The European Society of Intensive Care Medicine (ESICM) recently recommended changes to the criteria of acute respiratory distress syndrome (ARDS), patients with high-flow oxygen were included, ...however, the effect of these changes remains unclear. Our objectives were to evaluate the performance of these new criteria and to compare the outcomes of patients meeting the new ARDS criteria with those meeting the Berlin ARDS criteria.
This was a retrospective cohort. The patients admitted to the intensive care unit (ICU) were diagnosed with ARDS. Patients were classified as meeting Berlin criteria ARDS (n = 4279), high-flow nasal oxygen (HFNO) criteria ARDS (n = 559), or new criteria ARDS (n = 4838).
In comparison with HFNO criteria ARDS and new criteria ARDS, patients with Berlin criteria ARDS demonstrated lower blood oxygen levels assessed by PaO
/FiO
, SpO
/FiO
, and ROX (SpO
/FiO
/respiratory rate) (p < 0.001); and higher severity of illness assessed by the Sequential Organ Failure Assessment (SOFA) score, Acute Physiology And Chronic Health Evaluations (APACHE II), Simplified Acute Physiology Score (SAPS II) (p < 0.001), (p < 0.001), and longer ICU and hospital stays (p < 0.001). In comparison with the HFNO criteria, patients meeting Berlin criteria ARDS had higher hospital mortality (10.6% vs. 16.9%; p = 0.0082), 28-day mortality (10.6% vs. 16.5%; p = 0.0079), and 90-day mortality (10.7% vs. 17.1%; p = 0.0083). ARDS patients with HFNO did not have severe ARDS; Berlin criteria ARDS patients with severe ARDS had the highest mortality rate (approximately 33%). PaO
/FiO
, SpO
/FiO
, and ROX negatively correlated with the SOFA and APACHE II scores. The SOFA and APACHE II scores had high specificity and sensitivity for prognosis in patients with new criteria ARDS.
The new criteria of ARDS reduced the severity of illness, length of stay in the ICU, length of hospital stays, and overall mortality. SOFA and APACHE II scores remain important in assessing the prognosis of patients with new criteria ARDS.
Registration number: ChiCTR2200067084.
Sepsis-associated encephalopathy (SAE) is a significant cause of mortality in patients with sepsis. Despite extensive research, its exact cause remains unclear. Our previous research indicated a ...relationship between non-hepatic hyperammonemia (NHH) and SAE. This study aimed to investigate the relationship between NHH and SAE and the potential mechanisms causing cognitive impairment. In the in vivo experimental results, there were no significant abnormalities in the livers of mice with moderate cecal ligation and perforation (CLP); however, ammonia levels were elevated in the hippocampal tissue and serum. The ELISA study suggest that fecal microbiota transplantation in CLP mice can reduce ammonia levels. Reduction in ammonia levels improved cognitive dysfunction and neurological impairment in CLP mice through behavioral, neuroimaging, and molecular biology studies. Further studies have shown that ammonia enters the brain to regulate the expression of aquaporins-4 (AQP4) in astrocytes, which may be the mechanism underlying brain dysfunction in CLP mice. The results of the in vitro experiments showed that ammonia up-regulated AQP4 expression in astrocytes, resulting in astrocyte damage. The results of this study suggest that ammonia up-regulates astrocyte AQP4 expression through the gut-brain axis, which may be a potential mechanism for the occurrence of SAE.
Using an engineered pyrrolysyl-tRNA synthetase mutant together with tRNACUA Pyl, we have genetically encoded Nε -(7-azidoheptanoyl)-l-lysine (AzHeK) by amber codon in Escherichia coli for recombinant ...expression of a number of AzHeK-containing histone H3 proteins. We assembled in vitro acyl-nucleosomes from these recombinant acyl-H3 histones. All these acyl-nucleosomes contained an azide functionality that allowed quick click labeling with a strained alkyne dye for in-gel fluorescence analysis. Using these acyl-nucleosomes as substrates and click labeling as a detection method, we systematically investigated chromatin deacylation activities of SIRT7, a class III NAD+-dependent histone deacylase with roles in aging and cancer biology. Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. We further demonstrated that this H3K36 deacylation activity is nucleosome dependent and can be significantly enhanced when appending the acyl-nucleosome substrate with a short double-stranded DNA that mimics the bridging DNA between nucleosomes in native chromatin. By overexpressing SIRT7 in human cells, we verified that SIRT7 natively removes acetylation from histone H3K36. Moreover, SIRT7-deficient cells exhibited H3K36 hyperacetylation in whole cell extracts, at rDNA sequences in nucleoli, and at select SIRT7 target loci, demonstrating the physiologic importance of SIRT7 in determining endogenous H3K36 acetylation levels. H3K36 acetylation has been detected at active gene promoters, but little is understood about its regulation and functions. Our findings establish H3K36 as a physiologic substrate of SIRT7 and implicate this modification in potential SIRT7 pathways in heterochromatin silencing and genomic stability.
A facile method was developed to fabricate Pt nanoparticles loaded porous graphene (Pt-PGR) composites via impregnation and reduction. The PGR was first immersed into a H2PtCl6 ethanol solution, and ...then the H2PtCl6 was reduced to Pt nanoparticles with NaBH4 to produce the Pt-PGR composites. Morphologies and composition of the Pt-PGR composites were characterized by filed-emission scanning electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy and nitrogen physisorption. It was found that the obtained Pt-PGR composites had three-dimensional interpenetrating porous structure, and the Pt nanoparticles from 50 to 150nm uniformly distributed on the graphene surfaces. Electrochemical and electrocatalytical properties of the Pt-PGR composite were investigated by cyclic voltammogram and linear sweep voltammogram. The results indicated that the Pt-PGR composites had excellent catalytical activity towards the oxygen reduction reaction (ORR), and showed the higher diffusion-limited current densities (4.0mAcm−2 and 25mAmgpt−1 at −0.6V) and stability compared with the commercial 20% Pt/C catalyst. The electrocatalytical kinetics experiments showed that the electron transfer number was 3.6 calculated from the Koutecky-Levich plot, indicating an approximate four-electron process and the oxygen directly reduced to water for the ORR.
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•Pt nanoparticles loaded porous graphene was prepared.•The Pt nanoparticles loaded porous graphene exhibited good electrocatalytical activity for oxygen reduction reaction.•The Pt nanoparticles loaded porous graphene gave higher current density and stability than the commercial catalyst.
Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy, which is the most common and severe acute leukemia in adults. Its occurrence, development and prognosis are affected by many ...factors, and more research is still needed to further guide its treatment. Here, we found that roundabout3 (ROBO3) was associated with poor prognosis in AML through bioinformatics analysis. We then found that overexpression of ROBO3 promoted AML cell proliferation, adhesion and migration while knockdown of ROBO3 had opposite effects. We subsequently found that ROBO3 regulated CD34 expression in AML cells, and this regulatory effect may be achieved through the Hippo-YAP pathway. The inhibitors of this pathway, K-975 and verteporfin, showed an inhibitory effect on AML cells with high ROBO3 expression. ROBO3 was also found to be significantly increased in bone marrow samples from AML patients. Our research indicates that ROBO3 plays an important role in the development of AML, which suggests that ROBO3 can be a prognostic biomarker and potential therapeutic target for AML.
•ROBO3 was associated with poor prognosis in acute myeloid leukemia.•ROBO3 promoted acute myeloid leukemia cell proliferation, adhesion and migration.•ROBO3 regulated the expression of YAP1, CD34 and PPARγ.•Hippo-YAP inhibitor reversed the enhanced metastatic ability of ROBO3-overexpressing AML cells.•Hippo-YAP inhibitor K-975 and verteporfin showed enhanced cytotoxicity against ROBO3-overexpressing AML cells.
We describe a new method to produce histone H2B by semisynthesis with an engineered sortase transpeptidase. N-Terminal tail site-specifically modified acetylated, lactylated, and β-hydroxybutyrylated ...histone H2Bs were incorporated into nucleosomes and investigated as substrates of histone deacetylase (HDAC) complexes and sirtuins. A wide range of rates and site-specificities were observed by these enzyme forms suggesting distinct biological roles in regulating chromatin structure and epigenetics.
Age-related macular degeneration (AMD) and high myopia are frequent causes of progressive visual impairment, so it is critical to identify animal models with resembling human retinal physiology, AMD ...and high myopia pathological features for therapeutic studies.
We screened elderly cynomolgus monkeys for fundus lesions by slit-lamp biomicroscope combined with fundus pre-set lens and further examined positive cases by color fundus photography (CFP), optical coherence tomography (OCT), fundus fluorescein angiography (FFA), streak retinoscopy, and A-scan ultrasonography.
Among the 156 animals examined, 10 males and 5 females (30 eyes) exhibited fundus abnormalities (9.6% prevalence). Multi-modal imaging revealed drusen in 20 eyes of 11 animals (prevalence rate of 7.1%), tessellated fundus in 22 eyes of 11 animals, and myopia choroidal neovascularization (CNV) in 4 eyes of 3 animals.
Aged cynomolgus monkeys exhibit spontaneous fundus lesions resembling human AMD and high myopia, which could be an ideal model for clinical research.
•We applied multimodal imaging to examine fundus lesions in aged cynomolgus monkeys.•A part of the monkeys exhibited spontaneous drusen, tessellated fundus, and myopic CNV.•Elderly cynomolgus monkeys are a promising animal model for research on AMD and high myopia.•An optimal animal model helps elucidate the pathophysiology, and pathogenesis of fundus diseases.
Apelin is the endogenous ligand of APJ receptor. Both monocytes (MCs) and human umbilical vein endothelial cells (HUVECs) express apelin and APJ, which play important roles in the physiological ...processes of atherosclerosis. Our previous research indicated that apelin‐13 promoted MCs‐HUVECs adhesion. Here, we further explore the mechanism responsible for MCs‐HUVECs adhesion induced by apelin‐13. Apelin‐13 promoted reactive oxygen species (ROS) generation and NOX4 expression in HUVECs. Apelin‐13 inducedautophagy, increased proteins beclin1 and LC3‐II/I expression and induced autophagy flux in HUVECs, which was blocked by NAC, catalase and DPI. Autophagy flux induced by apelin‐13 was inhibited by NAC and catalase but not hydroxychloroquine (HCQ). NAC, catalase, and DPI prevented apelin‐13 induced ICAM‐1 expression in HUVECs. Rapamycin enhanced MCs–HUVECs adhesion that was reversed by NAC, catalase, and DPI. Down‐regulation of beclin1 and LC3 by siRNA blocked MCs‐HUVECs adhesion. Apelin‐13 induced atherosclerotic plaque and increased NOX4, LC3‐II/I expression in ApoE−/−(HFD) mouse model. Our results demonstrated that apelin‐13 induced MCs–HUVECs adhesion via a ROS‐autophagy pathway.
Apelin‐13 increased ROS expression and induced autophagy in HUVECs. ROS‐autophagy pathway mediated monocytes‐HUVECs adhesion induced by apelin‐13.
Recent studies have shown that the epigenetic protein histone deacetylase 11 (HDAC11) is highly expressed in the brain and critically modulates neuroimmune functions, making it a potential ...therapeutic target for neurological disorders. Herein, we report the development of PB94, which is a novel HDAC11 inhibitor. PB94 exhibited potency and selectivity against HDAC11 with IC50 = 108 nM and >40-fold selectivity over other HDAC isoforms. Pharmacokinetic/pharmacodynamic evaluation indicated that PB94 possesses promising drug-like properties. Additionally, PB94 was radiolabeled with carbon-11 as 11CPB94 for positron emission tomography (PET), which revealed significant brain uptake and metabolic properties suitable for drug development in live animals. Furthermore, we demonstrated that neuropathic pain was associated with brain upregulation of HDAC11 and that pharmacological inhibition of HDAC11 by PB94 ameliorated neuropathic pain in a mouse model. Collectively, our findings support further development of PB94 as a selective HDAC11 inhibitor for neurological indications, including pain.
We incorporate time-varying consumption volatility in the representative-agent asset pricing model with generalized recursive smooth ambiguity preferences developed by Ju and Miao (2012). We ...calibrate the model to data on consumption and asset returns since the Great Depression period. Uncertainty aversion amplifies the perceived probability of the disastrous state coupled with high consumption volatility. We find that the model with time-varying volatility generates a high equity risk premium. When we impose the condition that no consumption disasters ever realized in simulated samples, the model with time-varying volatility can reproduce predictability of returns and non-predictability of consumption growth simultaneously, which are consistent with empirical findings.
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