Porcine zygotic genome activation (ZGA) occurs along with global epigenetic remodeling at the 4-cell stage. These processes are regulated by histone acetylation, which requires acetyl-coenzyme A ...(CoA). Pyruvate dehydrogenase complex (PDC) is a crucial enzyme in glucose metabolism that converts pyruvate into acetyl-CoA. In mammalian cells, acetyl-CoA is produced by pyruvate dehydrogenase alpha 1 (PDHA1) translocated into the nucleus in special conditions. To determine whether zygotic PDHA1 plays a critical role in promoting histone acetylation during ZGA, a CRISPR/Cas9 genome editing system using multiple guide RNAs was employed to generate a PDHA1-targeted parthenogenetic embryo model. Results of immunofluorescent staining showed that the nuclear accumulation of PDHA1 during ZGA was significantly inhibited by PDHA1 targeting. Meanwhile, the 4-cell arrest rate significantly increased at 72 h after activation, indicating impeded embryonic development. In addition, nuclear histone acetylation significantly decreased when PDHA1 was targeted, and quantitative PCR showed that expression of several zygotic genes was significantly decreased in the PDHA1-targeting group compared to the control group. Overexpression of PDHA1 recovered the nuclear PDHA1, H3K9Ac and H3K27Ac and EIF1A expression levels. Moreover, the 5-to-8-cell-stage embryo development rate was only partially rescued. In conclusion, expression of zygotic origin PDHA1 contributes to porcine ZGA by maintaining histone acetylation in porcine embryos.
•The existence of PDHA1 inside the nucleus of porcine embryo during zygotic genome activation was first reported.•Cas9 mediated targeting of PDHA1 significantly reduced the nuclear histone acetylation level.•Targeting of zygotic PDHA1 impeded zygotic genome transcription activities.
Though genome sequencing of Eimeria tenella predicts more than 8,000 genes, the molecular functions of many proteins remain unknown. In this study, the coding region corresponding to the mature ...peptide of a hypothetical protein of E. tenella (ETH_00023950) was amplified and expressed in a bacterial system. Following preparation of polyclonal antibody that recognizes ETH_00023950, the expression of ETH_00023950 in merozoites was examined. Meanwhile, we determined the transcriptomic responses of the leghorn male hepatoma (LMH) cells to its expression. Sequencing analysis showed that one single nucleotide polymorphism and one indel of ETH_00023950 of E. tenella SD-01 strain were found compared with that of the UK reference Houghton strain, leading to a frame shift and a premature stop codon. The expression of ETH_00023950 in E. tenella merozoites was confirmed by indirect immunofluorescence and Western blot analysis. Transcriptomic analysis showed that ETH_00023950 altered the expression of 2,680 genes (321 downregulated genes and 2,359 upregulated genes) in LMH cells. The RNA-sequencing data were consistent with the results of the quantitative real-time polymerase chain reaction (qRT-PCR). Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that differentially expressed transcripts were significantly related to 8 pathways, including oxidative phosphorylation and TGF-beta signaling pathway. These findings contribute to understanding host-pathogen interaction and secondary bacterial infections related to E. tenella.
P2-Na0.6Li0.11Fe0.27−xMn0.62YxO2 (x = 0, 0.5%, 1%, and 2%) cathode materials were successfully prepared using a traditional solid-state method with ball milling-assisted modification. The effect of ...Y-doping on the crystal structure, grain size, morphology and sodium storage performance of Na0.6Li0.11Fe0.27Mn0.62O2 was investigated using X-ray diffraction (XRD), scanning electron microscopy (SEM), galvanostatic charge–discharge cycling tests, cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The results demonstrated that the ball-milling pre-treatment method could effectively reduce the grain size and mitigate the aggregation of Na0.6Li0.11Fe0.27Mn0.62O2. Additionally, reasonable Y-doping (x = 1%) significantly enhances the rate capability and cycling stability of Na0.6Li0.11Fe0.27Mn0.62O2via improving the Na+ diffusion kinetics and the reversibility of the oxygen redox reaction. These results indicate that Na0.6Li0.11Fe0.26Mn0.62Y0.01O2 is a promising candidate material for high-rate and long-life cathodes for Na-ion battery application.
Reperfusion exceeded time window may induce ischemia/reperfusion injury, increase hemorrhagic transformation, and deteriorate neurological outcomes in ischemic stroke models. However, the increasing ...clinical evidences supported that reperfusion even within 6–24 h may salvage ischemic tissue and improve neurological outcomes in selected large vessel occlusion patients, without inducing serious ischemia/reperfusion injury and hemorrhagic transformation. The underlying molecular mechanisms are less clear. In present study, we demonstrated that delayed recanalization at 3 days after permanent middle cerebral artery occlusion (MCAO) decreased infarct volumes and improved neurobehavioral deficits in rats, with no increasing animal mortality and intracerebral hemorrhage. Meanwhile, we observed that endogenous neuroprotective agent fibroblast growth factor 21 (FGF21) significantly increased in serum after MCAO, but which did not synchronously increase in penumbra due to permanent MCAO. Recanalization dramatically increased the endogenous FGF21 expression on neurons in penumbra after MCAO. We confirmed that FGF21 activated the FGFR1/PI3K/Caspase-3 signaling pathway, which attenuated neuronal apoptosis in penumbra. Conversely, knockdown of FGFR1 via FGFR1 siRNA abolished the anti-apoptotic effects of FGF21, and in part abrogated beneficial effects of recanalization on neurological outcomes. These findings suggested that delayed recanalization at 3 days after MCAO improved neurological outcomes in rats via increasing endogenous FGF21 expression and activating FGFR1/PI3K/Caspase-3 pathway to attenuate neuronal apoptosis in penumbra. Delayed recanalization at 3 days after ischemic stroke onset may be a promising treatment strategy in selected patients.
The first example of arylboronic acid catalyzed 4 + 3 cycloaddition reaction is reported. 3,5-Bis-(trifluoromethyl) phenylboronic acid is shown to be the best catalyst in this reaction. The method ...has also enabled the preparation of cycloheptabbenzofurans and cycloheptabindoles in excellent yields.
Stress hyperglycemia and glycemic variability (GV) can reflect dramatic increases and acute fluctuations in blood glucose, which are associated with adverse cardiovascular events. This study aimed to ...explore whether the combined assessment of the stress hyperglycemia ratio (SHR) and GV provides additional information for prognostic prediction in patients with coronary artery disease (CAD) hospitalized in the intensive care unit (ICU).
Patients diagnosed with CAD from the Medical Information Mart for Intensive Care-IV database (version 2.2) between 2008 and 2019 were retrospectively included in the analysis. The primary endpoint was 1-year mortality, and the secondary endpoint was in-hospital mortality. Levels of SHR and GV were stratified into tertiles, with the highest tertile classified as high and the lower two tertiles classified as low. The associations of SHR, GV, and their combination with mortality were determined by logistic and Cox regression analyses.
A total of 2789 patients were included, with a mean age of 69.6 years, and 30.1% were female. Overall, 138 (4.9%) patients died in the hospital, and 404 (14.5%) patients died at 1 year. The combination of SHR and GV was superior to SHR (in-hospital mortality: 0.710 vs. 0.689, p = 0.012; 1-year mortality: 0.644 vs. 0.615, p = 0.007) and GV (in-hospital mortality: 0.710 vs. 0.632, p = 0.004; 1-year mortality: 0.644 vs. 0.603, p < 0.001) alone for predicting mortality in the receiver operating characteristic analysis. In addition, nondiabetic patients with high SHR levels and high GV were associated with the greatest risk of both in-hospital mortality (odds ratio OR = 10.831, 95% confidence interval CI 4.494-26.105) and 1-year mortality (hazard ratio HR = 5.830, 95% CI 3.175-10.702). However, in the diabetic population, the highest risk of in-hospital mortality (OR = 4.221, 95% CI 1.542-11.558) and 1-year mortality (HR = 2.013, 95% CI 1.224-3.311) was observed in patients with high SHR levels but low GV.
The simultaneous evaluation of SHR and GV provides more information for risk stratification and prognostic prediction than SHR and GV alone, contributing to developing individualized strategies for glucose management in patients with CAD admitted to the ICU.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
New approaches for the engineering of well-defined, pore modality, and multi-chemical functionality nanocomposites are crucial to generate the next generation of functional materials with recoverable ...and easy preparation properties. Here, a catalyst and heat free polymerization reaction is exploited and fabricated zwitterionic system around magnetic nanoparticles. N-aminoethyl piperazine propane sulfonate (AEPPS) and dopamine (DA) are introduced as the zwitterionic system, which provided abundant zwitterionic groups (NH
2
, SO
3
−
, N
+
) and strong adhesion and various oxidation state properties. And that, the zwitterionic engineering will assemble between AEPPS and DA whereby Schiff base formation or Michael type addition. Whereafter, a series of sophisticated array of microscopic, spectroscopic, and structure techniques verify the formation of highly crosslinking internal zwitterionic architectures, well-defined core–shell structure, and better porosity. The zwitterionic structure–function relationships and striking porous structure are explored in a multi-interaction adsorption assay. The adsorption capacity of the magnetic nanocomposites was 1065.8 mg/g. And that, the system exhibited with hydrophilic-hydrophobic activity towards glycoprotein and better performance to bioactive protein (Ig-G) isolation form human whole blood sample. The synergistic enhancement interaction in hydrophilic target enrichment, easy preparation, and soft substrate properties of the AEPPS-DA zwitterionic materials make them intriguing candidates for sustainable biomedical loading and chromatographic separation.
•The sandwich beam has time-varied neutral surface and cross section for the collapse deformation mode of foam core.•A dynamic yielding criterion for metallic sandwich beams with time-varied neutral ...surface is established.•The yield surface is asymmetric for partially densified core.•Membrane factor is introduced and the criterion is applied to predict response of sandwich beams under blasting loading.
The objective of this paper is to establish a yielding criterion for a sandwich beam by considering the time inhomogeneity of foam core deformation, which results in the time-varied neutral surface and cross-sectional area. Taking into account of the bending and axial stretching, a unified dynamic yielding criterion for metallic sandwich beams considering the mass redistribution along with the core compression is established. A membrane factor is proposed and an analytical solution for the large deflection of the beam under high velocity impact is given. Different from the traditional yielding surface, when the core is partially densified, the yielding surface is asymmetric. Comparison of analytical solutions with numerical ones reveals that the present model improves the prediction accuracy of high-velocity impact responses of fully clamped sandwich beams. The present method can also be degenerated to predict the low velocity/energy impact responses of sandwich beams.
How amphipathic phospholipids are shuttled between the membrane bilayer remains an essential but elusive process, particularly at the endoplasmic reticulum (ER). One prominent phospholipid shuttling ...process concerns the biogenesis of APOB-containing lipoproteins within the ER lumen, which may require bulk trans-bilayer movement of phospholipids from the cytoplasmic leaflet of the ER bilayer. Here, we show that TMEM41B, present in the lipoprotein export machinery, encodes a previously conceptualized ER lipid scramblase mediating trans-bilayer shuttling of bulk phospholipids. Loss of hepatic TMEM41B eliminates plasma lipids, due to complete absence of mature lipoproteins within the ER, but paradoxically also activates lipid production. Mechanistically, scramblase deficiency triggers unique ER morphological changes and unsuppressed activation of SREBPs, which potently promotes lipid synthesis despite stalled secretion. Together, this response induces full-blown nonalcoholic hepatosteatosis in the TMEM41B-deficient mice within weeks. Collectively, our data uncovered a fundamental mechanism safe-guarding ER function and integrity, dysfunction of which disrupts lipid homeostasis.
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•TMEM41B associates with lipoproteins and encodes an ER lipid scramblase•Hepatic TMEM41B is required for lipoprotein biogenesis and lipid homeostasis•TMEM41B deficiency triggers drastic morphological changes of the ER membrane•TMEM41B deficiency causes unsuppressed SREBP activation and full-blown NASH
Chen and colleagues showed that TMEM41B encodes an ER lipid scramblase and executes a produce-and-protect mechanism for ER function and integrity. Deficiency of TMEM41B triggers severe metabolic defects independent of the canonical ER stress pathway and potently promotes lipid synthesis.
The risk of cardiovascular disease (CVD) is a serious health threat to human society worldwide. The use of machine learning methods to predict the risk of CVD is of great relevance to identify ...high-risk patients and take timely interventions. In this study, we propose the XGBH machine learning model, which is a CVD risk prediction model based on key contributing features. In this paper, the generalisation of the model was enhanced by adding retrospective data of 14,832 Chinese Shanxi CVD patients to the kaggle dataset. The XGBH risk prediction model proposed in this paper was validated to be highly accurate (AUC = 0.81) compared to the baseline risk score (AUC = 0.65), and the accuracy of the model for CVD risk prediction was improved with the inclusion of the conventional biometric BMI variable. To increase the clinical application of the model, a simpler diagnostic model was designed in this paper, which requires only three characteristics from the patient (age, value of systolic blood pressure and whether cholesterol is normal or not) to enable early intervention in the treatment of high-risk patients with a slight reduction in accuracy (AUC = 0.79). Ultimately, a CVD risk score model with few features and high accuracy will be established based on the main contributing features. Of course, further prospective studies, as well as studies with other populations, are needed to assess the actual clinical effectiveness of the XGBH risk prediction model.
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