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12 pages, 1226 KiB

Open AccessArticle

Biomarkers for Non-Invasive Stratification of Coronary Artery Disease and Prognostic Impact on Long-Term Survival in Patients with Stable Coronary Heart Disease

by Jeffrey Netto, Andrej Teren, Ralph Burkhardt, Anja Willenberg, Frank Beutner, Sylvia Henger, Gerhard Schuler, Holger Thiele, Berend Isermann, Joachim Thiery, Markus Scholz and Thorsten Kaiser

Nutrients 2022, 14(16), 3433; https://doi.org/10.3390/nu14163433 - 20 Aug 2022

Cited by 5 | Viewed by 1851

Abstract

Knowledge about cardiac and inflammatory biomarkers in patients with stable coronary artery disease (CAD) is limited. To address this, we analyzed 3072 patients (36% female) with a median follow-up of 10 years in the Leipzig LIFE Heart Study with suspected CAD with coronary [...] Read more.

Knowledge about cardiac and inflammatory biomarkers in patients with stable coronary artery disease (CAD) is limited. To address this, we analyzed 3072 patients (36% female) with a median follow-up of 10 years in the Leipzig LIFE Heart Study with suspected CAD with coronary angiography. Selected biomarkers included troponin T (hsTNT), N-terminal pro B-type natriuretic peptide (NT-proBNP), copeptin, C-reactive protein (hsCRP), and interleukin-6 (IL-6). Patients were stratified by CAD severity: CAD0 (no sclerosis), CAD1 (non-obstructive, i.e., stenosis < 50%), and CAD2 (≥one stenosis ≥ 50%). Group comparison (GC) included GC1: CAD0 + 1 vs. CAD2; GC2: CAD0 vs. CAD1 + 2. CAD0, CAD1, and CAD2 were apparent in 1271, 631, and 1170 patients, respectively. Adjusted for classical risk factors, hs-cTnT, NT-proBNP, and IL-6 differed significantly in both GC and hsCRP only in GC2. After multivariate analysis, hs-cTnT, NT-proBNP, and IL-6 remained significant in GC1. In GC2, hs-cTnT (p < 0.001) and copeptin (p = 0.014) reached significance. Ten-year survival in groups CAD0, CAD1, and CAD2 was 88.3%, 77.3%, and 72.4%. Incorporation of hs-cTnT, NT-proBNP, copeptin, and IL-6 improved risk prediction (p < 0.001). The studied cardiac and inflammatory biomarkers enable fast and precise non-invasive identification of mortality risk in CAD patients, allowing the tailoring of primary and secondary CAD prevention. Full article

(This article belongs to the Special Issue Nutrition and Vascular Disease)

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14 pages, 1083 KiB

Open AccessArticle

Influence of Trimethylamine N-Oxide on Platelet Activation

by Julian Josef Emonds, Clemens Ringel, Madlen Reinicke, Daniel Müller, Arnold Von Eckardstein, Jürgen Meixensberger, Uta Ceglarek and Alexander Gaudl

Nutrients 2022, 14(16), 3261; https://doi.org/10.3390/nu14163261 - 10 Aug 2022

Cited by 4 | Viewed by 1869

Abstract

Microbiome-derived trimethylamine N-oxide (TMAO) has been associated with platelet hyperreactivity and subsequent atherogenesis. Whether physiological TMAO-levels influence platelet-derived lipid mediators remains unknown. Little is known about pre-analytic factors potentially influencing TMAO concentrations. We aimed at developing a quantitative LC-MS/MS method to investigate [...] Read more.

Microbiome-derived trimethylamine N-oxide (TMAO) has been associated with platelet hyperreactivity and subsequent atherogenesis. Whether physiological TMAO-levels influence platelet-derived lipid mediators remains unknown. Little is known about pre-analytic factors potentially influencing TMAO concentrations. We aimed at developing a quantitative LC-MS/MS method to investigate in-vivo and in-vitro pre-analytical factors in TMAO analysis to properly assess the proposed activating effect of TMAO on platelets. TMAO, betaine, carnitine, and choline were analyzed by HILIC-ESI-MS/MS within 6 min total run time. Method validation included investigation of reproducibility, recovery, sensitivity, and in-vitro pre-analytical factors. A 24-h monitoring experiment was performed, evaluating in-vivo pre-analytical factors like daytime or diet. Finally, the effects of different TMAO concentrations on platelet activation and corresponding alterations of platelet-derived eicosanoid release were analyzed. The method showed high reproducibility (CVs ≤ 5.3%), good recovery rates (96–98%), and negligible in-vitro pre-analytical effects. The influence of in-vivo pre-analytical factors on TMAO levels was not observable within the applied experimental conditions. We did not find any correlation between TMAO levels and platelet activation at physiological TMAO concentrations, whereas platelet-derived eicosanoids presented activation of the cyclooxygenase and lipoxygenase pathways. In contrast to previously published results, we did not find any indications regarding diet dependency or circadian rhythmicity of TMAO levels. Our results do not support the hypothesis that TMAO increases platelet responsiveness via the release of lipid-mediators. Full article

(This article belongs to the Special Issue Nutrition and Vascular Disease)

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17 pages, 2291 KiB

Open AccessArticle

Activated Protein C Ameliorates Tubular Mitochondrial Reactive Oxygen Species and Inflammation in Diabetic Kidney Disease

by Rajiv Rana, Jayakumar Manoharan, Anubhuti Gupta, Dheerendra Gupta, Ahmed Elwakiel, Hamzah Khawaja, Sameen Fatima, Silke Zimmermann, Kunal Singh, Saira Ambreen, Ihsan Gadi, Ronald Biemann, Shihai Jiang, Khurrum Shahzad, Shrey Kohli and Berend Isermann

Nutrients 2022, 14(15), 3138; https://doi.org/10.3390/nu14153138 - 29 Jul 2022

Cited by 4 | Viewed by 1968

Abstract

Diabetic kidney disease (DKD) is an emerging pandemic, paralleling the worldwide increase in obesity and diabetes mellitus. DKD is now the most frequent cause of end-stage renal disease and is associated with an excessive risk of cardiovascular morbidity and mortality. DKD is a [...] Read more.

Diabetic kidney disease (DKD) is an emerging pandemic, paralleling the worldwide increase in obesity and diabetes mellitus. DKD is now the most frequent cause of end-stage renal disease and is associated with an excessive risk of cardiovascular morbidity and mortality. DKD is a consequence of systemic endothelial dysfunction. The endothelial-dependent cytoprotective coagulation protease activated protein C (aPC) ameliorates glomerular damage in DKD, in part by reducing mitochondrial ROS generation in glomerular cells. Whether aPC reduces mitochondrial ROS generation in the tubular compartment remains unknown. Here, we conducted expression profiling of kidneys in diabetic mice (wild-type and mice with increased plasma levels of aPC, APC^high mice). The top induced pathways were related to metabolism and in particular to oxidoreductase activity. In tubular cells, aPC maintained the expression of genes related to the electron transport chain, PGC1-α expression, and mitochondrial mass. These effects were associated with reduced mitochondrial ROS generation. Likewise, NLRP3 inflammasome activation and sterile inflammation, which are known to be linked to excess ROS generation in DKD, were reduced in diabetic APC^high mice. Thus, aPC reduces mitochondrial ROS generation in tubular cells and dampens the associated renal sterile inflammation. These studies support approaches harnessing the cytoprotective effects of aPC in DKD. Full article

(This article belongs to the Special Issue Nutrition and Vascular Disease)

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14 pages, 1267 KiB

Open AccessArticle

The Extent of Lifestyle-Induced Weight Loss Determines the Risk of Prediabetes and Metabolic Syndrome Recurrence during a 5-Year Follow-Up

by Silke Zimmermann, Mandy Vogel, Akash Mathew, Thomas Ebert, Rajiv Rana, Shihai Jiang, Berend Isermann and Ronald Biemann

Nutrients 2022, 14(15), 3060; https://doi.org/10.3390/nu14153060 - 26 Jul 2022

Cited by 1 | Viewed by 1723

Abstract

It is controversial whether lifestyle-induced weight loss (LIWL) intervention provides long-term benefit. Here, we investigated whether the degree of weight loss (WL) in a controlled LIWL intervention study determined the risk of prediabetes and recurrence of metabolic syndrome (MetS) during a 5-year follow-up. [...] Read more.

It is controversial whether lifestyle-induced weight loss (LIWL) intervention provides long-term benefit. Here, we investigated whether the degree of weight loss (WL) in a controlled LIWL intervention study determined the risk of prediabetes and recurrence of metabolic syndrome (MetS) during a 5-year follow-up. Following LIWL, 58 male participants (age 45–55 years) were divided into four quartiles based on initial WL: Q1 (WL 0–8.1%, n = 15), Q2 (WL 8.1–12.8%, n = 14), Q3 (WL 12.8–16.0%, n = 14), and Q4 (WL 16.0–27.5%, n = 15). We analyzed changes in BMI, HDL cholesterol, triglycerides (TGs), blood pressure, and fasting plasma glucose (FPG) at annual follow-up visits. With a weight gain after LIWL between 1.2 (Q2) and 2.5 kg/year (Q4), the reduction in BMI was maintained for 4 (Q2, p = 0.03) or 5 (Q3, p = 0.03; Q4, p < 0.01) years, respectively, and an increase in FPG levels above baseline values was prevented in Q2–Q4. Accordingly, there was no increase in prediabetes incidence after LIWL in participants in Q2 (up to 2 years), Q3 and Q4 (up to 5 years). A sustained reduction in MetS was maintained in Q4 during the 5-year follow-up. The present data indicate that a greater initial LIWL reduces the risk of prediabetes and recurrence of MetS for up to 5 years. Full article

(This article belongs to the Special Issue Nutrition and Vascular Disease)

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11 pages, 1554 KiB

Open AccessArticle

Dietary PUFA Preferably Modify Ethanolamine-Containing Glycerophospholipids of the Human Plasma Lipidome

by Christine Dawczynski, Johannes Plagge, Gerhard Jahreis, Gerhard Liebisch, Marcus Höring, Claudine Seeliger and Josef Ecker

Nutrients 2022, 14(15), 3055; https://doi.org/10.3390/nu14153055 - 26 Jul 2022

Cited by 3 | Viewed by 1763

Abstract

The content of polyunsaturated fatty acids (PUFA) in complex lipids essentially influences their physicochemical properties and has been linked to health and disease. To investigate the incorporation of dietary PUFA in the human plasma lipidome, we quantified glycerophospholipids (GPL), sphingolipids, and sterols using [...] Read more.

The content of polyunsaturated fatty acids (PUFA) in complex lipids essentially influences their physicochemical properties and has been linked to health and disease. To investigate the incorporation of dietary PUFA in the human plasma lipidome, we quantified glycerophospholipids (GPL), sphingolipids, and sterols using electrospray ionization coupled to tandem mass spectrometry of plasma samples obtained from a dietary intervention study. Healthy individuals received foods supplemented with different vegetable oils rich in PUFA. These included sunflower, linseed, echium, and microalgae oil as sources of linoleic acid (LA; FA 18:2 n-6), alpha-linolenic acid (ALA; FA 18:3 n-3), stearidonic acid (SDA; FA 18:4 n-3), and docosahexaenoic acid (DHA; FA 22:6 n-3). While LA and ALA did not influence the species profiles of GPL, sphingolipid, and cholesteryl ester drastically, SDA and DHA were integrated primarily in ethanolamine-containing GPL. This significantly altered phosphatidylethanolamine and plasmalogen species composition, especially those with 38–40 carbons and 6 double bonds. We speculate that diets enriched with highly unsaturated FA more efficiently alter plasma GPL acyl chain composition than those containing primarily di- and tri-unsaturated FA, most likely because of their more pronounced deviation of FA composition from typical western diets. Full article

(This article belongs to the Special Issue Nutrition and Vascular Disease)

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15 pages, 2559 KiB

Open AccessArticle

Neutrophil Extracellular Traps Promote NLRP3 Inflammasome Activation and Glomerular Endothelial Dysfunction in Diabetic Kidney Disease

by Anubhuti Gupta, Kunal Singh, Sameen Fatima, Saira Ambreen, Silke Zimmermann, Ruaa Younis, Shruthi Krishnan, Rajiv Rana, Ihsan Gadi, Constantin Schwab, Ronald Biemann, Khurrum Shahzad, Vibha Rani, Shakir Ali, Peter Rene Mertens, Shrey Kohli and Berend Isermann

Nutrients 2022, 14(14), 2965; https://doi.org/10.3390/nu14142965 - 20 Jul 2022

Cited by 19 | Viewed by 3832 | Correction

Abstract

Diabetes mellitus is a metabolic disease largely due to lifestyle and nutritional imbalance, resulting in insulin resistance, hyperglycemia and vascular complications. Diabetic kidney disease (DKD) is a major cause of end-stage renal failure contributing to morbidity and mortality worldwide. Therapeutic options to prevent [...] Read more.

Diabetes mellitus is a metabolic disease largely due to lifestyle and nutritional imbalance, resulting in insulin resistance, hyperglycemia and vascular complications. Diabetic kidney disease (DKD) is a major cause of end-stage renal failure contributing to morbidity and mortality worldwide. Therapeutic options to prevent or reverse DKD progression are limited. Endothelial and glomerular filtration barrier (GFB) dysfunction and sterile inflammation are associated with DKD. Neutrophil extracellular traps (NETs), originally identified as an innate immune mechanism to combat infection, have been implicated in sterile inflammatory responses in non-communicable diseases. However, the contribution of NETs in DKD remains unknown. Here, we show that biomarkers of NETs are increased in diabetic mice and diabetic patients and that these changes correlate with DKD severity. Mechanistically, NETs promote NLRP3 inflammasome activation and glomerular endothelial dysfunction under high glucose stress in vitro and in vivo. Inhibition of NETs (PAD4 inhibitor) ameliorate endothelial dysfunction and renal injury in DKD. Taken together, NET-induced sterile inflammation promotes diabetes-associated endothelial dysfunction, identifying a new pathomechanism contributing to DKD. Inhibition of NETs may be a promising therapeutic strategy in DKD. Full article

(This article belongs to the Special Issue Nutrition and Vascular Disease)

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15 pages, 3119 KiB

Open AccessArticle

ER-Stress and Senescence Coordinately Promote Endothelial Barrier Dysfunction in Diabetes-Induced Atherosclerosis

by Sameen Fatima, Saira Ambreen, Akash Mathew, Ahmed Elwakiel, Anubhuti Gupta, Kunal Singh, Shruthi Krishnan, Rajiv Rana, Hamzah Khawaja, Dheerendra Gupta, Jayakumar Manoharan, Christian Besler, Ulrich Laufs, Shrey Kohli, Berend Isermann and Khurrum Shahzad

Nutrients 2022, 14(14), 2786; https://doi.org/10.3390/nu14142786 - 06 Jul 2022

Cited by 6 | Viewed by 2272

Abstract

Diabetes mellitus is hallmarked by accelerated atherosclerosis, a major cause of mortality among patients with diabetes. Efficient therapies for diabetes-associated atherosclerosis are absent. Accelerated atherosclerosis in diabetic patients is associated with reduced endothelial thrombomodulin (TM) expression and impaired activated protein C (aPC) generation. [...] Read more.

Diabetes mellitus is hallmarked by accelerated atherosclerosis, a major cause of mortality among patients with diabetes. Efficient therapies for diabetes-associated atherosclerosis are absent. Accelerated atherosclerosis in diabetic patients is associated with reduced endothelial thrombomodulin (TM) expression and impaired activated protein C (aPC) generation. Here, we directly compared the effects of high glucose and oxidized LDL, revealing that high glucose induced more pronounced responses in regard to maladaptive unfolded protein response (UPR), senescence, and vascular endothelial cell barrier disruption. Ex vivo, diabetic ApoE^−/− mice displayed increased levels of senescence and UPR markers within atherosclerotic lesions compared with nondiabetic ApoE^−/− mice. Activated protein C pretreatment maintained barrier permeability and prevented glucose-induced expression of senescence and UPR markers in vitro. These data suggest that high glucose-induced maladaptive UPR and associated senescence promote vascular endothelial cell dysfunction, which—however—can be reversed by aPC. Taken together, current data suggest that reversal of glucose-induced vascular endothelial cell dysfunction is feasible. Full article

(This article belongs to the Special Issue Nutrition and Vascular Disease)

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10 pages, 895 KiB

Open AccessArticle

Simultaneous Mass Spectrometry-Based Apolipoprotein Profiling and Apolipoprotein E Phenotyping in Patients with ASCVD and Mild Cognitive Impairment

by Ilijana Begcevic Brkovic, Benedikt Zöhrer, Markus Scholz, Madlen Reinicke, Julia Dittrich, Surab Kamalsada, Ronny Baber, Frank Beutner, Andrej Teren, Christoph Engel, Kerstin Wirkner, Holger Thiele, Markus Löffler, Steffi G. Riedel-Heller and Uta Ceglarek

Nutrients 2022, 14(12), 2474; https://doi.org/10.3390/nu14122474 - 15 Jun 2022

Cited by 5 | Viewed by 1895

Abstract

Apolipoprotein E (apoE) occurs on the majority of plasma lipoproteins and plays a major role in the lipid metabolism in the periphery and in the central nervous system. ApoE is a polymorphic protein with three common isoforms, apoE2, apoE3 and apoE4, derived from [...] Read more.

Apolipoprotein E (apoE) occurs on the majority of plasma lipoproteins and plays a major role in the lipid metabolism in the periphery and in the central nervous system. ApoE is a polymorphic protein with three common isoforms, apoE2, apoE3 and apoE4, derived from respective alleles ε2, ε3 and ε4. The aim of this study was to develop a sample pretreatment protocol combined with rapid mass spectrometry (MS)-based assay for simultaneous apolipoprotein profiling and apoE phenotype identification. This assay was validated in 481 samples from patients with stable atherosclerotic cardiovascular disease (ASCVD) and applied to study association with mild cognitive impairment (MCI) in the LIFE Adult study, including overall 690 study subjects. Simultaneous quantification of 8–12 major apolipoproteins including apoA-I, apoB-100 and apoE could be performed within 6.5 min. Phenotyping determined with the developed MS assay had good agreement with the genotyping by real-time fluorescence PCR (97.5%). ApoE2 isoform was associated with the highest total apoE concentration compared to apoE3 and apoE4 (p < 0.001). In the subgroup of diabetic atherosclerotic cardiovascular disease (ASCVD) patients, apoE2 isoform was related to higher apoC-I levels (apoE2 vs. apoE3, p < 0.05), while in the subgroup of ASCVD patients under statin therapy apoE2 was related to lower apoB-100 levels (apoE2 vs. apoE3/apoE4, p < 0.05). A significant difference in apoE concentration observed between mild cognitive impairment (MCI) subjects and controls was confirmed for each apoE phenotype. In conclusion, this study provides evidence for the successful implementation of an MS-based apoE phenotyping assay, which can be used to assess phenotype effects on plasma lipid and apolipoprotein levels. Full article

(This article belongs to the Special Issue Nutrition and Vascular Disease)

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15 pages, 2801 KiB

Open AccessArticle

Hypercoagulability Impairs Plaque Stability in Diabetes-Induced Atherosclerosis

by Saira Ambreen, Sameen Fatima, Ahmed Elwakiel, Rajiv Rana, Kunal Singh, Anubhuti Gupta, Dheerendra Gupta, Hamzah Khawaja, Jayakumar Manoharan, Christian Besler, Ulrich Laufs, Shrey Kohli, Berend Isermann and Khurrum Shahzad

Nutrients 2022, 14(10), 1991; https://doi.org/10.3390/nu14101991 - 10 May 2022

Cited by 1 | Viewed by 2171

Abstract

Diabetes mellitus, which is largely driven by nutritional and behavioral factors, is characterized by accelerated atherosclerosis with impaired plaque stability. Atherosclerosis and associated complications are the major cause of mortality in diabetic patients. Efficient therapeutic concepts for diabetes-associated atherosclerosis are lacking. Atherosclerosis among [...] Read more.

Diabetes mellitus, which is largely driven by nutritional and behavioral factors, is characterized by accelerated atherosclerosis with impaired plaque stability. Atherosclerosis and associated complications are the major cause of mortality in diabetic patients. Efficient therapeutic concepts for diabetes-associated atherosclerosis are lacking. Atherosclerosis among diabetic patients is associated with reduced endothelial thrombomodulin (TM) expression and impaired activated protein C (aPC) generation. Here, we demonstrate that atherosclerotic plaque stability is reduced in hyperglycemic mice expressing dysfunctional TM (TM^Pro/Pro mice), which have a pro-coagulant phenotype due to impaired thrombin inhibition and markedly reduced aPC generation. The vessel lumen and plaque size of atherosclerotic lesions in the truncus brachiocephalic were decreased in diabetic TM^Pro/Pro ApoE^-/- mice compared to diabetic ApoE^-/- mice. While lipid accumulation in lesions of diabetic TM^Pro/Pro ApoE^-/- mice was lower than that in diabetic ApoE^-/- mice, morphometric analyses revealed more prominent signs of instable plaques, such as a larger necrotic core area and decreased fibrous cap thickness in diabetic TM^Pro/Pro ApoE^-/- mice. Congruently, more macrophages and fewer smooth muscle cells were observed within lesions of diabetic TM^Pro/Pro ApoE^-/- mice. Thus, impaired TM function reduces plaque stability, a characteristic of hyperglycemia-associated plaques, thus suggesting the crucial role of impaired TM function in mediating diabetes-associated atherosclerosis. Full article

(This article belongs to the Special Issue Nutrition and Vascular Disease)

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17 pages, 2930 KiB

Open AccessArticle

Targeted Lipidomics for Characterization of PUFAs and Eicosanoids in Extracellular Vesicles

by Madlen Reinicke, Saikal Shamkeeva, Max Hell, Berend Isermann, Uta Ceglarek and Mitja L. Heinemann

Nutrients 2022, 14(7), 1319; https://doi.org/10.3390/nu14071319 - 22 Mar 2022

Cited by 5 | Viewed by 2147

Abstract

Lipids are increasingly recognized as bioactive mediators of extracellular vesicle (EV) functions. However, while EV proteins and nucleic acids are well described, EV lipids are insufficiently understood due to lack of adequate quantitative methods. We adapted an established targeted and quantitative mass spectrometry [...] Read more.

Lipids are increasingly recognized as bioactive mediators of extracellular vesicle (EV) functions. However, while EV proteins and nucleic acids are well described, EV lipids are insufficiently understood due to lack of adequate quantitative methods. We adapted an established targeted and quantitative mass spectrometry (LC-MS/MS) method originally developed for analysis of 94 eicosanoids and seven polyunsaturated fatty acids (PUFA) in human plasma. Additionally, the influence of freeze–thaw (FT) cycles, injection volume, and extraction solvent were investigated. The modified protocol was applied to lipidomic analysis of differently polarized macrophage-derived EVs. We successfully quantified three PUFAs and eight eicosanoids within EVs. Lipid extraction showed reproducible PUFA and eicosanoid patterns. We found a particularly high impact of FT cycles on EV lipid profiles, with significant reductions of up to 70%. Thus, repeated FT will markedly influence analytical results and may alter EV functions, emphasizing the importance of a standardized sample pretreatment protocol for the analysis of bioactive lipids in EVs. EV lipid profiles differed largely depending on the polarization of the originating macrophages. Particularly, we observed major changes in the arachidonic acid pathway. We emphasize the importance of a standardized sample pretreatment protocol for the analysis of bioactive lipids in EVs. Full article

(This article belongs to the Special Issue Nutrition and Vascular Disease)

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1 pages, 778 KiB

Open AccessCorrection

Correction: Gupta et al. Neutrophil Extracellular Traps Promote NLRP3 Inflammasome Activation and Glomerular Endothelial Dysfunction in Diabetic Kidney Disease. Nutrients 2022, 14, 2965

by Anubhuti Gupta, Kunal Singh, Sameen Fatima, Saira Ambreen, Silke Zimmermann, Ruaa Younis, Shruthi Krishnan, Rajiv Rana, Ihsan Gadi, Constantin Schwab, Ronald Biemann, Khurrum Shahzad, Vibha Rani, Shakir Ali, Peter Rene Mertens, Shrey Kohli and Berend Isermann

Nutrients 2023, 15(11), 2429; https://doi.org/10.3390/nu15112429 - 23 May 2023

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Error in Figure [...] Full article

(This article belongs to the Special Issue Nutrition and Vascular Disease)

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