Analysis of risk factors for weaning failure from mechanical ventilation in critically ill older patients with coronavirus disease 2019.

Objective: This study aimed to investigate the factors influencing weaning failure from invasive mechanical ventilation (IMV) in critically ill older patients with coronavirus disease 2019 (COVID-19). Methods: We enrolled critically ill older patients with COVID-19 who were admitted to the medical intensive care unit (ICU) and received IMV between December 2022 and June 2023. Results: We included 68 critically ill older patients with COVID-19 (52 male [76.5 %] and 16 female individuals [23.5 %]). The patients' median age (interquartile range) was 75.5 (70.3-82.8) years. The median length of ICU stay was 11.5 (7.0-17.8) days; 34 cases (50.0 %) were successfully weaned from IMV. The successfully weaned group had a higher proportion of underlying chronic obstructive pulmonary disease [6 (17.6 %) vs. 0, P = 0.033] and fewer cases of diabetes [7 (20.6 %) vs. 16 (47.1 %), P = 0.021] compared with the weaning failure group. Serum lactate levels [1.5 (1.2-2.3) vs. 2.6 (1.9-3.1) mmol/L, P < 0.001], blood urea nitrogen [8.2 (6.3-14.4) vs. 11.4 (8.0-21.3) mmol/L, P = 0.033], Acute Physiology and Chronic Health Evaluation (APACHE) II score [19.0 (12.0-23.3) vs. 22.5 (16.0-29.3), P = 0.014], and hospitalization days before endotracheal intubation [1.0 (0.0-5.0) vs. 3.0 (0.0-11.0), P = 0.023] were significantly decreased in the successfully weaned group, whereas PaO2/FiO2 [148.3 (94.6-200.3) vs. 101.1 (67.0-165.1), P = 0.038] and blood lymphocyte levels [0.6 (0.4-1.0) vs. 0.5 (0.2-0.6) 109/L, P = 0.048] were significantly increased, compared with the weaning failure group. Multivariate logistic regression analysis showed that diabetes (OR= 3.413, 95 %CI 1.029-11.326), P = 0.045), APACHE II Score (OR = 1.089, 95 % CI 1.008-1.175), P = 0.030), and hospitalization days before endotracheal intubation (OR = 1.137, 95 % CI 1.023-1.264), P = 0.017) were independent risk factors for weaning failure. Conclusion: In critically ill older patients with COVID-19 with diabetes, higher APACHE II Score, and longer hospitalization days before endotracheal intubation, weaning from IMV was more challenging. The study could help develop strategies for improving COVID-19 treatment.

LncRNA CARMN inhibits abdominal aortic aneurysm formation and vascular smooth muscle cell phenotypic transformation by interacting with SRF.

Phenotypic transformation of vascular smooth muscle cells (VSMCs) plays a crucial role in abdominal aortic aneurysm (AAA) formation. CARMN, a highly conserved, VSMC-enriched long noncoding RNA (lncRNA), is integral in orchestrating various vascular pathologies by modulating the phenotypic dynamics of VSMCs. The influence of CARMN on AAA formation, particularly its mechanisms, remains enigmatic. Our research, employing single-cell and bulk RNA sequencing, has uncovered a significant suppression of CARMN in AAA specimens, which correlates strongly with the contractile function of VSMCs. This reduced expression of CARMN was consistent in both 7- and 14-day porcine pancreatic elastase (PPE)-induced mouse models of AAA and in human clinical cases. Functional analyses disclosed that the diminution of CARMN exacerbated PPE-precipitated AAA formation, whereas its augmentation conferred protection against such formation. Mechanistically, we found CARMN's capacity to bind with SRF, thereby amplifying its role in driving the transcription of VSMC marker genes. In addition, our findings indicate an enhancement in CAMRN transcription, facilitated by the binding of NRF2 to its promoter region. Our study indicated that CARMN plays a protective role in preventing AAA formation and restrains the phenotypic transformation of VSMC through its interaction with SRF. Additionally, we observed that the expression of CARMN is augmented by NRF2 binding to its promoter region. These findings suggest the potential of CARMN as a viable therapeutic target in the treatment of AAA.

Nanoplastics causes heart aging/myocardial cell senescence through the Ca2+/mtDNA/cGAS-STING signaling cascade.

BACKGROUND: Nanoplastics (NPs) are now a new class of pollutants widely present in the soil, atmosphere, freshwater and marine environments. Nanoplastics can rapidly penetrate cell membranes and accumulate in human tissues and organs, thus posing a potential threat to human health. The heart is the main power source of the body. But up to now, the toxicological effects of long-term exposure to nanoplastics on the heart has not been revealed yet. RESULTS: We evaluated the effects of long term exposure of nanoplastics on cardiac cell/tissue in vitro and in vivo model. Furthermore, we explored the molecular mechanism by which nanoplastics exposure causes myocardial cell senescence. Immunohistochemistry, indirect immunofluorescence and ELISA were performed to detect the effects of nanoplastics on heart aging. We found that nanoplastics were able to induce significant cardiac aging through a series of biochemical assays in vivo. In vitro, the effects of nanoplastics on cardiac cell were investigated, and found that nanoplastics were able to internalize into cardiomyocytes in time and dose-dependant manner. Further biochemical analysis showed that nanoplastics induces cardiomyocytes senescence by detecting a series of senescence marker molecules. Molecular mechanism research shows that nanoplastics may cause mitochondrial destabilization by inducing oxidative stress, which leads to the leakage of mtDNA from mitochondria into the cytoplasm, and then cytoplasm-localized mt-DNA activates the cGAS-STING signaling pathway and promotes inflammation response, ultimately inducing cardiomyocytes senescence. CONCLUSIONS: In this work, we found that nanoplastics exposure induces premature aging of heart. Current research also reveals the molecular mechanism by which nanoplastics induces cardiomyocyte senescence. This study laid the foundation for further studying the potential harm of nanoplastics exposure on heart.

Successful management of camrelizumab-induced immune-checkpoint-inhibitors-related myocarditis.

INTRODUCTION: Immune checkpoint inhibitors can cause immune-related toxicity in various systems, with myocarditis being the most severe and life-threatening manifestation. This report presents a case in which myocarditis developed following administration of programmed cell death protein-1 (PD-1) inhibitors therapy. We describe the diagnosis and treatment of this patient in detail. CASE REPORT: We present the case of a 59-year-old female diagnosed with post-operative esophageal cancer and hepatic metastases. The patient underwent second-line treatment with domestically-made PD-1 inhibitor, camrelizumab, in combination with paclitaxel (albumin-bound) and carboplatin for two cycles. During the course of treatment, an electrocardiogram (ECG) revealed ST segment elevation in leads II, III, aVF, V2, V3, and V4, along with T wave changes in leads I and aVL. Laboratory examinations showed abnormal levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT). Despite the absence of clinical symptoms, the patient was routinely hospitalized three weeks later. Based on the findings from the ECG, cardiac biomarkers, echocardiography, echocardiogram, cardiac magnetic resonance, and angiography, she was diagnosed with immune-checkpoint-inhibitors-related myocarditis. MANAGEMENT AND OUTCOME: The patient received immunoglobulin (0.5 g/kg/day) and was initially given methylprednisolone (1000 mg/day). Methylprednisolone was gradually reduced to 40 mg/day in 2 weeks. During this time, the levels of biomarkers indicative of myocardial injury also exhibited a simultaneous decline. DISCUSSION: This case highlights the importance of early detection and prompt intervention, including initiating appropriate steroid therapy and discontinuing of immune checkpoint inhibitors. Such measures can effectively prevent morbidity and mortality, ultimately leading to an improved prognosis.

The role of metabolism in cellular quiescence.

Cellular quiescence is a dormant, non-dividing cell state characterized by significant shifts in physiology and metabolism. Quiescence plays essential roles in a wide variety of biological processes, ranging from microbial sporulation to human reproduction and wound repair. Moreover, when the regulation of quiescence is disrupted, it can drive cancer growth and compromise tissue regeneration after injury. In this Review, we examine the dynamic changes in metabolism that drive and support dormant and transiently quiescent cells, including spores, oocytes and adult stem cells. We begin by defining quiescent cells and discussing their roles in key biological processes. We then examine metabolic factors that influence cellular quiescence in both healthy and disease contexts, and how these could be leveraged in the treatment of cancer.

Zearalenone induces the senescence of cardiovascular cells in vitro and in vivo.

Zearalenone is a contaminant in food and feed products. It has been reported that zearalenone could lead to serious damage to health. So far, it is unclear whether zearalenone could lead to cardiovascular aging-related injury. For this, we assessed the effect of zearalenone on cardiovascular aging. Cardiomyocyte cell lines and primary coronary endothelial cells were used as two cell models in vitro experiments, and Western-blot, indirect immunofluorescence, and flow cytometry were performed to study the effect of zearalenone on cardiovascular aging. Experimental results indicated zearalenone treatment increased Sa-ß-gal positive cell ratio, and the expression of senescence markers (p16 and p21) was significantly upregulated. Additionally zearalenone upregulated the inflammation and oxidative stress in cardiovascular cells. Furthermore, the effect of zearalenone on cardiovascular aging was also evaluated in vivo, and the results indicated that zearalenone treatment also led to the aging of myocardial tissue. These findings suggest that zearalenone could lead to cardiovascular aging-related injury. Furthermore, we also preliminarily explored the potential effect of zeaxanthin (which is a powerful antioxidant) on zearalenone-caused aging-related damage in vitro cell model, and found that zeaxanthin could alleviate zearalenone-induced aging-related damage. Collectively, the most important finding of the current work is that zearalenone could lead to cardiovascular aging. Next in importance, we also found that zeaxanthin could partially alleviate zearalenone-induced cardiovascular aging in vitro, indicating that zeaxanthin can be used as a drug or functional food to treat cardiovascular damage caused by zearalenone.

HDAC Inhibitors Alleviate Uric Acid-Induced Vascular Endothelial Cell Injury by Way of the HDAC6/FGF21/PI3K/AKT Pathway.

ABSTRACT: Uric acid (UA) accumulation triggers endothelial dysfunction, oxidative stress, and inflammation. Histone deacetylase (HDAC) plays a vital role in regulating the pathological processes of various diseases. However, the influence of HDAC inhibitor on UA-induced vascular endothelial cell injury (VECI) remains undefined. Hence, this study aimed to investigate the effect of HDACs inhibition on UA-induced vascular endothelial cell dysfunction and its detailed mechanism. UA was used to induce human umbilical vein endothelial cell (HUVEC) injury. Meanwhile, potassium oxonate-induced and hypoxanthine-induced hyperuricemia mouse models were also constructed. A broad-spectrum HDAC inhibitor trichostatin A (TSA) or selective HDAC6 inhibitor TubastatinA (TubA) was given to HUVECs or mice to determine whether HDACs can affect UA-induced VECI. The results showed pretreatment of HUVECs with TSA or HDAC6 knockdown-attenuated UA-induced VECI and increased FGF21 expression and phosphorylation of AKT, eNOS, and FoxO3a. These effects could be reversed by FGF21 knockdown. In vivo, both TSA and TubA reduced inflammation and tissue injury while increased FGF21 expression and phosphorylation of AKT, eNOS, and FoxO3a in the aortic and renal tissues of hyperuricemia mice. Therefore, HDACs, especially HDAC6 inhibitor, alleviated UA-induced VECI through upregulating FGF21 expression and then activating the PI3K/AKT pathway. This suggests that HDAC6 may serve as a novel therapeutic target for treating UA-induced endothelial dysfunction.

IRX2 activated by jumonji domain-containing protein 2A is crucial for cardiac hypertrophy and dysfunction in response to the hypertrophic stimuli.

BACKGROUND: Iroquois homeobox 2 (IRX2) is a member of the Iroquois family whose upregulation has been potentially correlated to cardiac hypertrophy. This work studied the function of IRX2 and its related molecules in hypertrophic cardiomyopathy (HCM). METHODS: A GEO dataset GSE32453 was analyzed to identify aberrantly expressed genes in HCM. Altered expression of IRX2 was induced in mice by lentivirus injection, followed by angiotensin II (Ang II) treatment to induce HCM. The function of IRX2 knockdown in ventricular dysfunction, heart volume and pathological changes in mice, and in surface area, oxidative stress and apoptosis of isolated cardiomyocytes were examined. Binding relationship between jumonji domain-containing protein 2A (JMJD2A) and IRX2 was predicted by online tools and validated. The interaction between JMJD2A and IRX2 in HCM development was examined by joint interventions. RESULTS: IRX2 was highly expressed in heart tissues with HCM. IRX2 knockdown prevented mice from Ang II-induced ventricular dysfunction, cardiac hypertrophy, inflammation and fibrosis in mouse heart, and it decreased the levels of cardiac hypertrophy-related markers, oxidative stress response, and apoptosis of Ang II-treated cardiomyocytes. JMJD2A catalyzed demethylation of H3K9me3 near the IRX2 promoter to activate its transcription. JMJD2A knockdown similarly exerted protective functions against cardiac hypertrophy in vivo and in vitro, but the protection was blocked upon further IRX2 upregulation. IRX2 was found to increase the Wnt/ß-catenin signaling activation. CONCLUSION: This work reports that JMJD2A activates IRX2 transcription and the Wnt/ß-catenin signaling to induce cardiac hypertrophy and dysfunction in HCM.

Metabolic labeling of cardiomyocyte-derived small extracellular-vesicle (sEV) miRNAs identifies miR-208a in cardiac regulation of lung gene expression.

Toxoplasma gondii uracil phosphoribosyltransferase (UPRT) converts 4-thiouracil (4TUc) into 4-thiouridine (4TUd), which is incorporated into nascent RNAs and can be biotinylated, then labelled with streptavidin conjugates or isolated via streptavidin-affinity methods. Here, we generated mice that expressed T. gondii UPRT only in cardiomyocytes (CM UPRT mice) and tested our hypothesis that CM-derived miRNAs (CM miRs) are transferred into remote organs after myocardial infarction (MI) by small extracellular vesicles (sEV) that are released from the heart into the peripheral blood (PB sEV). We found that 4TUd was incorporated with high specificity and sensitivity into RNAs isolated from the hearts and PB sEV of CM UPRT mice 6 h after 4TUc injection. In PB sEV, 4TUd was incorporated into CM-specific/enriched miRs including miR-208a, but not into miRs with other organ or tissue-type specificities. 4TUd-labelled miR208a was also present in lung tissues, especially lung endothelial cells (ECs), and CM-derived miR-208a (CM miR-208a) levels peaked 12 h after experimentally induced MI in PB sEV and 24 h after MI in the lung. Notably, miR-208a is expressed from intron 29 of α myosin heavy chain (αMHC), but αMHC transcripts were nearly undetectable in the lung. When PB sEV from mice that underwent MI (MI-PB sEV) or sham surgery (Sham-PB sEV) were injected into intact mice, the expression of Tmbim6 and NLK, which are suppressed by miR-208a and cooperatively regulate inflammation via the NF-κB pathway, was lower in the lungs of MI-PB sEV-treated animals than the lungs of animals treated with Sham-PB sEV or saline. In MI mice, Tmbim6 and NLK were downregulated, whereas endothelial adhesion molecules and pro-inflammatory cells were upregulated in the lung; these changes were significantly attenuated when the mice were treated with miR-208a antagomirs prior to MI surgery. Thus, CM UPRT mice enables us to track PB sEV-mediated transport of CM miRs and identify an miR-208a-mediated mechanism by which myocardial injury alters the expression of genes and inflammatory response in the lung.

IENet: a robust convolutional neural network for EEG based brain-computer interfaces.

Objective.Brain-computer interfaces (BCIs) based on electroencephalogram (EEG) develop into novel application areas with more complex scenarios, which put forward higher requirements for the robustness of EEG signal processing algorithms. Deep learning can automatically extract discriminative features and potential dependencies via deep structures, demonstrating strong analytical capabilities in numerous domains such as computer vision and natural language processing. Making full use of deep learning technology to design a robust algorithm that is capable of analyzing EEG across BCI paradigms is our main work in this paper.Approach.Inspired by InceptionV4 and InceptionTime architecture, we introduce a neural network ensemble named InceptionEEG-Net (IENet), where multi-scale convolutional layer and convolution of length 1 enable model to extract rich high-dimensional features with limited parameters. In addition, we propose the average receptive field (RF) gain for convolutional neural networks (CNNs), which optimizes IENet to detect long patterns at a smaller cost. We compare with the current state-of-the-art methods across five EEG-BCI paradigms: steady-state visual evoked potentials (VEPs), epilepsy EEG, overt attention P300 VEPs, covert attention P300 visual-EPs and movement-related cortical potentials.Main results.The classification results show that the generalizability of IENet is on par with the state-of-the-art paradigm-agnostic models on test datasets. Furthermore, the feature explainability analysis of IENet illustrates its capability to extract neurophysiologically interpretable features for different BCI paradigms, ensuring the reliability of algorithm.Significance.It can be seen from our results that IENet can generalize to different BCI paradigms. And it is essential for deep CNNs to increase the RF size using average RF gain.

Cardioprotective Role of SIRT5 in Response to Acute Ischemia Through a Novel Liver-Cardiac Crosstalk Mechanism.

Protein posttranslational modifications play important roles in cardiovascular diseases. The authors' previous report showed that the abundance of succinylated and glutarylated proteins was significantly lower in the serum of patients with acute myocardial infarction (AMI) than in that of healthy volunteers, suggesting a potential relationship between protein acylation and AMI. Sirtuin 5 (SIRT5) facilitates the removal of malonyl, succinyl, and glutaryl modification; however, its effects on AMI remain unknown. In this study, the levels of SIRT5 in AMI mouse model was compared. Results showed elevated hepatic SIRT5 after myocardial infarction. Hepatocyte-specific SIRT5 overexpressing mice (liver SIRT5 OE) were generated to address the possible involvement of hepatic SIRT5 in AMI. The areas of myocardial infarction, myocardial fibrosis, and cardiac function in a model of experimental myocardial infarction were compared between liver SIRT5 OE mice and wild-type (WT) mice. The liver SIRT5 OE mice showed a significantly smaller area of myocardial infarction and myocardial fibrosis than the WT mice. The fibroblast growth factor 21 (FGF21) in the blood and myocardium of liver SIRT5 OE mice after AMI was markedly elevated compared with that in WT mice. The results of mass spectrometry showed increased levels of proteins regulating tricarboxylic acid cycle, oxidative phosphorylation, and fatty acid ß-oxidation pathways in the liver mitochondria of liver SIRT5 OE mice. These findings showed that SIRT5 may exhibit a cardioprotective effect in response to acute ischemia through a liver-cardiac crosstalk mechanism, probably by increasing the secretion of FGF21 and the improvement of energy metabolism.

LncRNA Chaer Prevents Cardiomyocyte Apoptosis From Acute Myocardial Infarction Through AMPK Activation.

Long non-coding RNA (lncRNA) is widely reported to be involved in cardiac (patho)physiology. Acute myocardial infarction, in which cardiomyocyte apoptosis plays an important role, is a life-threatening disease. Here, we report the lncRNA Chaer that is anti-apoptotic in cardiomyocytes during Acute myocardial infarction. Importantly, lncRNA Chaer is significantly downregulated in both oxygen-glucose deprivation (oxygen-glucose deprivation)-treated cardiomyocytes in vitro and AMI heart. In vitro, overexpression of lncRNA Chaer with adeno virus reduces cardiomyocyte apoptosis induced by OGD-treated while silencing of lncRNA Chaer increases cardiomyocyte apoptosis instead. In vivo, forced expression of lncRNA Chaer with AAV9 attenuates cardiac apoptosis, reduces infarction area and improves mice heart function in AMI. Interestingly, overexpression of lncRNA Chaer promotes the phosphorylation of AMPK, and AMPK inhibitor Compound C reverses the overexpression of lncRNA Chaer effect of reducing cardiomyocyte apoptosis under OGD-treatment. In summary, we identify the novel ability of lncRNA Chaer in regulating cardiomyocyte apoptosis by promoting phosphorylation of AMPK in AMI.

Deciphering the in vivo Dynamic Proteomics of Mesenchymal Stem Cells in Critical Limb Ischemia.

OBJECTIVE: Regenerative therapy using mesenchymal stem cells (MSC) is a promising therapeutic method for critical limb ischemia (CLI). To understand how the cells are involved in the regenerative process of limb ischemia locally, we proposed a metabolic protein labeling method to label cell proteomes in situ and then decipher the proteome dynamics of MSCs in ischemic hind limb. METHODS AND RESULTS: In this study, we overexpressed mutant methionyl-tRNA synthetase (MetRS), which could utilize azidonorleucine (ANL) instead of methionine (Met) during protein synthesis in MSCs. Fluorescent non-canonical amino-acid tagging (FUNCAT) was performed to detect the utilization of ANL in mutant MSCs. Mice with hindlimb ischemia (HLI) or Sham surgery were treated with MetRSmut MSCs or PBS, followed by i.p. administration of ANL at days 0, 2 6, and 13 after surgery. FUNCAT was also performed in hindlimb tissue sections to demonstrate the incorporation of ANL in transplanted cells in situ. At days 1, 3, 7, and 14 after the surgery, laser doppler imaging were performed to detect the blood reperfusion of ischemic limbs. Ischemic tissues were also collected at these four time points for histological analysis including HE staining and vessel staining, and processed for click reaction based protein enrichment followed by mass spectrometry and bioinformatics analysis. The MetRSmut MSCs showed strong green signal in cell culture and in HLI muscles as well, indicating efficient incorporation of ANL in nascent protein synthesis. By 14 days post-treatment, MSCs significantly increased blood reperfusion and vessel density, while reducing inflammation in HLI model compared to PBS. Proteins enriched by click reaction were distinctive in the HLI group vs. the Sham group. 34, 31, 49, and 26 proteins were significantly up-regulated whereas 28, 32, 62, and 27 proteins were significantly down-regulated in HLI vs. Sham at days 1, 3, 7, and 14, respectively. The differentially expressed proteins were more pronounced in the pathways of apoptosis and energy metabolism. CONCLUSION: In conclusion, mutant MetRS allows efficient and specific identification of dynamic cell proteomics in situ, which reflect the functions and adaptive changes of MSCs that may be leveraged to understand and improve stem cell therapy in critical limb ischemia.

Visualization and Identification of Bioorthogonally Labeled Exosome Proteins Following Systemic Administration in Mice.

Exosomes transport biologically active cargo (e.g., proteins and microRNA) between cells, including many of the paracrine factors that mediate the beneficial effects associated with stem-cell therapy. Stem cell derived exosomes, in particular mesenchymal stem cells (MSCs), have been shown previously to largely replicate the therapeutic activity associated with the cells themselves, which suggests that exosomes may be a useful cell-free alternative for the treatment of cardiovascular disorders. However, the mechanisms that govern how exosomes home to damaged cells and tissues or the uptake and distribution of exosomal cargo are poorly characterized, because techniques for distinguishing between exosomal proteins and proteins in the targeted tissues are lacking. Here, we report the development of an in vivo model that enabled the visualization, tracking, and quantification of proteins from systemically administered MSC exosomes. The model uses bioorthogonal chemistry and cell-selective metabolic labeling to incorporate the non-canonical amino acid azidonorleucine (ANL) into the MSC proteome. ANL incorporation is facilitated via expression of a mutant (L274G) methionyl-tRNA-synthetase (MetRS∗) and subsequent incubation with ANL-supplemented media; after which ANL can be covalently linked to alkyne-conjugated reagents (e.g., dyes and resins) via click chemistry. Our results demonstrate that when the exosomes produced by ANL-treated, MetRS∗-expressing MSCs were systemically administered to mice, the ANL-labeled exosomal proteins could be accurately and reliably identified, isolated, and quantified from a variety of mouse organs, and that myocardial infarction (MI) both increased the abundance of exosomal proteins and redistributed a number of them from the membrane fraction of intact hearts to the cytosol of cells in infarcted hearts. Additionally, we found that Desmoglein-1c is enriched in MSC exosomes and taken up by ischemic myocardium. Collectively, our results indicate that this newly developed bioorthogonal system can provide crucial insights into exosome homing, as well as the uptake and biodistribution of exosomal proteins.

Ultrasonographic Assessment of Anatomic Relationship Between the Internal Jugular Vein and the Common Carotid Artery in Infants and Children After ETT or LMA Insertion: A Prospective Observational Study.

Background: Central venous catheterization is used for fluid management and infusion of drugs, but it is difficult to perform and carries a high incidence of complications in infants and children. In adults, the anatomic relationship and the overlap index between the internal jugular vein (IJV) and the common carotid artery (CCA) changed significantly after laryngeal mask airway (LMA) placement. However, there are conflicting results regarding the anatomic relationship between the IJV and the CCA after endotracheal tube (ETT) or LMA insertion in pediatric populations. Aim: The aim of this study was to compare the overlap index and anatomic relationship between the IJV and the CCA in infants and children after ETT or LMA insertion by ultrasonography. Method: This single-center, prospective, observational study including 92 infants and children, aged 1 month to 6 years, were grouped according to the airway devices placed: Group ETT (n = 44) and Group LMA (n = 48). The overlap index and anatomic relationship between the IJV and the CCA before and after airway device insertion at neutral and 30° head rotation position were evaluated by ultrasonography. Results: Before airway device insertion, as the head was rotated 30° to the contralateral side, the overlap index increased significantly on the right side of the neck compared to the neutral head position. In Group ETT, there was no significant difference in the overlap index after intubation in the neutral head position or 30° head rotated position on either side. In Group LMA, the overlap indexes were increased significantly after LMA insertion in the neutral head position on both sides. Likewise, the overlap indexes were increased significantly after LMA insertion in the 30° head rotated position on both sides. The most common positional relationship between the IJV and the CCA was anterolateral (AL) in both the right side and left side in the neutral head position. In Group ETT, the AL position was still the most common position relationship between the IJV and the CCA before and after intubation in the 30° head rotated position. In Group LMA, the anterior (A) position increased significantly after LMA insertion in the left side. In the 30° head rotated position, there was a significant increase to the A position after LMA insertion in both the right side and left side. The change from AL to A was increased after LMA insertion, especially in the 30° head rotated position. Conclusions: The overlap indexes of the IJV and the CCA increased significantly in both sides of the neck after LMA placement in the neutral head position, especially in 30° head rotated position. The IJVs after LMA placement had a tendency to become anterior to the CCA when the head of the patient rotated to the opposite direction in infants and children.

Author Correction: Increased circulating ß2-adrenergic receptor autoantibodies are associated with smoking-related emphysema.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Identification of Malonylation, Succinylation, and Glutarylation in Serum Proteins of Acute Myocardial Infarction Patients.

PURPOSE: To identify protein malonylation, succinylation, and glutarylation in human and rat serum. EXPERIMENTAL DESIGN: Immunoprecipitation coupled with MS/MS is employed to compare the relative abundance of malonylation, succinylation, and glutarylation of serum protein in acute myocardial infarction human and rat. RESULTS: One hundred thirty and 48 unique malonylated, succinylated, or glutarylated peptides are found in human and rat serum, respectively. Succinylation is the most predominant modification. The most modified protein is albumin. Abundance of serum protein succinylation and glutarylation is significantly (p < 0.05) lower in the peripheral serum of ST-segment elevation myocardial infarction patients compared with healthy volunteers, which is also observed in acute myocardial infarction rats. CONCLUSIONS AND CLINICAL RELEVANCE: Malonylation, succinylation, and glutarylation widely exist in mammalian serum proteins, and may reveal novel mechanism of acute myocardial infarction.

Genetically Encoded FapR-NLuc as a Biosensor to Determine Malonyl-CoA in Situ at Subcellular Scales.

Malonyl-CoA is one of the key metabolic intermediates in fatty acid metabolism as well as a key player in protein post-translational modifications. Detection of malonyl-CoA in live cells is challenging because of the lack of effective measuring tools. Here we developed a genetically encoded biosensor, FapR-NLuc, by combining a malonyl-CoA responsive bacterial transcriptional factor, FapR, with an engineered luciferase, NanoLuciferase (NLuc). FapR-NLuc specifically responds to malonyl-CoA and enables the rapid detection of malonyl-CoA at the micromolar level. More importantly, it is reflective of the fluctuations of malonyl-CoA in live cells. Upon being targeted to subcellular compartments, this biosensor can detect the changes of malonyl-CoA in situ within organelles. Thus, FapR-NLuc can potentially be used as a tool to study the kinetics of malonyl-CoA in live cells, which will shed light on the underlying mechanisms of malonyl-CoA-mediated biological processes.

SIRT5 deacylates metabolism-related proteins and attenuates hepatic steatosis in ob/ob mice.

BACKGROUND: Sirtuin 5 (SIRT5) is a NAD+-dependent lysine deacylase. The SIRT5 deficiency mouse model shows that it is dispensable for metabolic homeostasis under normal conditions. However, the biological role of SIRT5 and acylation in pathological states such as obesity and type 2 diabetes (T2D) remains elusive. METHODS: The hepatic SIRT5-overexpressing ob/ob mouse model (ob/ob-SIRT5 OE) was established by CRISPR/Cas9 gene editing tool Protein malonylation and succinylation lysine sites were identified by immunoprecipitation coupled lipid chromatography - tandem mass spectrometry (LC-MS/MS) methods. FINDINGS: The ob/ob-SIRT5 OE mice showed decreased malonylation and succinylation, improved cellular glycolysis, suppressed gluconeogenesis, enhanced fatty acid oxidation, and attenuated hepatic steatosis. A total of 955 malonylation sites on 434 proteins and 1377 succinylation sites on 429 proteins were identified and quantitated. Bioinformatics analysis revealed that malonylation was the major SIRT5 target in the glycolysis/gluconeogenesis pathway, whereas succinylation was the preferred SIRT5 target in the oxidative phosphorylation pathway. INTERPRETATION: Hepatic overexpression of SIRT5 ameliorated the metabolic abnormalities of ob/ob mice, probably through demalonylating and desuccinylating proteins in the main metabolic pathways. SIRT5 and related acylation might be potential targets for metabolic disorders. FUND: National Key R&D Program of China, the National Natural Science Foundation of China, the Strategic Priority Research Programs (Category A) of the Chinese Academy of Sciences, the Interdisciplinary Medicine Seed Fund of Peking University and the National Laboratory of Biomacromolecules.

Cardiovascular benefits of short-term indoor air filtration intervention in elderly living in Beijing: An extended analysis of BIAPSY study.

BACKGROUND: Adverse cardiovascular effects associated with air pollution exposure have been widely demonstrated. However, inconsistent cardiovascular responses were observed from reducing indoor air pollution exposure. We aimed to assess whether short-term air filtration intervention could benefit cardiovascular health in elderly living in high pollution area. METHODS: A randomized crossover intervention study of short-term indoor air filtration intervention on cardiovascular health was conducted among 35 non-smoking elderly participants living in Beijing in the winter of 2013, as part of Beijing Indoor Air Purifier StudY (BIAPSY). Portable air filtration units were randomly allocated to active filtration for 2 weeks and sham filtration for 2 weeks in the households. Twelve-hour daytime ambulatory heart rate variability (HRV) and blood pressure (ABP) were measured during active and sham filtration. Concurrently, real-time indoor and outdoor particulate matter with diameter less than 2.5 µm (PM2.5) and indoor black carbon (BC) concentrations were measured. We applied generalized additive mixed models to evaluate the associations of 1- to 10-h moving average (MA) exposures of indoor PM2.5 and BC with HRV and ABP indices, and to explore whether these associations could be modified by air filtration. RESULTS: We observed decreases of 34.8% in indoor PM2.5 and 35.3% in indoor BC concentrations during active filtration. Indoor PM2.5 and BC exposures were significantly associated with reduced HRV and increased ABP indices, and greater changes were observed during sham filtration. In specific, each 10 µg/m3 increase in indoor PM2.5 at MA8-h was associated with a significant reduction of 1.34% (95% CI: -2.42, -0.26) in SDNN during sham filtration, compared with a non-significant reduction of 0.81% (95% CI: -6.00, 4.68) during active filtration (Pinter< 0.001). Each 1 µg/m3 increase in indoor BC at MA8-h was associated with a significant increase of 2.41% (95% CI: 0.38, 4.47) in SBP during sham filtration, compared with a non-significant increase of -1.09% (95% CI: -4.06, 1.96) during active filtration (Pinter = 0.135). Nonlinear inverse exposure-response relationships of indoor air pollution exposures with predicted HRV and ABP indices also confirmed some cardiovascular benefits of short-term air filtration intervention. CONCLUSIONS: Our results suggested that short-term indoor air filtration intervention can be of some cardiovascular benefits in elderly living with high pollution episodes.