Synthesis of Visible Light Excitable Carbon Dot Phosphor-Al2 O3 Hybrids for Anti-Counterfeiting and Information Encryption.

The preparation of room temperature phosphorescent carbon dots still faces great challenges, especially in the case of carbon dots endowed of visible-light excitable room temperature phosphorescence (RTP). To date, a limited number of substrates have been exploited to synthesize room temperature phosphorescent carbon dots, and most of them can emit RTP only in solid state. Here, the synthesis of a composite obtained from the calcination of green carbon dots (g-CDs) blended with aluminum hydroxide (Al(OH)3 ) is reported. The resultant hybrid material g-CDs@Al2 O3 exhibits blue fluorescence and green RTP emissions in an on/off switch process at 365 nm. Notably, this composite manifests strong resistance to extreme acid and basic conditions up to 30 days of treatment. The dense structure of Al2 O3 formed by calcination contributes to the phosphorescent emission of g-CDs. Surprisingly, g-CDs@Al2 O3 can also emit yellow RTP under irradiation with white light. The multicolor emissions can be employed for anti-counterfeiting and information encryption. This work provides a straightforward approach to produce room temperature phosphorescent carbon dots for a wide range of applications.

Benchmarking network-based gene prioritization methods for cerebral small vessel disease.

Network-based gene prioritization algorithms are designed to prioritize disease-associated genes based on known ones using biological networks of protein interactions, gene-disease associations (GDAs) and other relationships between biological entities. Various algorithms have been developed based on different mechanisms, but it is not obvious which algorithm is optimal for a specific disease. To address this issue, we benchmarked multiple algorithms for their application in cerebral small vessel disease (cSVD). We curated protein-gene interactions (PGIs) and GDAs from databases and assembled PGI networks and disease-gene heterogeneous networks. A screening of algorithms resulted in seven representative algorithms to be benchmarked. Performance of algorithms was assessed using both leave-one-out cross-validation (LOOCV) and external validation with MEGASTROKE genome-wide association study (GWAS). We found that random walk with restart on the heterogeneous network (RWRH) showed best LOOCV performance, with median LOOCV rediscovery rank of 185.5 (out of 19 463 genes). The GenePanda algorithm had most GWAS-confirmable genes in top 200 predictions, while RWRH had best ranks for small vessel stroke-associated genes confirmed in GWAS. In conclusion, RWRH has overall better performance for application in cSVD despite its susceptibility to bias caused by degree centrality. Choice of algorithms should be determined before applying to specific disease. Current pure network-based gene prioritization algorithms are unlikely to find novel disease-associated genes that are not associated with known ones. The tools for implementing and benchmarking algorithms have been made available and can be generalized for other diseases.

Ontology-driven and weakly supervised rare disease identification from clinical notes.

BACKGROUND: Computational text phenotyping is the practice of identifying patients with certain disorders and traits from clinical notes. Rare diseases are challenging to be identified due to few cases available for machine learning and the need for data annotation from domain experts. METHODS: We propose a method using ontologies and weak supervision, with recent pre-trained contextual representations from Bi-directional Transformers (e.g. BERT). The ontology-driven framework includes two steps: (i) Text-to-UMLS, extracting phenotypes by contextually linking mentions to concepts in Unified Medical Language System (UMLS), with a Named Entity Recognition and Linking (NER+L) tool, SemEHR, and weak supervision with customised rules and contextual mention representation; (ii) UMLS-to-ORDO, matching UMLS concepts to rare diseases in Orphanet Rare Disease Ontology (ORDO). The weakly supervised approach is proposed to learn a phenotype confirmation model to improve Text-to-UMLS linking, without annotated data from domain experts. We evaluated the approach on three clinical datasets, MIMIC-III discharge summaries, MIMIC-III radiology reports, and NHS Tayside brain imaging reports from two institutions in the US and the UK, with annotations. RESULTS: The improvements in the precision were pronounced (by over 30% to 50% absolute score for Text-to-UMLS linking), with almost no loss of recall compared to the existing NER+L tool, SemEHR. Results on radiology reports from MIMIC-III and NHS Tayside were consistent with the discharge summaries. The overall pipeline processing clinical notes can extract rare disease cases, mostly uncaptured in structured data (manually assigned ICD codes). CONCLUSION: The study provides empirical evidence for the task by applying a weakly supervised NLP pipeline on clinical notes. The proposed weak supervised deep learning approach requires no human annotation except for validation and testing, by leveraging ontologies, NER+L tools, and contextual representations. The study also demonstrates that Natural Language Processing (NLP) can complement traditional ICD-based approaches to better estimate rare diseases in clinical notes. We discuss the usefulness and limitations of the weak supervision approach and propose directions for future studies.

Effect of SAM junctional tourniquet on respiration when applied in the axilla: A swine model.

PURPOSE: SAM junctional tourniquet (SJT) has been applied to control junctional hemorrhage. However, there is limited information about its safety and efficacy when applied in the axilla. This study aims to investigate the effect of SJT on respiration when used in the axilla in a swine model. METHODS: Eighteen male Yorkshire swines, aged 6-month-old and weighing 55 - 72 kg, were randomized into 3 groups, with 6 in each. An axillary hemorrhage model was established by cutting a 2 mm transverse incision in the axillary artery. Hemorrhagic shock was induced by exsanguinating through the left carotid artery to achieve a controlled volume reduction of 30% of total blood volume. Vascular blocking bands were used to temporarily control axillary hemorrhage before SJT was applied. In Group I, the swine spontaneously breathed, while SJT was applied for 2 h with a pressure of 210 mmHg. In Group II, the swine were mechanically ventilated, and SJT was applied for the same duration and pressure as Group I. In Group III, the swine spontaneously breathed, but the axillary hemorrhage was controlled using vascular blocking bands without SJT compression. The amount of free blood loss was calculated in the axillary wound during the 2 h of hemostasis by SJT application or vascular blocking bands. After then, a temporary vascular shunt was performed in the 3 groups to achieve resuscitation. Pathophysiologic state of each swine was monitored for 1 h with an infusion of 400 mL of autologous whole blood and 500 mL of lactated ringer solution. Tb and T0 represent the time points before and immediate after the 30% volume-controlled hemorrhagic shock, respectively. T30, T60, T90 and T120, denote 30, 60, 90, and 120 min after T0 (hemostasis period), while T150, and T180 denote 150 and 180 min after T0 (resuscitation period). The mean arterial pressure and heart rate were monitored through the right carotid artery catheter. Blood samples were collected at each time point for the analysis of blood gas, complete cell count, serum chemistry, standard coagulation tests, etc., and thromboelastography was conducted subsequently. Movement of the left hemidiaphragm was measured by ultrasonography at Tb and T0 to assess respiration. Data were presented as mean ± standard deviation and analyzed using repeated measures of two-way analysis of variance with pairwise comparisons adjusted using the Bonferroni method. All statistical analyses were processed using GraphPad Prism software. RESULTS: Compared to Tb, a statistically significant increase in the left hemidiaphragm movement at T0 was observed in Groups I and II (both p < 0.001). In Group III, the left hemidiaphragm movement remained unchanged (p = 0.660). Compared to Group I, mechanical ventilation in Group II significantly alleviated the effect of SJT application on the left hemidiaphragm movement (p < 0.001). Blood pressure and heart rate rapidly increased at T0 in all three groups. Respiratory arrest suddenly occurred in Group I after T120, which required immediate manual respiratory assistance. PaO2 in Group I decreased significantly at T120, accompanied by an increase in PaCO2 (both p < 0.001 vs. Groups II and III). Other biochemical metabolic changes were similar among groups. However, in all 3 groups, lactate and potassium increased immediately after 1 min of resuscitation concurrent with a drop in pH. The swine in Group I exhibited the most severe hyperkalemia and metabolic acidosis. The coagulation function test did not show statistically significant differences among three groups at any time point. However, D-dimer levels showed a more than 16-fold increase from T120 to T180 in all groups. CONCLUSION: In the swine model, SJT is effective in controlling axillary hemorrhage during both spontaneous breathing and mechanical ventilation. Mechanical ventilation is found to alleviate the restrictive effect of SJT on thoracic movement without affecting hemostatic efficiency. Therefore, mechanical ventilation could be necessary before SJT removal.

Dual Photo-Responsive Diphenylacetylene Enables PET In-Situ Upcycling with Reverse Enhanced UV-Resistance and Strength.

A novel in situ chemical upcycling strategy for plastic waste is proposed by the customized diphenylacetylene monomer with dual photo-response. That is, diphenylacetylene reactive monomers are in situ inserted into the macromolecular chain of polyethylene terephthalate (PET) plastics/fibers through one-pot transesterification of slight-depolymerization and re-polymerization. On the one hand, the diphenylacetylene group absorbs short-wave high-energy UV rays and then releases long-wave low-energy harmless fluorescence. On the other hand, the UV-induced photo-crosslinking reaction among diphenylacetylene groups produces extended π-conjugated structure, resulting in a red-shift (due to decreased HOMO-LUMO separation) in the UV absorption band and locked crosslink points between PET chains. Therefore, with increasing UV exposure time, the upcycled PET plastics exhibit reverse enhanced UV resistance and mechanical strength (superior to original performance), instead of serious UV-photodegradation and damaged performance. This upcycling strategy at oligomer-scale not only provides a new idea for traditional plastic recycling, but also solves the common problem of gradual degradation of polymer performance during use.

Receptor activity-modifying protein 1 regulates mouse skin fibroblast proliferation via the Gαi3-PKA-CREB-YAP axis.

BACKGROUND: Skin innervation is crucial for normal wound healing. However, the relationship between nerve receptors and wound healing and the intrinsic mechanism remains to be further identified. In this study, we investigated the role of a calcitonin gene-related peptide (CGRP) receptor component, receptor activity-modifying protein 1 (RAMP1), in mouse skin fibroblast (MSF) proliferation. METHODS: In vivo, Western blotting and immunohistochemical (IHC) staining of mouse skin wounds tissue was used to detect changes in RAMP1 expression. In vitro, RAMP1 was overexpressed in MSF cell lines by infection with Tet-On-Flag-RAMP1 lentivirus and doxycycline (DOX) induction. An IncuCyte S3 Live-Cell Analysis System was used to assess and compare the proliferation rate differences between different treatment groups. Total protein and subcellular extraction Western blot analysis, quantitative real-time-polymerase chain reaction (qPCR) analysis, and immunofluorescence (IF) staining analysis were conducted to detect signalling molecule expression and/or distribution. The CUT & RUN assay and dual-luciferase reporter assay were applied to measure protein-DNA interactions. RESULTS: RAMP1 expression levels were altered during skin wound healing in mice. RAMP1 overexpression promoted MSF proliferation. Mechanistically, total Yes-associated protein (YAP) and nuclear YAP protein expression was increased in RAMP1-overexpressing MSFs. RAMP1 overexpression increased inhibitory guanine nucleotide-binding protein (G protein) α subunit 3 (Gαi3) expression and activated downstream protein kinase A (PKA), and both elevated the expression of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and activated it, promoting the transcription of YAP, elevating the total YAP level and promoting MSF proliferation. CONCLUSIONS: Based on these data, we report, for the first time, that changes in the total RAMP1 levels during wound healing and RAMP1 overexpression alone can promote MSF proliferation via the Gαi3-PKA-CREB-YAP axis, a finding critical for understanding RAMP1 function, suggesting that this pathway is an attractive and accurate nerve target for skin wound treatment. Video Abstract.

Molecular and morphological analyses clarify species delimitation in section Costatae and reveal Betula buggsii sp. nov. (sect. Costatae, Betulaceae) in China.

BACKGROUND AND AIMS: Delineating closely related and morphologically similar species is difficult. Here, we integrate morphology, genetics, ploidy and geography to resolve species and subspecies boundaries in four trees of section Costatae (genus Betula): Betula ashburneri, B. costata, B. ermanii and B. utilis, as well as multiple subspecies and polyploid races. METHODS: We genotyped 371 individuals (20-133 per species) from 51 populations at 15 microsatellite markers, as well as a subset of individuals, using restriction-site associated DNA sequencing and nuclear internal transcribed spacers. We determined the ploidy level of eight individuals using flow cytometry and characterized leaf variation for a subset of 109 individuals by morphometric analysis. KEY RESULTS: Integration of multiple lines of evidence suggested a series of revisions to the taxonomy of section Costatae. Betula costata and B. ermanii were found to be valid. Molecular and leaf morphology analyses revealed little differentiation between diploid B. albosinensis and some samples of B. utilis ssp. utilis. By contrast, other B. utilis ssp. utilis samples and ssp. albosinensis formed a morphological continuum but differed based on genetics. Specifically, B. utilis ssp. albosinensis was divided into two groups with group I genetically similar to B. utilis ssp. utilis and group II, a distinct cluster, proposed as the new diploid species Betula buggsii sp. nov. Phylogenomic analysis based on 2285 620 single nucleotide polymorphisms identified a well-supported monophyletic clade of B. buggsii. Morphologically, B. buggsii is characterized by elongated lenticels and a distinct pattern of bark peeling and may be geographically restricted to the Qinling-Daba Mountains. CONCLUSIONS: Our integrated approach identifies six taxa within section Costatae: B. ashburneri, B. buggsii, B. costata, B. utilis ssp. utilis, B. utilis ssp. albosinensis and B. ermanii. Our research demonstrates the value of an integrative approach using morphological, geographical, genetic and ploidy-level data for species delineation.

Towards Double Defense Network Security Based on Multi-Identifier Network Architecture.

Recently, more and more mobile devices have been connected to the Internet. The Internet environment is complicated, and network security incidents emerge endlessly. Traditional blocking and killing passive defense measures cannot fundamentally meet the network security requirements. Inspired by the heuristic establishment of multiple lines of defense in immunology, we designed and prototyped a Double Defense strategy with Endogenous Safety and Security (DDESS) based on multi-identifier network (MIN) architecture. DDESS adopts the idea of a zero-trust network, with identity authentication as the core for access control, which solves security problems of traditional IP networks. In addition, DDESS achieves individual static security defense through encryption and decryption, consortium blockchain, trusted computing whitelist, and remote attestation strategies. At the same time, with the dynamic collection of data traffic and access logs, as well as the understanding and prediction of the situation, DDESS can realize the situation awareness of network security and the cultivation of immune vaccines against unknown network attacks, thus achieving the active herd defense of network security.

Evaluation and improvement of the National Early Warning Score (NEWS2) for COVID-19: a multi-hospital study.

BACKGROUND: The National Early Warning Score (NEWS2) is currently recommended in the UK for the risk stratification of COVID-19 patients, but little is known about its ability to detect severe cases. We aimed to evaluate NEWS2 for the prediction of severe COVID-19 outcome and identify and validate a set of blood and physiological parameters routinely collected at hospital admission to improve upon the use of NEWS2 alone for medium-term risk stratification. METHODS: Training cohorts comprised 1276 patients admitted to King's College Hospital National Health Service (NHS) Foundation Trust with COVID-19 disease from 1 March to 30 April 2020. External validation cohorts included 6237 patients from five UK NHS Trusts (Guy's and St Thomas' Hospitals, University Hospitals Southampton, University Hospitals Bristol and Weston NHS Foundation Trust, University College London Hospitals, University Hospitals Birmingham), one hospital in Norway (Oslo University Hospital), and two hospitals in Wuhan, China (Wuhan Sixth Hospital and Taikang Tongji Hospital). The outcome was severe COVID-19 disease (transfer to intensive care unit (ICU) or death) at 14 days after hospital admission. Age, physiological measures, blood biomarkers, sex, ethnicity, and comorbidities (hypertension, diabetes, cardiovascular, respiratory and kidney diseases) measured at hospital admission were considered in the models. RESULTS: A baseline model of 'NEWS2 + age' had poor-to-moderate discrimination for severe COVID-19 infection at 14 days (area under receiver operating characteristic curve (AUC) in training cohort = 0.700, 95% confidence interval (CI) 0.680, 0.722; Brier score = 0.192, 95% CI 0.186, 0.197). A supplemented model adding eight routinely collected blood and physiological parameters (supplemental oxygen flow rate, urea, age, oxygen saturation, C-reactive protein, estimated glomerular filtration rate, neutrophil count, neutrophil/lymphocyte ratio) improved discrimination (AUC = 0.735; 95% CI 0.715, 0.757), and these improvements were replicated across seven UK and non-UK sites. However, there was evidence of miscalibration with the model tending to underestimate risks in most sites. CONCLUSIONS: NEWS2 score had poor-to-moderate discrimination for medium-term COVID-19 outcome which raises questions about its use as a screening tool at hospital admission. Risk stratification was improved by including readily available blood and physiological parameters measured at hospital admission, but there was evidence of miscalibration in external sites. This highlights the need for a better understanding of the use of early warning scores for COVID.

A renewed understanding of anti-human globulin reagents: interference constraints using an optimization method in pretransfusion compatibility tests.

Anti-human globulin (AHG) reagents are widely applied in pretransfusion compatibility tests. The accuracy of detection with AHG reagents is mainly affected by irregular antibodies or cold agglutinins in blood samples, which are related to the human complement system. Although much has been written about various types and applications of AHG reagents, their characteristics, interference factors and optimal selection in pretransfusion compatibility tests still need to be further clarified. Here, we review clinical practice and basic studies that describe each AHG reagent, summarize the advantages and disadvantages of using different AHG reagents in the presence of cold agglutinins or complement-fixing antibodies, explore the potential mechanisms by which the complement system influences detection with AHG reagents and address the question of how to optimally select AHG reagents for clinically significant antibody detection.

Management of non-compressible torso hemorrhage: An update.

With the widespread adoption of advanced tourniquets, the mortality rate of limb wound hemorrhage has decreased significantly, and non-compressible torso hemorrhage has gradually occupied the leading position of potentially preventable death, both in military and civilian circumstances. With the emergence of novel hemostatic devices and materials, strategies for the management of non-compressible torso hemorrhage have changed significantly. This review summarizes the current treatment strategies and types of equipment for non-compressible torso hemorrhage and suggests future research directions, hoping to provide a comprehensive review for the medical personnel and researchers engaging in this field.

Aberrant functional connectivity in resting state networks of ADHD patients revealed by independent component analysis.

BACKGROUND: ADHD is one of the most common psychiatric disorders in children and adolescents. Altered functional connectivity has been associated with ADHD symptoms. This study aimed to investigate abnormal changes in the functional connectivity of resting-state brain networks (RSNs) among adolescent patients with different subtypes of ADHD. METHODS: The data were obtained from the ADHD-200 Global Competition, including fMRI data from 88 ADHD patients (56 patients of ADHD-Combined, ADHD-C and 32 patients of ADHD-Inattentive, ADHD-I) and 67 typically developing controls (TD-C). Group ICA was utilized to research aberrant brain functional connectivity within the different subtypes of ADHD. RESULTS: In comparison with the TD-C group, the ADHD-C group showed clusters of decreased functional connectivity in the left inferior occipital gyrus (p = 0.0041) and right superior occipital gyrus (p = 0.0011) of the dorsal attention network (DAN), supplementary motor area (p = 0.0036) of the executive control network (ECN), left supramarginal gyrus (p = 0.0081) of the salience network (SN), middle temporal gyrus (p = 0.0041), and superior medial frontal gyrus (p = 0.0055) of the default mode network (DMN), while the ADHD-I group showed decreased functional connectivity in the right superior parietal gyrus (p = 0.0017) of the DAN and left middle temporal gyrus (p = 0.0105) of the DMN. In comparison with the ADHD-I group, the ADHD-C group showed decreased functional connectivity in the superior temporal gyrus (p = 0.0062) of the AN, inferior temporal gyrus (p = 0.0016) of the DAN, and the dorsolateral superior frontal gyrus (p = 0.0082) of the DMN. All the clusters surviving at p < 0.05 (AlphaSim correction). CONCLUSION: The results suggested that decreased functional connectivity within the DMN and DAN was responsible, at least in part, for the symptom of inattention in ADHD-I patients. Similarly, we believed that the impaired functional connectivity within networks may contribute to the manifestations of ADHD-C patients, including inattention, hyperactivity/impulsivity, and unconscious movements.

CD271 promotes STZ-induced diabetic wound healing and regulates epidermal stem cell survival in the presence of the pTrkA receptor.

Diabetes mellitus (DM) often causes delayed wound healing in patients, which can lead to limb loss, disability, and even death. Many conventional therapeutic strategies have been proposed, but there is still no effective therapy for DM wounds. This study aimed to explore the effects of CD271 and phosphorylated tyrosine kinase receptor A (pTrkA) on the migration and proliferation abilities of epidermal stem cells (eSCs) and on the activation of DM wound healing. We investigated the interventional effects of CD271-overexpressing eSC (CD271 eSC) treatment and pTrkA inhibition (through k252a treatment) on delayed wound healing using mice with streptozotocin-induced DM. The migration and proliferation abilities of control eSCs, CD271 eSCs, and k252a-treated CD271 eSCs were observed under high-glucose conditions. Decreases in CD271 and increases in pTrkA were observed in DM mouse skin compared with control mouse skin; in addition, the rate of wound closure in DM mice was promoted by CD271 eSC treatment but delayed by pTrkA inhibition. Furthermore, the CD271 eSC migration and proliferation were greater than of control eSCs. Compared with that of CD271 eSCs, the number of CD271+k252a eSCs decreased significantly under high-glucose conditions. In parallel, the expression levels of the pERK, pAkt, and pJNK pathways increased in CD271 eSCs and decreased in CD271+k252a eSCs under high glucose. Our findings demonstrate that CD271 and pTrkA affect DM wound closure by promoting the eSC migration and proliferation. This mechanism involving the pERK, pAkt, and pJNK pathways might be a new therapeutic target for the treatment of delayed wound re-epithelialization in DM.

Aberrant gray matter volumes and functional connectivity in adolescent patients with ADHD.

BACKGROUND: Altered gray matter (GM) volumes and functional connectivity (FC) happens in attention-deficit/hyperactivity disorder (ADHD) patients and the intelligence quotient (IQ) of ADHD patients is generally lower than healthy subjects, while few studies have focused on the association among the three. PURPOSE: To investigate the abnormal changes of GM volumes and FC in ADHD patients compared with typically-developing control (TD-C), as well as the association between the changes and IQ. STUDY TYPE: Case control. POPULATION: 36 ADHD patients and 36 TD-C, aged 8-17. FIELD STRENGTH/SEQUENCE: 3.0T/single shot echo planar imaging (EPI). ASSESSMENT: Preprocessing of fMRI data and seed-based FC calculation using DPABI4.0, and VBM was performed by CAT12. STATISTICAL TESTS: Comparison between groups of smoothed GM volumes was performed using two-sample t-test within SPM 12, age and total intracranial volume (TIV) were returned as covariates. Comparison between groups of FCs was performed using a two-sample t-test within RESTplus; age was returned as a covariate. False discovery rate (FDR)-corrected and P < 0.05 was considered statistically significant. RESULTS: Compared with TD-C, reduced GM volumes occurred in the left superior frontal gyrus (t = -3.61, P < 0.001), right middle frontal gyrus (t = -3.97, P < 0.001), left middle cingulum (t = -3.93, P < 0.001), and left cuneus (t = -4.42, P < 0.001). Decreased FC was found between the left precuneus and left middle cingulum (t = -5.86, P < 0.001), left middle temporal gyrus, and left superior frontal gyrus (t = -5.67, P < 0.001), as well as left medial superior frontal gyrus and left superior frontal gyrus (t = -6.73, P < 0.001). DATA CONCLUSION: The results confirmed that FCs between the regions with declined GM volumes and others were altered in ADHD patients. We speculated that abnormal changes of GM volume and FC maybe used as an imaging metric of ADHD. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2020;51:719-726.

High-performance mesoporous γ-Fe2O3 sphere/graphene aerogel composites towards enhanced lithium storage.

Transition metal oxides have recently been demonstrated as highly attractive anodes for high-capacity lithium ion batteries, whose electrochemical properties could be further improved through rational architecture design and incorporating reliable conductive network. Herein, mesoporous γ-Fe2O3 spheres/graphene aerogel composites were synthesized via a solvothermal pathway followed by suitable annealing. Experimental results reveal the uniform mesoporous structure and well-dispersed γ-Fe2O3 spheres with the size of 300-400 nm embedded in the mesopores of the graphene aerogel network. Compared with α-Fe2O3/graphene aerogel and pure γ-Fe2O3, the as-synthesized composite delivers, at the first cycle, a high discharging capacity of 1080 mAh g-1 at current density of 200 mA g-1. Even at much higher current density of 8000 mA g-1, satisfactory discharging capacities of 421.5 mAh g-1 can still be achieved. Upon 100 charging-discharging cycles, the specific capacity of as high as 890.5 mAh g-1 at 200 mA g-1 is maintained. The enhanced electrochemical properties could be attributed to their favorable three-dimensional graphene aerogel network, which accounts for the improved structural stability and electronic conductivity of γ-Fe2O3 during the lithiation/delithiation process.

Ephs and Ephrins in Adult Endothelial Biology.

Eph receptors and their ephrin ligands are important guidance molecules during neurological and vascular development. In recent years, it has become clear that the Eph protein family remains functional in adult physiology. A subset of Ephs and ephrins is highly expressed by endothelial cells. As endothelial cells form the first barrier between the blood and surrounding tissues, maintenance of a healthy endothelium is crucial for tissue homeostasis. This review gives an overview of the current insights of the role of ephrin ligands and receptors in endothelial function and leukocyte recruitment in the (patho)physiology of adult vascular biology.

Endothelial Semaphorin 3F Maintains Endothelial Barrier Function and Inhibits Monocyte Migration.

In normal physiology, endothelial cells (ECs) form a vital barrier between the blood and underlying tissue controlling leukocyte diapedesis and vascular inflammation. Emerging data suggest that neuronal guidance cues, typically expressed during development, have roles outside the nervous system in vascular biology and immune responses. In particular, Class III semaphorins have been reported to affect EC migration and angiogenesis. While ECs express high levels of semaphorin 3F (SEMA3F), little is known about its function in mature ECs. Here we show that SEMA3F expression is reduced by inflammatory stimuli and increased by laminar flow. Endothelial cells exposed to laminar flow secrete SEMA3F, which subsequently binds to heparan sulfates on the surface of ECs. However, under pro-inflammatory conditions, reduced levels of SEMA3F make ECs more prone to monocyte diapedesis and display impaired barrier function as measured with an electric cell-substrate impedance sensing system and a microfluidic system. In addition, we demonstrate that SEMA3F can directly inhibit the migration of activated monocytes. Taken together, our data suggest an important homeostatic function for EC-expressed SEMA3F, serving as a mediator of endothelial quiescence.

Prediction Power on Cardiovascular Disease of Neuroimmune Guidance Cues Expression by Peripheral Blood Monocytes Determined by Machine-Learning Methods.

Atherosclerosis is the underlying pathology in a major part of cardiovascular disease, the leading cause of mortality in developed countries. The infiltration of monocytes into the vessel walls of large arteries is a key denominator of atherogenesis, making monocytes accountable for the development of atherosclerosis. With the development of high-throughput transcriptome profiling platforms and cytometric methods for circulating cells, it is now feasible to study in-depth the predicted functional change of circulating monocytes reflected by changes of gene expression in certain pathways and correlate the changes to disease outcome. Neuroimmune guidance cues comprise a group of circulating- and cell membrane-associated signaling proteins that are progressively involved in monocyte functions. Here, we employed the CIRCULATING CELLS study cohort to classify cardiovascular disease patients and healthy individuals in relation to their expression of neuroimmune guidance cues in circulating monocytes. To cope with the complexity of human datasets featured by noisy data, nonlinearity and multidimensionality, we assessed various machine-learning methods. Of these, the linear discriminant analysis, Naïve Bayesian model and stochastic gradient boost model yielded perfect or near-perfect sensibility and specificity and revealed that expression levels of the neuroimmune guidance cues SEMA6B, SEMA6D and EPHA2 in circulating monocytes were of predictive values for cardiovascular disease outcome.

Vascular Semaphorin 7A Upregulation by Disturbed Flow Promotes Atherosclerosis Through Endothelial ß1 Integrin.

OBJECTIVE: Accumulating evidence suggests a role of semaphorins in vascular homeostasis. Here, we investigate the role of Sema7A (semaphorin 7A) in atherosclerosis and its underlying mechanism. APPROACH AND RESULTS: Using genetically engineered Sema7A-/-ApoE-/- mice, we showed that deletion of Sema7A attenuates atherosclerotic plaque formation primarily in the aorta of ApoE-/- mice on a high-fat diet. A higher level of Sema7A in the atheroprone lesser curvature suggests a correlation of Sema7A with disturbed flow. This notion is supported by elevated Sema7A expression in human umbilical venous endothelial cells either subjected to oscillatory shear stress or treated with the PKA (protein kinase A)/CREB (cAMP response element-binding protein) inhibitor H89 (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide·2HCl hydrate). Further studies using the partial carotid artery ligation model showed that disturbed flow in the left carotid artery of Sema7A+/+ApoE-/- mice promoted the expression of endothelial Sema7A and cell adhesion molecules, leukocyte adhesion, and plaque formation, whereas such changes were attenuated in Sema7A-/-ApoE-/- mice. Further studies showed that blockage of ß1 integrin, a known Sema7A receptor, or inhibition of FAK (focal adhesion kinase), MEK1/2 (mitogen-activated protein kinase kinase 1/2), or NF-κB (nuclear factor-κB) significantly reduced the expression of cell adhesion molecules and THP-1 (human acute monocytic leukemia cell line) monocyte adhesion in Sema7A-overexpressing human umbilical venous endothelial cells. Studies using chimeric mice suggest that vascular, most likely endothelial, Sema7A plays a major role in atherogenesis. CONCLUSIONS: Our findings indicate a significant role of Sema7A in atherosclerosis by mediating endothelial dysfunction in a ß1 integrin-dependent manner.

Understanding netrins and semaphorins in mature endothelial cell biology.

Netrins and semaphorins are known as neuronal guidance molecules that are important to the facilitate patterning of the nervous system in embryonic development. In recent years, their function has been broadened to guide development in other systems, including the vascular system, where netrins and semaphorins critically contribute to the development of the vascular system. Evidence is accumulating that these guidance cues are also of critical importance in the biology of the mature endothelium by regulating the maintenance of endothelial quiescence. Here we review our current insights into the roles of netrins and semaphorins in endothelial cell survival, self-renewing, barrier function, response to wall shear stress, and control of the vascular tone. We also provide suggestions for future research into the functions of netrins and semaphorins in mature endothelial cell biology.