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Nicotinamide Riboside: What It Takes to Incorporate It into RNA
Get PDFNicotinamide is an important functional compound and, in the form of nicotinamide adenine dinucleotide (NAD), is used as a co-factor by protein-based enzymes to catalyze redox reactions. In the context of the RNA world hypothesis, it is therefore reasonable to assume that ancestral ribozymes could have used co-factors such as NAD or its simpler analog nicotinamide riboside (NAR) to catalyze redox reactions. The only described example of such an engineered ribozyme uses a nicotinamide moiety bound to the ribozyme through non-covalent interactions. Covalent attachment of NAR to RNA could be advantageous, but the demonstration of such scenarios to date has suffered from the chemical instability of both NAR and its reduced form, NARH, making their use in oligonucleotide synthesis less straightforward. Here, we review the literature describing the chemical properties of the oxidized and reduced species of NAR, their synthesis, and previous attempts to incorporate either species into RNA. We discuss how to overcome the stability problem and succeed in generating RNA structures incorporating NAR
Modification of the Biorelevant Release Testing of Esophageal Applied Mucoadhesive Films and Development of Formulation Strategies to Increase the Mucosal Contact Time
Get PDFThe increasing prevalence of esophageal disease highlights the clinical relevance of novel, long-lasting mucoadhesive oral dosage forms. The EsoCap device enables targeted local application of films in the esophagus. Biorelevant test systems such as EsoPeriDiss are essential for early formulation development. To this end, the developed and already described release model for simulating the esophagus is being further developed for its potential for biorelevant mapping of the application site through complete tempering and investigation of biorelevant release media. Particularly viscous saliva formulations led to an extension of the retention time. In addition, possible formulation strategies for increasing the retention time of esophageal applied films are being evaluated, such as different film thicknesses, polymer grades and the influence of different active ingredient properties on the retention time. For highly soluble active ingredients, the film thickness represents an option for extending the retention time, while for less soluble substances, the choice of polymer grade may be of particular interest
Photocatalytic CO2 Reduction Using CO2‐Binding Enzymes
Get PDFNovel concepts to utilize carbon dioxide are required to reach a circular carbon economy and minimize environmental issues. To achieve these goals, photo-, electro-, thermal-, and biocatalysis are key tools to realize this, preferentially in aqueous solutions. Nevertheless, catalytic systems that operate efficiently in water are scarce. Here, we present a general strategy for the identification of enzymes suitable for CO2 reduction based on structural analysis for potential carbon dioxide binding sites and subsequent mutations. We discovered that the phenolic acid decarboxylase from Bacillus subtilis (BsPAD) promotes the aqueous photocatalytic CO2 reduction selectively to carbon monoxide in the presence of a ruthenium photosensitizer and sodium ascorbate. With engineered variants of BsPAD, TONs of up to 978 and selectivities of up to 93 % (favoring the desired CO over H2 generation) were achieved. Mutating the active site region of BsPAD further improved turnover numbers for CO generation. This also revealed that electron transfer is rate-limiting and occurs via multistep tunneling. The generality of this approach was proven by using eight other enzymes, all showing the desired activity underlining that a range of proteins is capable of photocatalytic CO2 reduction
Effekt des Body-Mass-Index (BMI) auf das Aktivierungsmarkerprofil von Monozyten- und Granulozytensubpopulationen bei Schlaganfallpatienten
Get PDFDer Schlaganfall rangiert sowohl in Deutschland als auch weltweit an zweiter Stelle der häufigsten Todesursachen und führt in zahlreichen Fällen zu dauerhafter Behinderung. In der wissenschaftlichen Literatur gibt es begrenzte Daten zu den Auswirkungen eines Schlaganfalls auf Monozyten, Granulozyten und deren Subpopulationen beim Menschen. Humane Monozyten im peripheren Blut werden anhand der Expressionsdichte der Oberflächenproteine CD14 und CD16 auf der Zelloberfläche in klassische (CD14++ CD16-), intermediäre (CD14++ CD16+) und nicht-klassische (CD14dim CD16+) Subpopulationen unterteilt. Gleichermaßen werden humane Granulozyten im peripheren Blut anhand der Expressionsdichte der Oberflächenproteine CD16 und CD62L auf der Zelloberfläche in klassische (CD16++ CD62L+), proinflammatorische (CD16dim CD62L+) und antiinflammatorische (CD16++ CD62L-) Subpopulationen differenziert. Ziel der vorliegenden Arbeit war es, die Funktion von Monozyten, Granulozyten und den genannten Subpopulationen im peripheren Blut von Schlaganfallpatienten in Abhängigkeit vom BMI zu erforschen. In dieser explorativen prospektiven Kohortenstudie wurden die o.g. Immunzellen im EDTA-Blut von 17 Patienten an Tag 0 bis Tag 5 nach einem gesicherten Schlaganfall analysiert. Mittels Durchflusszytometer (FACS) wurde sowohl die Menge als auch der prozentuale Anteil dieser Zellen sowie bestimmter Aktivierungsmarker auf diesen Zellen untersucht und partiell mit den Werten gesunder Kontrollpatienten verglichen. Als Kontrollgruppe (n = 17) wurden Patienten vor einer Kataraktoperation herangezogen. Beide Kohorten wurden im Vorfeld in BMI-abhängigen Gruppen eingeteilt. Die Analyse von Quantitäts-, Charakterisierungs- und Aktivierungszustand der Monozyten und Granulozyten erfolgte mittels fluoreszenzmarkierter Antikörper (verwendete Marker: CD11b, CD14, CD16, CD32, CD62L, HLA-DR, TLR2). Die Auswertung der FACS-Rohdaten erfolgte mittels der FlowJo10-Software. Als statistische Tests dienten die einfaktorielle und zweifaktorielle Varianzanalyse sowie der Tukey-Kramer-Test als Post-Hoc-Test (GraphPad-PRISM 5.0). Für die Regressionsanalyse wurde ein verallgemeinertes lineares gemischtes Modell für eine Gamma-Verteilung mit Log-Link-Funktion verwendet (R Version 4.1.0 und den Paketen lmerTest und ggeffects). Innerhalb der Schlaganfallkohorte zeigte sich bei höherem BMI eine Erhöhung des prozentualen Anteils CD62L-positiver Granulozyten. Gleichzeitig war bei höherem BMI eine Reduktion des prozentualen Anteils der Granulozytensubpopulation (CD16++ CD62L-) mit antiinflammatorischen Profil zu verzeichnen. Diese Subpopulation wird als entzündungshemmend charakterisiert. Beispielsweise aufgrund der Begrenzung der T-Zell-Aktivierung, sowie ihrer verringerten Phagozytoseaktivität und reduzierten Produktion von reaktiven Sauerstoffspezies im Vergleich zur klassischen Granulozytensubpopulation (CD16++ CD62L+). Darüber hinaus war bei höherem BMI der Anteil der CD11b-positiven Granulozyten in der proinflammatorischen Granulozytensubpopulation prozentual erhöht. Hinsichtlich der Monozyten war bei höherem BMI der Anteil von CD16- positiven Monozyten prozentual reduziert. Es wurde zudem eine Abnahme der prozentualen Anteile der intermediären Monozytensubpopulation sowie eine Zunahme der prozentualen Anteile der klassischen Monozytensubpopulation bei höherem BMI beobachtet. Bei der intermediären Monozytensubpopulation ist die Funktion gemischt. Studien unterstützen sowohl die proinflammatorische als auch antiinflammatorische Rolle. Die klassische Monozytensubpopulation bildet mit ca. 85 % der zirkulierenden Monozyten den Hauptanteil. Sie spielt eine wichtige Rolle bei der Initiation und Progression von Entzündungsreaktionen. Weiter wurde bei höherem BMI beobachtet, dass der prozentuale Anteil der HLA-DR positiven Monozyten in der der klassischen Monozytensubpopulation erniedrigt war. Die vorliegende Studie ergab zudem, dass ein erhöhter BMI bei Schlaganfallpatienten mit einer Verringerung der antiinflammatorischen Granulozytensubpopulation sowie einer verstärkten Präsenz der proinflammatorischen Granulozytensubpopulation einherging. Die Ergebnisse bestätigen eine proinflammatorische Verschiebung innerhalb der Granulozyten bei Fettleibigkeit nach einem Schlaganfall. Es besteht die Vermutung, dass bei fettleibigen Schlaganfallpatienten die granulozytäre Immunabwehr gegenüber Bakterien verbessert ist, während normalgewichtige Schlaganfallpatienten schwereren Entzündungen ausgesetzt sein könnten. Die Erklärung für Letzteres besteht darin, dass bei den normalgewichtigen Schlaganfallpatienten ein signifikant höherer Prozentsatz an antiinflammatorischen Granulozytensubpopulation (CD16++ CD62L-) vorlag, welche während einer schweren Entzündung in den Kreislauf freigesetzt wird. Zudem war bei normalgewichtigen Schlaganfallpatienten der Aktivierungsmarker CD11b schwächer auf der Oberfläche der proinflammatorischen Granulozytensubpopulation exprimiert.
Es ist bekannt, dass er nur schwach auf der Oberfläche von ruhenden unstimmulierten Neutrophilen exprimiert wird und eine erhöhte CD11b Expression einen Indikator für das Vorliegen einer Infektion bzw. Inflammation darstellt. Im Gegensatz zu fettleibigen Kontrollpatienten zeigten fettleibige Schlaganfallpatienten reduzierte CD11b-MFI-Werte auf den Granulozyten, sowie auf den klassischen und proinflammatorischen Granulozytensubpopulation. Überdies traten im selben Vergleich bei den fettleibigen Schlaganfallpatienten auch erhöhte Prozentwerte der
proinflammatorischen Granulozytensubpopulation auf. Erhöhte Prozentwerte dieser proinflammatorischen Subpopulation waren bei Schlaganfallpatienten mit höherem BMI im Vergleich zu Schlaganfallpatienten mit niedrigerem BMI zu verzeichnen. Es wird daher vorgeschlagen, dass der BMI besonders bei Schlaganfallpatienten im Vergleich zu gesunden Personen einen Einfluss auf die CD11b Expression ausüben könnte. Basierend auf den vorliegenden experimentellen Ergebnissen deuten sich potenzielle therapeutische Ansätze für Schlaganfälle an, indem gezielt die Anzahl und/oder Aktivität spezifischer Monozyten- und Granulozytensubpopulationen in einem definierten Zeitfenster moduliert wird. Eine vielversprechende Möglichkeit besteht darin, biologische Agenzien zu entwickeln, die gezielt auf bestimmte Subpopulationen wirken und somit einen Beitrag zur Behandlung von Schlaganfallpatienten leisten könnten
Die Entwicklung des Psychologiestudiums in Deutschland
Get PDFDieser psychologiehistorische Beitrag zeichnet die Entwicklung des Psychologiestudiums und dessen Vorläufer seit Beginn des 19. Jahrhunderts nach, identifiziert die wesentlichen Entwicklungsschübe sowie deren Ursachen und betrachtet die Rolle der Deutschen Gesellschaft für Psychologie im Verlaufe dieses Prozesses. Analyseschwerpunkte bilden die Entwicklung des Diplomstudienganges Psychologie einschließlich der Rahmenprüfungsordnungen bis zum Ende des 20. Jahrhunderts, die Konsequenzen der Bologna-Reform für das Psychologiestudium Anfang des 21. Jahrhunderts und die jüngsten Entwicklungen im Zusammenhang mit der Reform der Psychotherapieausbildung.This historical contribution reviews how psychology studies developed in Germany since the beginning at the turn of the 19th century. It identifies the milestones in the development of psychology studies at German universities and the reasons for major changes, thereby addressing the German Psychological Society’s central role in this process. It focuses on the establishment of the diploma degree in psychology, which became the leading German study program in 20th-century psychology. It also analyzes in detail the major changes associated with the so-called Bologna reform at the beginning of the 21st century. Finally, it discusses recent developments in psychology studies caused by legal changes in psychotherapy training
An intensified trans-sectoral nutritional intervention in malnourished patients with chronic pancreatitis improves diseases prognosis and identifies potential biomarkers of nutritional status
Get PDFBackground
Malnutrition is a common complication in chronic pancreatitis and associated with reduced quality of life and life expectancy. Nutritional support is considered mandatory in malnourished patients with chronic pancreatitis but there is only scarce evidence on optimal treatment modalities and the efficacy of nutrition therapy. Here, we investigated the feasibility and efficacy of an intensified nutritional intervention in malnourished patients with chronic pancreatitis and aimed to identify suitable indicators for monitoring nutritional status.
Methods
We performed a single-arm feasibility study, in which malnourished patients with chronic pancreatitis received an intensified trans-sectoral nutritional intervention for 6 months. Multimodal treatment comprised face-to-face dietary counseling, oral nutritional supplementation, and a complementary telephone-based nutrition and exercise coaching. Patients underwent follow-up examinations after 28, 90, and 180 days, when we assessed changes in anthropometric and body composition measures, muscle function, Chronic Pancreatitis Prognosis Score (COPPS), as well as blood parameters and intestinal microbiota composition.
Results
Eleven out of 73 patients initially screened for study participation were enrolled in the trial of which 9 subjects (age (mean ± SD): 56.2 (±14.8) years; male: 67%; alcoholic etiology: 44%) underwent the complete intervention. Patients gained a median of 5.3 kg (8.6%) body weight, including 1.6 kg skeletal muscle mass, and significantly increased gait speed ( p < 0.001). Ameliorated nutritional status and muscle function were associated with increased blood levels of IGF-1 and cholinesterase as well as altered gut microbiota composition on the phyla and genera level. Moreover, significant improvements in COPPS indicated reduced disease severity after 90 and 180 days.
Conclusion
Malnourished patients with chronic pancreatitis benefit from intensified nutritional therapy. Besides ameliorated nutritional status, a multimodal intervention can improve muscle function as well disease prognosis. Future studies are needed to prove superiority to standard-of-care and to validate potential biomarkers for prospective monitoring of nutritional status.
Clinical trial registration
https://clinicaltrials.gov/study/NCT04476056 , NCT04476056
Real-life dosing conditions in older adults and geriatric patients in Poland – An international questionnaire study to investigate the regional differences in drug intake behaviour in the older population
Get PDFOlder people represent approximately 20% of the Polish population and are the primary population using medications. Behaviours connected with drug intake (such as dosage form modifications, type and amount of fluid and/or food accompanying administration) are crucial for drug efficacy and avoidance of adverse effects. The presented study had three research aims; firstly, to investigate the real-life drug administration process among older adults and geriatric patients in Poland. Secondly, to compare data from Poland with data from a previous study performed in Germany, based on the same questionnaire. Thirdly, to discuss the potential influence of dosing conditions on the behaviour of orally administered medications (especially drug absorption) and identify potential problems with drug intake itself. This questionnaire-based study was conducted in the form of in-person interviews led by research team members. In this study, 174 participants, aged 65–94 years old were recruited from three settings in the Pomeranian region of Poland: home setting, nursing home and hospital. In Poland, the preferred method of medication intake was administration of all medications simultaneously. Patients were taking their medications most often directly after food ingestion, which commonly consisted of bread with butter, ham or cheese and black tea. The most common fluid for drug administration was either a few sips or 100 mL of non-carbonated water (mineral or tap water) as well as black tea. Dividing tablets (defined as splitting tablets in parts) was the most common modification. There were many similarities in the way of administering medications between the Polish and German older populations, specifically the use of non-carbonated water as the most common fluid for medication intake as well as bread as the main ingredient of breakfast and dinner. The biggest difference between populations was the choice of black tea as a medium for medication intake much more frequently in the Polish population than the German (who also preferred mint, herbal and fruit teas), and using a smaller volume of fluid. The presented study gives insight into the medication intake process in the older Polish population from the Pomeranian region in North Poland in comparison to the German population from the Pomeranian region in North East Germany. The results may help to identify factors that could decrease medication efficacy and safety, which is crucial, especially for the older population. Furthermore, the collected data may be useful for in vitro or in silico simulations to enhance drug development based on real-life data
Seeking Mental Health Care – an analysis of the help-seeking process of people with depressive symptoms considering sociocultural self-construal
Get PDFThis cumulative dissertation consists of three publications in scientific journals based on a series of questions that build on each other. The study protocol is also attached to the thesis.
The topic of the dissertation is the analysis of help-seeking behaviour for psychological complaints (using the example of depressive symptoms) and the influence of socio-cultural self-construals. A particular focus is on psychological predictors of help-seeking behaviour that mediate between stigmatising attitudes and the initiation of help-seeking, such as self-efficacy beliefs. Specifically, it is examined (1) whether these mediating mechanisms can be influenced in principle, (2) the extent to which the model on which the analyses are based can be confirmed empirically in its extended form, and (3) whether the mediating mechanisms are moderated by overarching sociocultural self-construals.Die vorliegende kumulative Dissertation umfasst insgesamt drei Publikationen in wissenschaftlichen Fachzeitschriften, die auf der Bearbeitung inhaltlich aufeinander aufbauender Fragestellungen beruhen. Ergänzend ist der Arbeit das Studienprotokoll beigefügt.
Gegenstand der Arbeit ist die Analyse des Inanspruchnahmeverhaltens von Hilfe bei psychischen Beschwerden (am Beispiel von depressiven Symptomen) und des Einflusses soziokultureller „self-construals“. Ein besonderer Fokus liegt dabei auf psychologischen Prädiktoren der Inanspruchnahme, die zwischen stigmatisierenden Einstellungen und der Initiierung von Hilfesuche vermitteln, wie z.B. Selbstwirksamkeitserwartungen. Im Einzelnen wird analysiert, (1) ob diese vermittelnden Mechanismen prinzipiell beeinflussbar sind, (2) inwieweit sich das den Analysen zugrunde liegende Modell auch in seiner erweiterten Form empirisch bestätigen lässt und (3) ob die vermittelnden Mechanismen durch übergreifende soziokulturelle Konstruktionen des Selbst moderiert werden
Bone turnover: the role of lipoproteins in a population-based study
Get PDFBackground
Dyslipidemia has been associated with reduced bone mineral density and osteoporotic fractures, but the relation between lipid and bone metabolism remains poorly understood. Analysing the effects of lipoprotein subclasses on bone turnover may provide valuable insights into this association. We therefore examined whether lipoprotein subclasses, measured by proton nuclear magnetic resonance ( 1 H-NMR) spectroscopy, are associated with bone turnover markers (BTMs) and with the ultrasound-based bone stiffness index.
Methods
Data from 1.349 men and 1.123 women, who participated in the population-based Study of Health in Pomerania-TREND were analysed. Serum intact amino-terminal propeptide of type I procollagen (P1NP, bone formation) and carboxy-terminal telopeptide of type I collagen (CTX, bone resorption) concentrations were measured. Associations between the lipoprotein data and the BTMs or the stiffness index were investigated using linear regression models.
Results
The triglyceride or cholesterol content in very-low-density lipoprotein and intermediate-density lipoprotein particles was inversely associated with both BTMs, with effect estimates being slightly higher for CTX than for P1NP. The triglyceride content in low-density lipoprotein and high-density lipoprotein particles and the Apo-A2 content in high-density lipoprotein particles was further inversely associated with the BTMs. Associations with the ultrasound-based bone stiffness index were absent.
Conclusions
Consistent inverse associations of triglycerides with bone turnover were observed, which argue for a protective effect on bone health, at least in the normal range. Yet, the presented associations did not translate into effects on the ultrasound-based bone stiffness. Further, there was no relevant gain of information by assessing the lipoprotein subclasses. Nevertheless, our study highlights the close relations between lipid and bone metabolism in the general population
Impact of gene-by-trauma interaction in MDD-related multimorbidity clusters
Get PDFAbstract
Background
Major depressive disorder (MDD) is considerably heterogeneous in terms of comorbidities, which may hamper the disentanglement of its biological mechanism. In a previous study, we classified the lifetime trajectories of MDD-related multimorbidities into seven distinct clusters, each characterized by unique genetic and environmental risk-factor profiles. The current objective was to investigate genome-wide gene-by-environment (G × E) interactions with childhood trauma burden, within the context of these clusters.
Methods
We analyzed 77,519 participants and 6,266,189 single-nucleotide polymorphisms (SNPs) of the UK Biobank database. Childhood trauma burden was assessed using the Childhood Trauma Screener (CTS). For each cluster, Plink 2.0 was used to calculate SNP × CTS interaction effects on the participants' cluster membership probabilities. We especially focused on the effects of 31 candidate genes and associated SNPs selected from previous G × E studies for childhood maltreatment's association with depression.
Results
At SNP-level, only the high-multimorbidity Cluster 6 revealed a genome-wide significant SNP rs145772219. At gene-level, MPST and PRH2 were genome-wide significant for the low-multimorbidity Clusters 1 and 3, respectively. Regarding candidate SNPs for G × E interactions, individual SNP results could be replicated for specific clusters. The candidate genes CREB1, DBH, and MTHFR (Cluster 5) as well as TPH1 (Cluster 6) survived multiple testing correction.
Limitations
CTS is a short retrospective self-reported measurement. Clusters could be influenced by genetics of individual disorders.
Conclusions
The first G × E GWAS for MDD-related multimorbidity trajectories successfully replicated findings from previous G × E studies related to depression, and revealed risk clusters for the contribution of childhood trauma