MAEs, and MAPEs than models that added meteorological data and weekly number of infectious diarrhea cases. The LSTM had the best prediction performance among the four base models, and its RMSE, MAE, and MAPE were: 84.85, 57.50 and 15.92%, respectively. The stacking ensembled model outperformed the four base models, whose RMSE, MAE, and MAPE were 75.82, 55.93, and 15.70%, respectively. CONCLUSIONS: The incorporation of symptom surveillance data could improve the predictive accuracy of infectious diarrhea prediction models, and symptom surveillance data was more effective than meteorological data in enhancing model performance. Using stacking to combine multiple prediction models were able to alleviate the difficulty in selecting the optimal model, and could obtain a model with better performance than base models.