ALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice.

Cardiac macrophage contributes to the development of cardiac fibrosis, but factors that regulate cardiac macrophages transition and activation during this process remains elusive. Here we show, by single-cell transcriptomics, lineage tracing and parabiosis, that cardiac macrophages from circulating monocytes preferentially commit to macrophage-to-myofibroblast transition (MMT) under angiotensin II (Ang II)-induced hypertension, with accompanying increased expression of the RNA N6-methyladenosine demethylases, ALKBH5. Meanwhile, macrophage-specific knockout of ALKBH5 inhibits Ang II-induced MMT, and subsequently ameliorates cardiac fibrosis and dysfunction. Mechanistically, RNA immunoprecipitation sequencing identifies interlukin-11 (IL-11) mRNA as a target for ALKBH5-mediated m6A demethylation, leading to increased IL-11 mRNA stability and protein levels. By contrast, overexpression of IL11 in circulating macrophages reverses the phenotype in ALKBH5-deficient mice and macrophage. Lastly, targeted delivery of ALKBH5 or IL-11 receptor α (IL11RA1) siRNA to monocytes/macrophages attenuates MMT and cardiac fibrosis under hypertensive stress. Our results thus suggest that the ALKBH5/IL-11/IL11RA1/MMT axis alters cardiac macrophage and contributes to hypertensive cardiac fibrosis and dysfunction in mice, and thereby identify potential targets for cardiac fibrosis therapy in patients.

Electrical Doping of Metal Halide Perovskites by Co-evaporation and Application in PN Junctions.

Electrical doping of semiconductors is a revolutionary development that enabled many electronic and optoelectronic technologies. While doping of many inorganic and organic semiconductors has been well-established, controlled electrical doping of metal halide perovskites is yet to be demonstrated. In this work, we achieve efficient n- and p-type electrical doping of metal halide perovskites by co-evaporating the perovskite precursors alongside organic dopant molecules. We demonstrate that the Fermi level can be shifted by up to 500 meV towards the conduction band and by up to 400 meV towards the valence band by n- and p-doping, respectively, which increases the conductivity of the films. The doped layers were employed in PN and NP diodes, showing opposing trends in rectification. Demonstrating controlled electrical doping by a scalable, industrially relevant deposition method opens the route to developing perovskite devices beyond solar cells, such as thermoelectrics or complementary logic. This article is protected by copyright. All rights reserved.

[Construction and verification of a nomogram of factors influencing the risk of death in patient with sepsis-associated thrombocytopenia].

OBJECTIVE: To construct a nomogram prediction model for predicting the risk of death in patients with sepsis-associated thrombocytopenia (SAT) in intensive care unit (ICU) for early indentification and active intervention. METHODS: Clinical data of SAT patients admitted to ICU of the First Affiliated Hospital of Nanjing Medical University from December 2019 to August 2021 were retrospectively collected, including demographic data, laboratory indicators, etc. According to the prognosis at 28 days, the patients were divided into the death group and the survival group, and the differences of clinical variables between the two groups were compared. Multivariate Logistic regression analysis was performed to analyze the independent risk factors influencing mortality of patients within 28 days, then a nomogram predictive model was constructed and its performance was verified with internal data. Receiver operator characteristic curve (ROC curve) was used to evaluate the diagnostic effectiveness of the nomogram model, and the clinical applicability of this model was evaluated by clinical decision curve analysis (DCA). RESULTS: A total of 275 patients were included, with 95 deaths at 28 days and a 28-day mortality of 34.5%. Compared with the survival group, acute physiology and chronic health evaluation II (APACHE II), sequential organ failure assessment (SOFA), lactic acid (Lac), platelet distribution width (PDW) on day 5 of ICU admission, blood urea nitrogen (BUN), total bilirubin (TBIL), aspartate aminotransferase (AST), C-reactive protein (CRP) of patients in the death group were higher, activated partial thromboplastin time (APTT) and prothrombin time (PT) were longer, platelet count (PLT) on day 3 and day 5 of ICU admission, direct bilirubin (DBIL), fibrinogen (FIB) were lower, the history of chronic lung disease, mixed site infection, lung infection, bloodstream infection, Gram-negative bacterial infection and fungal infection accounted for a higher proportion, the history of diabetes mellitus, urinary tract infection and no pathogenic microorganisms cultured accounted for a lower proportion, and the proportion of the use of vasoactive drugs, mechanical ventilation (MV), continuous renal replacement therapy (CRRT), bleeding events and platelet transfusion were higher. Multivariate Logistic regression analysis showed that APACHE II score at the day of ICU admission [odds ratio (OR) = 1.417, 95% confidence interval (95%CI) was 1.153-1.743, P = 0.001], chronic lung disease (OR = 72.271, 95%CI was 4.475-1 167.126, P = 0.003), PLT on day 5 of ICU admission (OR = 0.954, 95%CI was 0.922-0.987, P = 0.007), vasoactive drug (OR = 622.943, 95%CI was 10.060-38 575.340, P = 0.002), MV (OR = 91.818, 95%CI was 3.973-2 121.966, P = 0.005) were independent risk factors of mortality in SAT patients. The above independent risk factors were used to build a nomogram prediction model, and the area under the curve (AUC), sensitivity and specificity were 0.979, 94.7% and 91.7%, respectively, suggesting that the model had good discrimination. The Hosmer-Lemeshow goodness of fit test showed a good calibration with P > 0.05. At the same time, DCA showed that the nomogram model had good clinical applicability. CONCLUSIONS: Patients with SAT has a higher risk of death. The nomogram model based on APACHE II score at the day of ICU admission, chronic lung disease, PLT on day 5 of ICU admission, the use of vasoactive drug and MV has good clinical significance for the prediction of 28-day mortality, and the discrimination and calibration are good, however, further verification is needed.

ASD2023: towards the integrating landscapes of allosteric knowledgebase.

Allosteric regulation, induced by perturbations at an allosteric site topographically distinct from the orthosteric site, is one of the most direct and efficient ways to fine-tune macromolecular function. The Allosteric Database (ASD; accessible online at http://mdl.shsmu.edu.cn/ASD) has been systematically developed since 2009 to provide comprehensive information on allosteric regulation. In recent years, allostery has seen sustained growth and wide-ranging applications in life sciences, from basic research to new therapeutics development, while also elucidating emerging obstacles across allosteric research stages. To overcome these challenges and maintain high-quality data center services, novel features were curated in the ASD2023 update: (i) 66 589 potential allosteric sites, covering > 80% of the human proteome and constituting the human allosteric pocketome; (ii) 748 allosteric protein-protein interaction (PPI) modulators with clear mechanisms, aiding protein machine studies and PPI-targeted drug discovery; (iii) 'Allosteric Hit-to-Lead,' a pioneering dataset providing panoramic views from 87 well-defined allosteric hits to 6565 leads and (iv) 456 dualsteric modulators for exploring the simultaneous regulation of allosteric and orthosteric sites. Meanwhile, ASD2023 maintains a significant growth of foundational allosteric data. Based on these efforts, the allosteric knowledgebase is progressively evolving towards an integrated landscape, facilitating advancements in allosteric target identification, mechanistic exploration and drug discovery.

Towards low-temperature processing of efficient γ-CsPbI3 perovskite solar cells.

Inorganic cesium lead iodide (CsPbI3) perovskite solar cells (PSCs) have attracted enormous attention due to their excellent thermal stability and optical bandgap (∼1.73 eV), well-suited for tandem device applications. However, achieving high-performance photovoltaic devices processed at low temperatures is still challenging. Here we reported a new method for the fabrication of high-efficiency and stable γ-CsPbI3 PSCs at lower temperatures than was previously possible by introducing the long-chain organic cation salt ethane-1,2-diammonium iodide (EDAI2) and regulating the content of lead acetate (Pb(OAc)2) in the perovskite precursor solution. We find that EDAI2 acts as an intermediate that can promote the formation of γ-CsPbI3, while excess Pb(OAc)2 can further stabilize the γ-phase of CsPbI3 perovskite. Consequently, improved crystallinity and morphology and reduced carrier recombination are observed in the CsPbI3 films fabricated by the new method. By optimizing the hole transport layer of CsPbI3 inverted architecture solar cells, we demonstrate efficiencies of up to 16.6%, surpassing previous reports examining γ-CsPbI3 in inverted PSCs. Notably, the encapsulated solar cells maintain 97% of their initial efficiency at room temperature and under dim light for 25 days, demonstrating the synergistic effect of EDAI2 and Pb(OAc)2 in stabilizing γ-CsPbI3 PSCs.

Convolutional neural network based on photoplethysmography signals for sleep apnea syndrome detection.

Introduction: The current method of monitoring sleep disorders is complex, time-consuming, and uncomfortable, although it can provide scientifc guidance to ensure worldwide sleep quality. This study aims to seek a comfortable and convenient method for identifying sleep apnea syndrome. Methods: In this work, a one-dimensional convolutional neural network model was established. To classify this condition, the model was trained with the photoplethysmographic (PPG) signals of 20 healthy people and 39 sleep apnea syndrome (SAS) patients, and the influence of noise on the model was tested by anti-interference experiments. Results and Discussion: The results showed that the accuracy of the model for SAS classifcation exceeds 90%, and it has some antiinterference ability. This paper provides a SAS detection method based on PPG signals, which is helpful for portable wearable detection.

An Asymmetric Encryption-Based Key Distribution Method for Wireless Sensor Networks.

Wireless sensor networks are usually applied in hostile areas where nodes can easily be monitored and captured by an adversary. Designing a key distribution scheme with high security and reliability, low hardware requirements, and moderate communication load is crucial for wireless sensor networks. To address the above objectives, we propose a new key distribution scheme based on an ECC asymmetric encryption algorithm. The two-way authentication mechanism in the proposed scheme not only prevents illegal nodes from accessing the network, but also prevents fake base stations from communicating with the nodes. The complete key distribution and key update methods ensure the security of session keys in both static and dynamic environments. The new key distribution scheme provides a significant performance improvement compared to the classical key distribution schemes for wireless sensor networks without sacrificing reliability. Simulation results show that the proposed new scheme reduces the communication load and key storage capacity, has significant advantages in terms of secure connectivity and attack resistance, and is fully applicable to wireless sensor networks.

A2AR-mediated lymphangiogenesis via VEGFR2 signaling prevents salt-sensitive hypertension.

AIMS: Excess dietary sodium intake and retention lead to hypertension. Impaired dermal lymphangiogenesis and lymphatic dysfunction-mediated sodium and fluid imbalance are pathological mechanisms. The adenosine A2A receptor (A2AR) is expressed in lymphatic endothelial cells (LECs), while the roles and mechanisms of LEC-A2AR in skin lymphangiogenesis during salt-induced hypertension are not clear. METHODS AND RESULTS: The expression of LEC-A2AR correlated with lymphatic vessel density in both high-salt diet (HSD)-induced hypertensive mice and hypertensive patients. Lymphatic endothelial cell-specific A2AR knockout mice fed HSD exhibited 17 ± 2% increase in blood pressure and 17 ± 3% increase in Na+ content associated with decreased lymphatic density (-19 ± 2%) compared with HSD-WT mice. A2AR activation by agonist CGS21680 increased lymphatic capillary density and decreased blood pressure in HSD-WT mice. Furthermore, this A2AR agonist activated MSK1 directly to promote VEGFR2 activation and endocytosis independently of VEGF as assessed by phosphoprotein profiling and immunoprecipitation assays in LECs. VEGFR2 kinase activity inhibitor fruquintinib or VEGFR2 knockout in LECs but not VEGF-neutralizing antibody bevacizumab suppressed A2AR activation-mediated decrease in blood pressure. Immunostaining revealed phosphorylated VEGFR2 and MSK1 expression in the LECs were positively correlated with skin lymphatic vessel density and A2AR level in hypertensive patients. CONCLUSION: The study highlights a novel A2AR-mediated VEGF-independent activation of VEGFR2 signaling in dermal lymphangiogenesis and sodium balance, which might be a potential therapeutic target in salt-sensitive hypertension.

USH2A Gene Mutations in Rabbits Lead to Progressive Retinal Degeneration and Hearing Loss.

Purpose: Mutations in USH2A gene are responsible for the greatest proportion of the Usher Syndrome (USH) population, among which more than 30% are frameshift mutations on exon 13. A clinically relevant animal model has been absent for USH2A-related vision loss. Here we sought to establish a rabbit model carrying USH2A frameshift mutation on exon 12 (human exon 13 equivalent). Methods: CRISPR/Cas9 reagents targeting the rabbit USH2A exon 12 were delivered into rabbit embryos to produce an USH2A mutant rabbit line. The USH2A knockout animals were subjected to a series of functional and morphological analyses, including acoustic auditory brainstem responses, electroretinography, optical coherence tomography, fundus photography, fundus autofluorescence, histology, and immunohistochemistry. Results: The USH2A mutant rabbits exhibit hyper-autofluorescent signals on fundus autofluorescence and hyper-reflective signals on optical coherence tomography images as early as 4 months of age, which indicate retinal pigment epithelium damage. Auditory brainstem response measurement in these rabbits showed moderate to severe hearing loss. Electroretinography signals of both rod and cone function were decreased in the USH2A mutant rabbits starting from 7 months of age and further decreased at 15 to 22 months of age, indicating progressive photoreceptor degeneration, which is confirmed by histopathological examination. Conclusions: Disruption of USH2A gene in rabbits is sufficient to induce hearing loss and progressive photoreceptor degeneration, mimicking the USH2A clinical disease. Translational Relevance: To our knowledge, this study presents the first mammalian model of USH2 showing the phenotype of retinitis pigmentosa. This study supports the use of rabbits as a clinically relevant large animal model to understand the pathogenesis and to develop novel therapeutics for Usher syndrome.

In vivo tracking of individual stem cells labeled with nanowire lasers using multimodality imaging.

Emerging cell-based regenerative medicine and stem cell therapies have drawn wide attention in medical research and clinical practice to treat tissue damage and numerous incurable diseases. In vivo observation of the distribution, migration, and development of the transplanted cells is important for both understanding the mechanism and evaluating the treatment efficacy and safety. However, tracking the 3D migration trajectories for individual therapeutic cells in clinically relevant pathological environments remains technically challenging. Using a laser photocoagulation model in living rabbit eyes, this study demonstrates a multimodality imaging technology integrating optical coherence tomography (OCT), fluorescence microscopy (FM), and lasing emission for in vivo longitudinal tracking of the 3D migration trajectories of individual human retinal pigment epithelium cells (ARPE-19) labeled with CdS nanowires. With unique lasing spectra generated from the subtle microcavity differences, the surface-modified nanowires perform as distinct spectral identifiers for labeling individual ARPE-19 cells. Meanwhile, with strong optical scattering and natural fluorescence emission, CdS nanowires also served as OCT and FM contrast agents to indicate the spatial locations of the transplanted ARPE-19 cells. A longitudinal study of tracking individual ARPE-19 cells in rabbit eyes over a duration of 28 days was accomplished. This method could potentially promote an understanding of the pharmacodynamics and pharmacokinetics of implanted cells in the development of cell-based therapies.

Association of remnant cholesterol and non-high density lipoprotein cholesterol with risk of cardiovascular mortality among US general population.

Background: There are strong association between remnant cholesterol (RC)/non-high density lipoprotein cholesterol (NHDL-C) and increase cardiovascular (CV) risk. The aim of present study was to investigate the association between target lipid parameters (RC and NHDL-C) and the risk of CV mortality in general population. Methods: Data set from an open database-National Health and Nutrition Examination Surveys (NHANES) 2003-2014 were extracted (n = 14992). Kaplan-Meier, multivariable COX regression, and restricted cubic spline (RCS) parameters. Results: Compared to the lowest quartile, RC (adjusted hazard ratio [HR] = 1.63 95%CI 1.05-2.52, P for trend = 0.037) and triglycerides (TG: Model 3: HR = 1.69 95%CI 1.10-2.60, P for trend = 0.049) in the highest quartile were independently associated with the increased cardiovascular mortality, while NHDL-C and apolipoprotein B (ApoB) in adjusted models did not show association (P for trend >0.05). In addition, RCS regression demonstrated that RC (P for nonlinearity = 0.011) and TG (P for nonlinearity = 0.010) levels had a similar J-shape association with CV mortality. Threshold effect analysis showed that when RC ≤ 29.3 mg/dL, the level of RC and CV mortality risk were positively correlated. Conclusions: Our findings suggest high RC levels are associated with an increased risk of CV mortality, which support that the integration of TG-rich lipoproteins parameters in risk assessment might optimize the identification and management of selected population.

Comprehensive Analysis of the E2F Transcription Factor Family in Human Lung Adenocarcinoma.

Background: E2F transcription factors (E2Fs), code a family of pivotal transcription factors, have been identified as key regulators in tumor tumorigenesis. However, the function of E2F family in human lung adenocarcinoma (LUAD) have not been fully elucidated. Methods: Herein, The Cancer Genome Atlas (TCGA) databases, Kaplan-Meier plotter, cBioPortal and TIMER were used to analyze differential expression, prognostic value, genetic alteration and immune cell infiltration of E2Fs in LUAD patients. Results: The expression levels of E2Fs (E2F1-8) were all significantly upregulated in LUAD tissues compared with normal lung tissues. All eight E2Fs had low rates of gene mutation in LUAD patients from cBioPortal databases. Survival analysis revealed that E2F2 (P=0.038; HR 1.36; 95% CI 1.02-1.81), E2F7 (P<0.001; HR 1.78; 95% CI 1.33-2.39) and E2F8 (P=0.03; HR 1.37; 95% CI 1.02-1.82) were significantly associated with poor prognosis. Multivariate cox regression analysis found that only E2F7 (P<0.001; HR 2.72; 95% CI 1.75-4.25) was an independent prognostic predictor in LUAD after adjusting common clinical parameters. The receiver operating characteristic (ROC) analysis also found that E2F7 had high diagnostic value for LUAD (AUC=0.901). Further analysis found that E2F7 was significantly associated with LUAD immune cell infiltration of B cell, T cell, neutrophil, and myeloid dendritic cell. E2F7 also have positive correlations with immune checkpoint genes including SIGLEC15, CD274, HAVCR2, PDCD1LG2, CTLA4, TIGIT, LAG3 and PDCD1 in LUAD. Conclusion: Our findings showed various association of E2F7 in LUAD diagnostic and prognostic aspects, which suggested its potential in becoming a novel biomarker.

Chorioretinal Hypoxia Detection Using Lipid-Polymer Hybrid Organic Room-Temperature Phosphorescent Nanoparticles.

Ischemia-induced hypoxia is a common complication associated with numerous diseases and is the most important prognostic factor in retinal vein occlusions (RVOs). Early detection and long-term visualization of retinal tissue hypoxia is essential to understand the pathophysiology and treatment of ischemic retinopathies. However, no effective solution exists to evaluate extravascular retinal tissue oxygen tension. Here, we demonstrate a lipid-polymer hybrid organic room-temperature phosphorescence (RTP) nanoparticle (NP) platform that optically detects tissue hypoxia in real-time with high signal-to-noise ratio. The fabricated NPs exhibit long-lived bright RTP, high sensitivity toward oxygen quenching, and desirable colloidal and optical stability. When tested as a hypoxia imaging probe in vivo using rabbit RVO and choroidal vascular occlusion (CVO) models via intravitreal and intravenous (IV) injections, respectively, its RTP signal is exclusively turned on where tissue hypoxia is present with a signal-to-noise ratio of 12.5. The RTP NP platform is compatible with multimodal imaging. No ocular or systemic complications are observed with either administration route. The developed organic RTP NPs present a novel platform approach that allows for biocompatible, nondestructive detection of tissue hypoxia and holds promise as a sensitive imaging tool to monitor longitudinal tissue oxygen levels and evaluate various hypoxia-driven vascular diseases.

Laser-induced nanobubbles safely ablate vitreous opacities in vivo.

In myopia, diabetes and ageing, fibrous vitreous liquefaction and degeneration is associated with the formation of opacities inside the vitreous body that cast shadows on the retina, appearing as 'floaters' to the patient. Vitreous opacities degrade contrast sensitivity function and can cause notable impairment in vision-related quality of life. Here we introduce 'nanobubble ablation' for safe destruction of vitreous opacities. Following intravitreal injection, hyaluronic acid-coated gold nanoparticles and indocyanine green, which is widely used as a dye in vitreoretinal surgery, spontaneously accumulate on collagenous vitreous opacities in the eyes of rabbits. Applying nanosecond laser pulses generates vapour nanobubbles that mechanically destroy the opacities in rabbit eyes and in patient specimens. Nanobubble ablation might offer a safe and efficient treatment to millions of patients suffering from debilitating vitreous opacities and paves the way for a highly safe use of pulsed lasers in the posterior segment of the eye.

Biodegradable silicon nanoneedles for ocular drug delivery.

Ocular drug delivery remains a grand challenge due to the complex structure of the eye. Here, we introduce a unique platform of ocular drug delivery through the integration of silicon nanoneedles with a tear-soluble contact lens. The silicon nanoneedles can penetrate into the cornea in a minimally invasive manner and then undergo gradual degradation over the course of months, enabling painless and long-term sustained delivery of ocular drugs. The tear-soluble contact lens can fit a variety of corneal sizes and then quickly dissolve in tear fluid within a minute, enabling an initial burst release of anti-inflammatory drugs. We demonstrated the utility of this platform in effectively treating a chronic ocular disease, such as corneal neovascularization, in a rabbit model without showing a notable side effect over current standard therapies. This platform could also be useful in treating other chronic ocular diseases.

Molecular Characteristics and Distribution of Adult Human Corneal Immune Cell Types.

Background: The limbus is located at a 2-mm-wide area between the bulbar conjunctiva and the cornea and has been suggested to be the niche of corneal epithelial stem cells and immune cells. Like the skin and intestines, the cornea is also an important mucosal surface, and immune cells on the cornea play critical roles in immune surveillance to ensure barrier surface homeostasis and protection from various environmental damage and infections. Single-cell RNA sequencing (scRNA-seq) analysis of protein tyrosine phosphatase receptor type C positive (PTPRC+) hematopoietic cells from the corneal limbus could provide a single cell atlas of all the immune cell subsets. Methods: We performed single-cell RNA sequencing to generate transcriptomic profile for 804 sort-purified hematopoietic cells from the corneal limbus of three healthy donors. Results: Our analysis identified a primary transcriptomic pattern for multiple immune cell subtypes, including naive T cells, antiviral effector CD8+ T cells, and innate immune cells such as IDO1+ mature regulatory dendritic cells (mregDCs), macrophages, monocytes, and basophils in the human corneal limbus. Conclusion: Overall, single-cell transcriptomic analysis of limbal immune cells suggested the possible contribution of these cells on the adaptive and innate immune response of the human cornea.

Characterization and genomic analysis of a Demerecviridae phage SP76 with lytic multiple-serotypes of Salmonella.

With the increase in antimicrobial resistance of Salmonella, phages have been paid more attention to as an alternative to antibiotics. In this study, a phage designated as SP76 was isolated from sewage. It can lyse several serotypes of Salmonella, including S. typhimurium (21/33), S. enteritidis (7/7), S. dublin (4/4), S. pullorum (2/2) and S. choleraesuis (1/2). SP76 showed a latent time of about 10 min, and maintained good lytic activity at a pH range of 3-10 and temperatures between 4 and 37 °C. Moreover, its optimal multiplicity of infection (MOI) was 0.0001. Based on the results of genomic sequence and analysis, SP76 was found to have a genome of 111,639 bp that encoded 166 predicted ORFs and belong to the Demerecviridae family, order Caudovirales. No virulence or lysogen formation gene clusters were identified in the SP76 genome. A pan-genome analysis based on 100 phages within the subfamily Markadamsvirinae indicated that SP76 had 23 core genes and 1199 accessory genes. We grouped the subfamily Markadamsvirinae and found that the main difference was in group III. In vitro bacteriostasis, experiments showed that the phage SP76 reduced planktonic bacteria by 1.52 log10 CFU/mL, and biofilms (24 h old) by 0.372 log10 CFU/mL, respectively. Thus, we isolated a safe and efficient phage that might be a good antibacterial agent.

Prognostic Association Between Perioperative Red Blood Cell Transfusion and Postoperative Cardiac Surgery Outcomes.

Objective: To investigate the correlation between red blood cell transfusion and clinical outcome in patients after cardiac surgery. Methods: Demographic, clinical characteristics, treatment with/without transfusion, and outcomes of patients after cardiac surgery from the Medical Information Mart for Intensive Care-III database were collected. Patients were divided into two groups according to perioperative transfusion. A multivariable logistic regression analysis was utilized to adjust for the effect of red blood cell transfusion on outcomes for baseline and covariates and to determine its association with outcomes. Results: In total, 6,752 patients who underwent cardiac surgery were enrolled for the analysis. Among them, 2,760 (40.9%) patients received a perioperative transfusion. Compared with patients without red blood cell transfusion, transfused patients demonstrated worse outcomes in inhospital mortality, 1-year mortality, and all-cause mortality. Adjusting odds ratios (ORs) for the significant characteristic, patients with perioperative transfusion remained significantly associated with an increased risk of inhospital mortality [OR = 2.8, 95% confidence interval (CI) 1.5-5.1, P = 0.001], 1-year mortality (OR = 2.0, 95% CI 1.4-2.7, P < 0.001), and long-term mortality (OR = 2.2, 95% CI 1.8-2.8, P < 0.001). Conclusion: Perioperative red blood cell transfusion is associated with a worse prognosis of cardiac surgery patients. Optimal perioperative management and restricted transfusion strategy might be considered in selected patients.

In Vivo Subretinal ARPE-19 Cell Tracking Using Indocyanine Green Contrast-Enhanced Multimodality Photoacoustic Microscopy, Optical Coherence Tomography, and Fluorescence Imaging for Regenerative Medicine.

Purpose: Cell-based regenerative therapies are being investigated as a novel treatment method to treat currently incurable eye diseases, such as geographic atrophy in macular degeneration. Photoacoustic imaging is a promising technology which can visualize transplanted stem cells in vivo longitudinally over time in the retina. In this study, a US Food and Drug Administration (FDA)-approved indocyanine green (ICG) contrast agent is used for labeling and tracking cell distribution and viability using multimodal photoacoustic microscopy (PAM), optical coherence tomography (OCT), and fluorescence imaging. Methods: Twelve rabbits (2.4-3.4 kg weight, 2-4 months old) were used in the study. Human retinal pigment epithelial cells (ARPE-19) were labeled with ICG dye and transplanted in the subretinal space in the rabbits. Longitudinal PAM, OCT, and fluorescence imaging was performed for up to 28 days following subretinal administration of ARPE-19 cells. Results: Cell migration location, viability, and cell layer thickness were clearly recognized and determined from the fluorescence, OCT, and PAM signal. The in vivo results demonstrated that fluorescence signal increased 37-fold and PAM signal enhanced 20-fold post transplantation. Conclusions: This study demonstrates that ICG-assisted PAM, OCT, and fluorescence imaging can provide a unique platform for tracking ARPE-19 cells longitudinally with high resolution and high image contrast. Translational Relevance: Multimodal PAM, OCT, and fluorescence in vivo imaging with ICG can improve our understanding of the fate, distribution, and function of regenerative cell therapies over time nondestructively.

Nobiletin Attenuates Pathological Cardiac Remodeling after Myocardial Infarction via Activating PPARγ and PGC1α.

MATERIALS AND METHODS: C57BL/6 mice were treated with coronary artery ligation to generate an MI model, followed by treatment for 3 weeks with NOB (50 mg/kg/d) or vehicle (50 mg/kg/d), with or without the peroxisome proliferator-activated receptor gamma (PPARγ) inhibitor T0070907 (1 mg/kg/d). Cardiac function (echocardiography, survival rate, Evans blue, and triphenyl tetrazolium chloride staining), fibrosis (Masson's trichrome staining, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot (WB)), hypertrophy (haematoxylin-eosin staining, wheat germ agglutinin staining, and qRT-PCR), and apoptosis (WB and terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining) were evaluated. Hypoxia-induced apoptosis (TUNEL, WB) and phenylephrine- (PE-) induced pathological hypertrophy (immunofluorescence staining, qRT-PCR) models were established in primary neonatal rat ventricular myocytes (NRVMs). The effects of NOB with or without T0070907 were examined for the expression of PPARγ and PPARγ coactivator 1α (PGC1α) by WB in mice and NRVMs. The potential downstream effectors of PPARγ were further analyzed by WB in mice. RESULTS: Following MI in mice, NOB intervention enhanced cardiac function across three predominant dimensions of pathological cardiac remodeling, which reflected in decreasing cardiac fibrosis, apoptosis, and hypertrophy decompensation. NOB intervention also alleviated apoptosis and hypertrophy in NRVMs. NOB intervention upregulated PPARγ and PGC1α in vivo and in vitro. Furthermore, the PPARγ inhibitor abolished the protective effects of NOB against pathological cardiac remodeling during the progression from MI to CHF. The potential downstream effectors of PPARγ were nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1). CONCLUSIONS: Our findings suggested that NOB alleviates pathological cardiac remodeling after MI via PPARγ and PGC1α upregulation.