Endothelial and epithelial cells are morphologically different and play a critical role in host defense during Candida albicans infection. Both cells respond to C. albicans infection by activating various signaling pathways and gene expression patterns. Their interactions with these pathogens can have beneficial and detrimental effects, and a better understanding of these interactions can help guide the development of new therapies for C. albicans infection. To identify the differences and similarities between human endothelial and oral epithelial cell transcriptomics during C. albicans infection, we performed consensus WGCNA on 32 RNA-seq samples by relating the consensus modules to endothelial-specific modules and analyzing the genes connected. This analysis resulted in the identification of 14 distinct modules. We demonstrated that the magenta module correlates significantly with C. albicans infection in each dataset. In addition, we found that the blue and cyan modules in the two datasets had opposite correlation coefficients with a C. albicans infection. However, the correlation coefficients and p-values between the two datasets were slightly different. Functional analyses of the hub of genes from endothelial cells elucidated the enrichment in TNF, AGE-RAGE, MAPK, and NF-κB signaling. On the other hand, glycolysis, pyruvate metabolism, amino acid, fructose, mannose, and vitamin B6 metabolism were enriched in epithelial cells. However, mitophagy, necroptosis, apoptotic processes, and hypoxia were enriched in both endothelial and epithelial cells. Protein-protein interaction analysis using STRING and CytoHubba revealed STAT3, SNRPE, BIRC2, and NFKB2 as endothelial hub genes, while RRS1, SURF6, HK2, and LDHA genes were identified in epithelial cells. Understanding these similarities and differences may provide new insights into the pathogenesis of C. albicans infections and the development of new therapeutic targets and interventional strategies.

Kaposi\'s sarcoma (KS) is a rare, malignant, multilocular vascular disease originating from lymphatic endothelial cells that can primarily affect the skin and mucous membranes, but also the lymphatic system and internal organs such as the gastrointestinal tract, lungs or liver. Five epidemiological subtypes of KS with variable clinical course and prognosis are distinguished, with increased incidence in specific populations: (1) Classical KS, (2) Iatrogenic KS in immunosuppression, (3) Endemic (African) lymphadenopathic KS, (4) Epidemic, HIV-associated KS and KS associated with immune reconstitution inflammatory syndrome (IRIS), and (5) KS in men who have sex with men (MSM) without HIV infection. This interdisciplinary guideline summarizes current practice-relevant recommendations on diangostics and therapy of the different forms of KS. The recommendations mentioned in this short guideline are elaborated in more detail in the extended version of the guideline (online format of the JDDG).

There is an urgent need for a safe and effective vaccine against dengue virus (DENV) which infects about 390 million humans per year. In the present study we combined modifications of two DENV proteins, the nonstructural protein 1 (NS1) and the envelope (E) protein, to produce a DENV vaccine candidate with enhanced features. One of these modified proteins was a C-terminal-deleted fragment of NS1 called ΔC NS1 which we have shown previously to be protective without the potentially harmful effects of cross-reactive epitopes common to surface antigens on platelets and endothelial cells. The other modified protein was an envelope protein domain III (cEDIII) containing a consensus amino acid sequence among the four serotypes of DENV, which induces neutralizing antibody against all four DENV serotypes. The cEDIII and ΔC NS1 were expressed as a fusion protein cEDIII-ΔC NS1 and its protective effects against DENV were evaluated in a mouse model. C3H/HeN mice were immunized three times with cEDIII-ΔC NS1 fusion protein mixed with alum as adjuvant. Sera collected from cEDIII-ΔC NS1-immunized mice neutralized four serotypes of DENV and also caused complement-mediated cytolysis of HMEC-1 cells infected with each of the four different DENV serotypes. Mice immunized with cEDIII-ΔC NS1 and challenged with DENV showed reduced serum virus titer, soluble NS1 and bleeding time, compared with mice infected with DENV alone. The results reveal that antibodies induced by cEDIII-ΔC NS1 not only show anti-viral efficacy by in vitro assays but also provide protective effects against DENV infection in a mouse model. The cEDIII-ΔC NS1 thus represents a novel, effective DENV vaccine candidate.

Background Impaired endothelial function is thought to contribute to the increased cardiovascular risk associated with above-normal blood pressure (BP). However, the association between endothelial function and BP classified by 2017 American College of Cardiology/American Heart Association guidelines is unknown. Our objective was to determine if endothelial function decreases in midlife/older adults across the 2017 American College of Cardiology/American Heart Association guidelines BP classifications and identify associated mechanisms of action. Methods and Results A retrospective analysis of endothelial function (brachial artery flow-mediated dilation) from 988 midlife/older adults (aged 50+ years) stratified by BP status (normal BP; elevated BP; stage 1 hypertension; stage 2 hypertension) was performed. Endothelium-independent dilation (sublingual nitroglycerin), reactive oxygen species-mediated suppression of endothelial function (∆brachial artery flow-mediated dilation with vitamin C infusion), and endothelial cell and plasma markers of oxidative stress and inflammation were assessed in subgroups. Compared with normal BP (n=411), brachial artery flow-mediated dilation was 12% (P=0.04), 15% (P<0.01) and 20% (P<0.01) lower with elevated BP (n=173), stage 1 hypertension (n=248) and stage 2 hypertension (n=156), respectively, whereas endothelium-independent dilation did not differ (P=0.14). Vitamin C infusion increased brachial artery flow-mediated dilation in those with above-normal BP (P≤0.02) but not normal BP (P=0.11). Endothelial cell p47phox (P<0.01), a marker of superoxide/reactive oxygen species-generating nicotinamide adenine dinucleotide phosphate oxidase, and circulating interleukin-6 concentrations (P=0.01) were higher in individuals with above-normal BP. Conclusions Vascular endothelial function is progressively impaired with increasing BP in otherwise healthy adults classified by 2017 American College of Cardiology/American Heart Association guidelines. Impaired endothelial function with above-normal BP is mediated by excessive reactive oxygen species signaling associated with increased endothelial expression of nicotinamide adenine dinucleotide phosphate oxidase and circulating interleukin-6.

Sepsis is an ongoing conundrum and challenge in medical field. With the rapid development and progress of modern medicine, sepsis has been researched and explored in greater depth across different fields. Although \"Surviving Sepsis Campaign\" (SSC) has been taken to tackle sepsis in the world for years, its incidence and mortality stay high. According to the updated definition of sepsis stated in the current international guidelines, sepsis is defined as the infection-induced host response disorder, which further results in circulation and/or organ dysfunction. The original source of sepsis is infection, and it is a complicated pathophysiological process from infection to sepsis, which involves the invasion of pathogens, release of cytokines, capillary leakage, and microcirculation dysfunction, thus causing organ metabolism disorder and failure. As shown in Sepsis-3, the sepsis diagnosis standard is stipulated as infection plus sequential organ failure assessment (SOFA) score ≥ 2, and the tackling of sepsis mainly lies on the \"life-saving\" treatment regarding organ functions. After about 20 years\' efforts, SSC has not achieved satisfactory results. As a frontier discipline of acute and critical diseases, emergency medical department is able to receive and cure the patients with acute infection at the earliest. The incidence and mortality of sepsis could be greatly reduced if the possibility of sepsis can be predicted from population characteristics, pathogens and locations of infection, and severity of illness at the early stage of infection. Besides, timely discovering \"inflammation storm\" by cytokine detection and accessing the patients with an effective clinical scoring system should also be helpful to take more active and effective treatment to the high-risk patients, and block the progression from infection to sepsis. On such a basis, Chinese emergency medicine specialists have put forward the concept of \"prevention and blocking\" of sepsis, and carried out \"Preventing Sepsis Campaign in China\" (PSCC) throughout China. They have also proposed the principles of performing targeted diagnosis, examination and treatment at the \"early stage of sepsis\" and \"peri-sepsis period\", so as to realize the early prevention, early discovery, and early intervention, and reduce the morbidity and mortality of sepsis, thus providing a new concept for diagnosis and treatment of patients with acute severe infection. This consensus is jointly advocated, discussed and written by four academic societies (associations) and five related publishing houses, and formed after several turns of discussions by more than 40 specialists and experts from emergency medicine, critical medicine, infectious medicine, pharmacy, laboratory medicine, and other professional disciplines. This consensus involves determination and recognition of patients with acute infection, anti-infective therapy, screening of high-risk sepsis patients, discovery of and response to \"inflammation storm\", protection of vascular endothelial cells and regulation of coagulation function, liquid support scheme and organ function protection strategy, etc. This consensus summarizes the commonly used Western medical diagnosis and treatment measures, and also integrates the advantages of traditional Chinese medicine in prevention and treatment of sepsis, so as to provide a comprehensive reference for the clinicians to perform diagnosis and treatment, and provide a reliable basis for reducing progression of infected patients to sepsis.

Endothelial cells (ECs) are sentinels of cardiovascular health. Their function is reduced by the presence of cardiovascular risk factors, and is regained once pathological stimuli are removed. In this European Society for Cardiology Position Paper, we describe endothelial dysfunction as a spectrum of phenotypic states and advocate further studies to determine the role of EC subtypes in cardiovascular disease. We conclude that there is no single ideal method for measurement of endothelial function. Techniques to measure coronary epicardial and micro-vascular function are well established but they are invasive, time-consuming, and expensive. Flow-mediated dilatation (FMD) of the brachial arteries provides a non-invasive alternative but is technically challenging and requires extensive training and standardization. We, therefore, propose that a consensus methodology for FMD is universally adopted to minimize technical variation between studies, and that reference FMD values are established for different populations of healthy individuals and patient groups. Newer techniques to measure endothelial function that are relatively easy to perform, such as finger plethysmography and the retinal flicker test, have the potential for increased clinical use provided a consensus is achieved on the measurement protocol used. We recommend further clinical studies to establish reference values for these techniques and to assess their ability to improve cardiovascular risk stratification. We advocate future studies to determine whether integration of endothelial function measurements with patient-specific epigenetic data and other biomarkers can enhance the stratification of patients for differential diagnosis, disease progression, and responses to therapy.

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Childhood-onset pulmonary arterial hypertension (PAH) is considered complex and multifactorial, with relatively poor estimates of the natural history of the disease. Strategies allowing earlier detection, establishment of disease aetiology together with more accurate and sensitive biomarkers could enable better estimates of prognosis and individualise therapeutic strategies. Evidence is accumulating that genetic defects play an important role in the pathogenesis of idiopathic and hereditary forms of PAH. Altogether nine genes have been reported so far to be associated with childhood onset PAH suggesting that comprehensive multigene diagnostics can be useful in the assessment. Identification of disease-causing mutations allows estimates of prognosis and forms the most effective way for risk stratification in the family. In addition to genetic determinants the analysis of blood biomarkers are increasingly used in clinical practice to evaluate disease severity and treatment responses. As in genetic diagnostics, a multiplex approach can be helpful, as a single biomarker for PAH is unlikely to meet all requirements. This consensus statement reviews the current evidence for the use of genetic diagnostics and use of blood biomarkers in the assessment of paediatric patients with PAH.

The endothelial cells lining the brain capillaries separate the blood from the brain parenchyma. The endothelial monolayer of the brain capillaries serves both as a crucial interface for exchange of nutrients, gases, and metabolites between blood and brain, and as a barrier for neurotoxic components of plasma and xenobiotics. This \"blood-brain barrier\" function is a major hindrance for drug uptake into the brain parenchyma. Cell culture models, based on either primary cells or immortalized brain endothelial cell lines, have been developed, in order to facilitate in vitro studies of drug transport to the brain and studies of endothelial cell biology and pathophysiology. In this review, we aim to give an overview of established in vitro blood-brain barrier models with a focus on their validation regarding a set of well-established blood-brain barrier characteristics. As an ideal cell culture model of the blood-brain barrier is yet to be developed, we also aim to give an overview of the advantages and drawbacks of the different models described.

BACKGROUND: Scientists working in the field of xenotransplantation do not employ a uniform method to measure and report natural and induced antibody responses to non-Galα(1,3)Gal (non-Gal) epitopes. Such humoral responses are thought to be particularly pathogenic after transplantation of vascularized GalTKO pig organs and having a more uniform assay and reporting format would greatly facilitate comparisons between laboratories.
METHODS: Flow cytometry allows examination of antibody reactivity to intact antigens in their natural location and conformation on cell membranes. We have established a simple and reproducible flow cytometric assay to detect antibodies specific for non-Gal pig antigens using primary porcine aortic endothelial cells (pAECs) and cell culture-adapted pAEC cell lines generated from wild type and α1,3galactosyl transferase knockout (GalTKO) swine.
RESULTS: The consensus protocol we propose here is based on procedures routinely used in four xenotransplantation centers and was independently evaluated at three sites using shared cells and serum samples. Our observation support use of the cell culture-adapted GalTKO pAEC KO:15502 cells as a routine method to determine the reactivity of anti-non-Gal antibodies in human and baboon serum.
CONCLUSIONS: We have developed an assay that allows the detection of natural and induced non-Gal xenoreactive antibodies present in human or baboon serum in a reliable and consistent manner. This consensus assay and format for reporting the data should be accessible to laboratories and will be useful for assessing experimental results between multiple research centers. Adopting this assay and format for reporting the data should facilitate the detection, monitoring, and detailed characterization of non-Gal antibody responses.