Elevated serum trimethylamine-N-oxide (TMAO) was previously reported to be associated with an elevated risk for cardiovascular events. TMAO originates from the microbiota-dependent breakdown of ...food-derived phosphatidylcholine (PC) to trimethylamine (TMA), which is oxidized by hepatic flavin-containing monooxygenases to TMAO. Our aim was to investigate the predominant site of absorption of the bacterial PC-breakdown product TMA. A healthy human proband was exposed to 6.9 g native phosphatidylcholine, either without concomitant treatment or during application with the topical antibiotic rifaximin, or exposed only to 6.9 g of a delayed-release PC formulation. Plasma and urine concentrations of TMA and TMAO were determined by electrospray ionization tandem mass spectrometry (plasma) and gas chromatography-mass spectrometry (urine). Native PC administration without concomitant treatment resulted in peak plasma TMAO levels of 43 ± 8 μM at 12 h post-ingestion, which was reduced by concomitant rifaximin treatment to 22 ± 8 μM (p < 0.05). TMAO levels observed after delayed-release PC administration were 20 ± 3 μM (p < 0.001). Accordingly, the peak urinary concentration at 24 h post-exposure dropped from 252 ± 33 to 185 ± 31 mmol/mmol creatinine after rifaximin treatment. In contrast, delayed-release PC resulted in even more suppressed urinary TMAO levels after the initial 12-h observation period (143 ± 18 mmol/mmol creatinine) and thereafter remained within the control range (24 h: 97 ± 9 mmol/mmol creatinine, p < 0.001 24 h vs. 12 h), indicating a lack of substrate absorption in distal intestine and large bowel. Our results showed that the microbiota in the small intestine generated the PC breakdown product TMA. The resulting TMAO, as a cardiovascular risk factor, was suppressed by topical-acting antibiotics or when PC was presented in an intestinally delayed release preparation.
Anthocyanins, which are found in high concentrations in fruit and vegetable, may play a beneficial role in retarding or reversing the course of chronic degenerative diseases. However, little is known ...about the biotransformation and the metabolism of anthocyanins so far.
The aim of the study was to investigate possible transformation pathways of anthocyanins by human faecal microflora and by rat liver microsomes as a source of cytochrome P450 enzymes as well as of glucuronyltransferases.
Pure anthocyanins, an aqueous extract of red radish as well as the assumed degradation products were incubated with human faecal suspension. The incubation mixtures were purified by solid-phase extraction and analysed by HPLC/DAD/MS and GC/MS. Quantification was done by the external standard method. Furthermore the biotransformation of anthocyanins by incubation with rat liver microsomes in the presence of the cofactor NADPH (as a model for the phase I oxidation) and in the presence of activated glucuronic acid (as a model for the phase II glucuronidation) was investigated.
Glycosylated and acylated anthocyanins were rapidly degraded by the intestinal microflora after anaerobic incubation with a human faecal suspension. The major stable products of anthocyanin degradation are the corresponding phenolic acids derived from the B-ring of the anthocyanin skeleton. Anthocyanins were not metabolised by cytochrome P450 enzymes, neither hydroxylated nor demethylated. However they were glucuronidated by rat liver microsomes to several products.
The gut microflora seem to play an important role in the biotransformation of anthocyanins. A rapid degradation could be one major reason for the poor bioavailability of anthocyanins in pharmacokinetic studies described so far in the literature. The formation of phenolic acids as the major stable degradation products gives an important hint to the fate of anthocyanins in vivo.
A comprehensive reference text explores the nature of chelating agents and the underlying reasons for their metal-binding properties and discusses the mechanisms of absorption for various metals and ...the possible role of chelating agents in influencing the utilization of certain minerals. Topics include: the physico-chemical characteristics of chelates and chelation and their measurements; the bioavailability of metals and proteins as ligands; the role of phytic acid and other phosphates as chelating agents; miscellaneous chelates (oxalic acid, ionophores, clays); the chelation, uptake, and transport of zinc, and the influence of various foods and synthetic chelates on zinc availability; the chelation, and bioavailability of iron, and the effect of various chelating agents on nonheme iron absorption; chelation of copper by food substances; the chelation of miscellaneous minerals; the role of iron and copper chelation in reproduction; chelate toxicity; the use chelates in metal detoxification and therapy; and the use of chelates for removing metals from dietary ingredients. Technical data and illustrations are presented throughout the text, and reference citations are appended to each of the 12 principal text chapters
Digitalisation, digital networks, and artificial intelligence are fundamentally changing our lives! We must understand the various developments and assess how they interact and how they affect our ...regular, analogue lives. What are the consequences of such changes for me personally and for our society? Digital networks and artificial intelligence are seminal innovations that are going to permeate all areas of society and trigger a comprehensive, disruptive structural change that will evoke numerous new advances in research and development in the coming years. Even though there are numerous books on this subject matter, most of them cover only specific aspects of the profound and multifaceted effects of the digital transformation. An overarching assessment is missing. In 2016, the Federation of German Scientists (VDW) has founded a study group to assess the technological impacts of digitalisation holistically. Now we present this compendium to you. We address the interrelations and feedbacks of digital innovation on policy, law, economics, science, and society from various scientific perspectives. Please consider this book as an invitation to contemplate with other people and with us, what kind of world we want to live in!
Large or complex bone fractures often need clinical treatments for sufficient bone repair. New treatment strategies have pursued the idea of using mesenchymal stromal cells (MSCs) in combination with ...osteoinductive materials to guide differentiation of MSCs into bone cells ensuring complete bone regeneration. To overcome the challenge of developing such materials, fundamental studies are needed to analyze and understand the MSC behavior on modified surfaces of applicable materials for bone healing. For this purpose, we developed a fibrous scaffold resembling the bone/bone marrow extracellular matrix (ECM) based on protein without addition of synthetic polymers. With this biomimetic in vitro model we identified the fibrous structure as well as the charge of the material to be responsible for its effects on MSC differentiation. Positive charge was introduced via cationization that additionally supported the stability of the scaffold in cell culture, and acted as nucleation point for mineralization during osteogenesis. Furthermore, we revealed enhanced focal adhesion formation and osteogenic differentiation of MSCs cultured on positively charged protein fibers. This pure protein-based and chemically modifiable, fibrous ECM model allows the investigation of MSC behavior on biomimetic materials to unfold new vistas how to direct cells' differentiation for the development of new bone regenerating strategies.
•High variability in clinical target-site drug concentrations by microdialysis•Patient-associated variability dominated technique-related variability•Lower relative recovery in obese versus non-obese ...patients•Target-site drug concentration via single relative recovery potentially imprecise•Recommendation: Single catheter but with multiple relative recoveries per patient
Target-site concentrations obtained via the catheter-based minimally invasive microdialysis technique often exhibit high variability. Catheter calibration is commonly performed via retrodialysis, in which a transformation factor, termed relative recovery (RR), is determined. Leveraging RR values from a rich data set of a very large clinical microdialysis study, promised to contribute critical insight into the origin of the reportedly high target-site variability. The present work aimed (i) to quantify and explain variability in RR associated with the patient (including non-obese vs. obese) and the catheter, and (ii) to derive recommendations on the design of future clinical microdialysis studies.
A prospective, age- and sex-matched parallel group, single-centre trial in non-obese and obese patients (BMI=18.7-86.9 kg/m2) was performed. 1-3 RR values were obtained in the interstitial fluid of the subcutaneous fat tissue in one catheter per upper arm of 120 patients via the retrodialysis method (nRR=1008) for a panel of drugs (linezolid, meropenem, tigecycline, cefazolin, fosfomycin, piperacillin and acetaminophen). A linear mixed-effects model was developed to quantify the different types of variability in RR and to explore the association between RR and patient body size descriptors.
Estimated RR was highest for acetaminophen (69.7%, 95%CI=65.0% to 74.3%) and lowest for piperacillin (40.4%, 95%CI=34.6% to 46.0%). The linear mixed-effects modelling analysis showed that variability associated with the patient (σ=15.9%) was the largest contributor (46.7%) to overall variability, whereas the contribution of variability linked to the catheter (σ=5.55%) was ~1/6 (16.8%). The relative contribution of residual unexplained variability (σ=12.0%, including intracatheter variability) was ~1/3 (36.4%). The limits of agreement of repeated RR determinations in a single catheter ranged from 0.694-1.64-fold (linezolid) to 0.510-3.02-fold (cefazolin). Calculated fat mass affected RR, explaining the observed lower RR in obese (ΔRRmean= -29.7% relative reduction) versus non-obese patients (p<0.001); yet only 15.8% of interindividual variability was explained by this effect. No difference in RR was found between catheters implanted into the left or right arm (p=0.732).
Three recommendations for clinical microdialysis trial design were derived: 1) High interindividual variability underscored the necessity of measuring individual RR per patient. 2) The low relative contribution of intercatheter variability to overall variability indicated that measuring RR with a single catheter per patient is sufficient for reliable catheter calibration. 3) The wide limits of agreement from multiple RR in the same catheter implied an uncertainty of a factor of two in target-site drug concentration estimation necessitating to perform catheter calibration (retrodialysis sampling) multiple times per patient. To allow routine clinical use of microdialysis, research efforts should aim at further understanding and minimising the method-related variability. Optimised study designs in clinical trials will ultimately yield more informative microdialysis data and increase our understanding of this valuable sampling technique to derive target-site drug exposure.
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Background
The determinants of successful humoral immune response to the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) are of critical importance for the design of effective vaccines ...and the evaluation of the degree of protective immunity conferred by exposure to the virus. As novel variants emerge, understanding their likelihood of suppression by population antibody repertoires has become increasingly important.
Methods
In this study, we analyzed the SARS‐CoV‐2 polyclonal antibody response in a large population of clinically well‐characterized patients after mild and severe COVID‐19 using a panel of microarrayed structurally folded and unfolded SARS‐CoV‐2 proteins, as well as sequential peptides, spanning the surface spike protein (S) and the receptor‐binding domain (RBD) of the virus.
Results
S‐ and RBD‐specific antibody responses were dominated by immunoglobulin G (IgG), mainly IgG1, and directed against structurally folded S and RBD and three distinct peptide epitopes in S2. The virus neutralization activity of patients´ sera was highly correlated with IgG antibodies specific for conformational but not sequential RBD epitopes and their ability to prevent RBD binding to its human receptor angiotensin‐converting enzyme 2 (ACE2). Twenty percent of patients selectively lacked RBD‐specific IgG. Only immunization with folded, but not with unfolded RBD, induced antibodies against conformational epitopes with high virus‐neutralizing activity. Conformational RBD epitopes required for protection do not seem to be altered in the currently emerging virus variants.
Conclusion
These results are fundamental for estimating the protective activity of antibody responses after natural infection or vaccination and for the design of vaccines, which can induce high levels of SARS‐CoV‐2–neutralizing antibodies conferring sterilizing immunity.
IgG response in convalescent COVID‐19 patients is directed to folded but not to unfolded RBD or RBD peptides. IgGs to folded RBD are required for virus neutralization. Twenty percent of convalescent COVID‐19 patients selectively lack RBD‐specific IgG. Only immunization with folded, but not with unfolded RBD, induces antibodies with virus‐neutralizing activity. Abbreviations: COVID‐19, coronavirus disease 2019; IgG, immunoglobulin G; RBD, receptor‐binding domain; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2.
Digitalisation, digital networks, and artificial intelligence are fundamentally changing our lives! We must understand the various developments and assess how they interact and how they affect our ...regular, analogue lives. What are the consequences of such changes for me personally and for our society? Digital networks and artificial intelligence are seminal innovations that are going to permeate all areas of society and trigger a comprehensive, disruptive structural change that will evoke numerous new advances in research and development in the coming years. Even though there are numerous books on this subject matter, most of them cover only specific aspects of the profound and multifaceted effects of the digital transformation. An overarching assessment is missing. In 2016, the Federation of German Scientists (VDW) has founded a study group to assess the technological impacts of digitalisation holistically. Now we present this compendium to you. We address the interrelations and feedbacks of digital innovation on policy, law, economics, science, and society from various scientific perspectives. Please consider this book as an invitation to contemplate with other people and with us, what kind of world we want to live in!
Digitalisierung, Vernetzung und Künstliche Intelligenz verändern unser Leben in grundlegender Weise! Wir müssen die verschiedenen Entwicklungen verstehen und analysieren, wie sie sich gegenseitig ...verstärken und auf unser "normales", analoges Leben wirken. Welche Konsequenzen haben die Veränderungen für mich und für die Gesellschaft, in der ich lebe? Digitale Vernetzung und Künstliche Intelligenz sind epochale Basisinnovationen, die schubartig alle Bereiche der Gesellschaft durchdringen und Motor eines umfassenden, disruptiv verlaufenden Strukturwandels sind, der in den nächsten Jahren zahlreiche neue Innovationen hervorbringen wird. Trotz zahlreicher Bücher zum Thema werden die tiefgehenden und vielseitigen Wirkungen der Digitalisierung meistens nur ausschnittsweise, also für einzelne Bereiche betrachtet. Was fehlt, ist ein Gesamtbild. Die Vereinigung Deutscher Wissenschaftler (VDW) beschäftigt sich deshalb seit 2016 eingehend mit Technikfolgen der Digitalisierung und hat hierzu eine Studiengruppe eingesetzt, die das vorliegende Kompendium vorlegt. Darin betrachten wir aus verschiedenen Wissenschaftsperspektiven Zusammenhänge und Rückwirkungen digitaler Innovation in unterschiedlichen gesellschaftlichen Bereichen. Sehen Sie das Buch als eine Einladung, mit anderen Menschen und mit uns darüber nachzudenken, wie wir leben wollen!
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