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Oral administration of drugs is the most common, convenient, safest and economical route of drug administration. There is lack of established tools to study the function of transporters in the intestinal absorption of drugs. Because of its favorable physico-chemical, pharmacokinetic and pharmacodynamic characteristics, trospium could be potentially used as a probe substrate to study the function of drug transporters. Therefore, this study was conducted to examine the suitability of trospium chloride as a probe drug to study the function of multidrug transporters in the human body. To this end, two randomized, controlled, four-period, cross-over pharmacokinetic drug interaction studies of oral and intravenous trospium with co-medication of oral clarithromycin or ranitidine were performed in 24 healthy subjects to mechanistically characterize the role of P-gp, OATP1A2, OCT1, OCT2, MATE1 and MATE2-K in the absorption and disposition of trospium. The contribution of the drug transporters in the absorption and disposition of trospium were examined in isolated systems using in vitro uptake and inhibition assays in transporter transfected human cell lines.
OCT1 (Vmax = 0.8 ± 0.1 nmol/min × mg) is a high capacity transporter of trospium compared to OCT2 (Vmax = 0.04 ± 0.01 nmol/min × mg). But the OCT2 (Km = 0.5 ± 0.1 µM) transporter demonstrated a high affinity in the transport of trospium compared to OCT1 (Km = 17.4 ± 2.1 µM). OCT1 genetic alleles *2, *3, *4 and *7 resulted in significant loss of activity and the alleles *5 and *6 caused complete loss of uptake of trospium. The common OCT2 genetic allele Ser270 caused slight but significant increase in activity of OCT2.
Ranitidine inhibits OCT1 (IC50 = 186 ± 25 µM), MATE1 (IC50 = 134 ± 37 µM) and MATE2-K (IC50 = 35 ± 11 µM)-mediated uptake of trospium in vitro. But it is a weak inhibitor of OCT2 transporter (IC50 = 482 ± 105 µM). Using FDA and EMA in vitro to in vivo extrapolation models, ranitidine was predicted to have a potential inhibition effect on intestinal OCT1 ([I]2/IC50 ~40), renal MATE1 ([I]1/IC50 ~0.02) and MATE2-K ([I]1/IC50 ~0.1) transporters in vivo. Clarithromycin was predicted to cause DDI by inhibiting P-gp-mediated efflux of trospium at the intestine ([I]2/IC50 of ~310) and hepatocytes ([I]3/IC50 ~1). Therefore, co-medication of oral clarithromycin was expected to result in an increase in oral absorption and hepatic clearance of trospium but not changes in distribution volume.
In healthy subjects, oral trospium is slowly (MAT ~10 h) and poorly (F ~10 %) absorbed from the jejunum and cecum/ascending colon, widely distributed into the body (Vss = 5 - 6 l/kg) and slowly eliminated (t1/2 = 9 - 10 h) majorly via renal glomerular filtration and tubular secretion (CLR ~500 ml/min). After co-medication of clarithromycin (inhibitor of P-gp), on the contrary to our IVIVE prediction, we found a non-expected but significant expansion of the shallow and deep distribution spaces for trospium by ~27 %. A single dose administration of trospium with co-medication of ranitidine (inhibitor of OCT1) resulted in no effect on the intestinal absorption of trospium. But the renal clearance of trospium decreased slightly (15 %) but significantly.
Intravenously administered trospium (2 mg TC) might be a suitable probe drug to evaluate the effects of a P-gp inhibitor on distribution of a drug. Oral trospium chloride can be selected for DDI studies with new chemical entities (NCE) with predicted inhibitory potential on OCT1 and P-gp and which are available after oral absorption along the small intestine and in the cecum/ascending colon. Another kind of application of trospium chloride might be pharmacogenomics studies in subjects with functionally relevant polymorphisms of P-gp and OCT1 or in patients with suspected transport failure due to intestinal diseases. The function of the efflux transporters MATE1 and MATE2-K in the PTC of the kidneys can be well assessed with the probe drug trospium by measuring its renal clearance.
National oral health survey on refugees in Germany 2016/2017: caries and subsequent complications
(2020)
Objectives To assess oral health, caries prevalence, and subsequent complications among recently arrived refugees in Germany and to ompare these findings with the German resident population. Methods This multicenter cross-sectional study recruited 544 refugees aged 3–75+ years; they were examined at ten registration institutions in four federal states in Germany by two calibrated dentists. The refugees were screened for caries (dmft/DMFT) and its complications pufa/PUFA); this data was compared to the resident population via the presentative national oral health surveys). Results The deciduous dentition of the 3-year-old refugees had a mean dmft value of 2.62 ± 3.6 compared with 0.48 dmft in the German resident population, and caries increased to 5.22 ± 3.4 for 6–7-year-olds (Germany: 1.73 dmft). Few refugee children had naturally healthy teeth (7% in 6–7-year-olds, Germany: 56%). In the permanent dentition, the gap in caries prevalence between refugees and the German population decreased with age (35–44-year-olds: 10.55 ± 7.1 DMFT; Germany: 11.2), but refugees exhibited more caries defects (35–44-year-olds DT = 3.13 ± 3.0; Germany: 0.5). German residents had more restorations (35–44-year-olds FT = 4.21 ± 4.6). Regarding complications, the 6–7-year-olds exhibited the highest pufa index (0.86 ± 1.4) which decreased in adolescence (13–17-year-olds, 0.18 ± 0.6) and increased in adults (45–64-year-olds, 0.45 ± 0.8). Conclusion The refugees had high caries experience, often untreated caries teeth and more complications compared with the German resident population, especially in children. Closing this gap by extending preventive systems to the refugees would decrease future treatment needs. Clinical relevance European countries should be prepared for the higher dental treatment needs in recent refugees, especially in
children.
In fixed orthodontic treatments debonding of brackets during treatment is an unpleasant occurrence for the clinician and the patients and resultes in an increase in treatment costs and duration. For Damon Q brackets recycling would considered as an economic saving option which could be done with using of in office methods such as the sandblasting.
A sample of sixty sound bovine first upper central incisers, were collected, cleaned, and mounted in acrylic blocks for shear bond strength testing.
The total sample was equally divided into two main groups. Each group had 30 teeth and 30 brackets.
The first group had 30 teeth bonded with metal Damon Q brackets, the second group had 30 teeth bonded with metal Mini-Mono® brackets.The study included bonding and rebonding experiments. Therefore the same brackets with their same teeth were used in bonding and in the rebonding experiments. The bonding and the rebonding procedures were done with using 3M Unitek etching, Grengloo adhasive, and Ortho solo bonding. In addition the rebonding procedure was done after cleaning the teeth and recycling their brackets with sandblasting. All specimens were recycled 5000 times for the bonding and rebonding experiments.
The first and second debonding forces were done in Newton using a Zwick Roell machine.
After that SBS and SRS were computed in MPa. Furthermore all the teeth, after each debonding, were examined under a digital scanning microscope VHX-5000, 50X magnifying, to performe the ARA and ARI.
The collected data was statistically analyzed for descriptive statistics as well as significance of differences among the different bracket types, and their ARI scores, in the bonding and rebonding experiments.
The results showed that SRS was significantly higher than SBS of both types of the brackets, and Damon Q brackets had higher SBS, and SRS than Mini-Mono® brackets, and there was no correlation between SBS, SRS and their ARI, ARA.
Infections with Helicobacter pylori are a global challenge that affects both developed and developing countries. This infection is currently treated using multiple antimicrobials that are mostly absorbed after oral administration and subsequently secreted into the gastric lumen. The eradication rates from the different therapeutic regimens, however, are declining nowadays, primarily due to high antibiotic resistance and possibly the mode of drug delivery. H. pylori is commonly found adhering to epithelial cells, and therefore, intragastric drug delivery may be a more direct treatment option. In this work, we developed a new strategy for the local eradication of H. pylori within the stomach.
Initial in vitro experiments revealed that penicillin G shows promising antibiotic activity against resistant strains of H. pylori with MIC values of 0.125 µg/mL. To provide luminal concentrations above the MIC for an extended time, we decided to follow two different formulation strategies: effervescent granules and HPMC-based hydrogel matrix tablets. Among the granule formulations, only one batch was stable and demonstrated excellent performance with respect to drug content, effervescent action, and drug release. It was therefore selected for further in vitro studies. All matrix tablets showed the desired tablet quality requirements and drug release was scalable in vitro by the HPMC concentration.
In order to quantify PGS in various formulations and media, an HPLC method was developed and validated. Due to the stability concerns, the degradation behavior of PGS was studied at different pH. PGS was found to be unstable at acidic pH values, but its stability was higher at more neutral pH values. Sufficient stability was exhibited at pH values above pH 4.5. Due to the instability of PGS in acidic media, alkalizers were added to the matrix tablets to prevent the degradation of the drug within the tablet. Among the alkalizers tested, NaHCO3 showed the most promising results as it significantly enhanced the stability within the matrix and also the concentration of PGS in the dissolution media. The stabilizing effect was caused mainly by the modulation of the microenvironmental pH rather than a pH change in the dissolution media. As a result, these matrix tablets were selected for further in vitro characterization.
In order to guide formulation development, a flow-through model (FTM), which was able to simulate various physiological conditions of the gastric environment, was developed and applied. In contrast to compendial dissolution methods, the FTM allowed studying the effect of gastric secretion, mixing and emptying on the gastric concentration of the drug in vitro. It could be shown that the granules generated a high initial concentration, which decreased over time. On the contrary, the matrix tablets did not provide such a profile due to the absence of pressure events in the model. Further investigations of the matrix tablets in a dissolution stress test device revealed faster drug release if pressure events of physiological relevance are simulated.
In the last part of this thesis, the two formulation concepts were compared in vivo by using the salivary tracer technique. For this purpose, caffeine was used as a model drug. The in vivo investigations suggested that granules administered in a fed state demonstrated longer gastric retention than in a fasted state. In a fed state, effervescent granules provided longer gastric retention of caffeine in comparison to the matrix tablets. Interestingly, the administration of the granules together with 240 mL of tap water provided an even better gastric retention of caffeine than the smaller volume (20 mL). Additional MRI investigations after 4 h of tablets’ intake revealed that the matrix tablets were already disintegrated in vivo.
In conclusion, effervescent granules dosed after food are expected to better maintain intragastric drug concentration over an extended period compared to matrix tablets. Moreover, the carbon dioxide generated after disintegration supports the mixing of the drug with the chyme and thus, provides a uniform distribution of the drug. By this, bacterial sanctuary sites within the stomach can be avoided. The major challenge could be the stability of PGS in acidic media. This problem could be addressed via concomitant administration of PPIs. H2 blockers could also be recommended to address nocturnal acid-breakthrough during the mid-night. In combination with an acid-reducing agent, PGS granule formulations alone or part of the treatment regimens could enable the local eradication of H. pylori directly within the stomach.
In agricultural grasslands, management practice highly determines reproductive success for ground-nesting bird species. The most effective conservation measure is the delay of first mowing dates until broods fledge or bird friendly mowing. Late mowing often implies economical losses for farmers and may increase land use abandonment, which will, in turn, cause habitat deterioration. Thus, grassland bird conservation involves the challenge to protect broods against land use and to promote an appropriate management to sustain habitat quality at the same time. Because of their late and extended breeding season Corncrakes Crex crex are in particular vulnerable to frequent mowing which increases nest destruction, chick mortality and habitat loss.
This thesis aims to gain knowledge on favourable habitat characteristics and brood protection in relation with grassland management to derive implications for the conservation of Corncrake breeding sites in floodplain meadows. Study area is the Lower Oder Valley National Park in northeastern Germany that holds a Corncrake population of 50 to 250 calling males. The study covered two study periods, before (1998-2000) and after (2012-2015) the implementation of new Corncrake conservation measures allowing inferences on the effects of different timing and intensity of mowing for brood protection and habitat conservation.
Breeding was only confirmed on meadows with high forb cover, low sedge cover, low litter heights and a close location to ditches. Radio-tracked females preferred areas with high cover of forbs (> 30%) and a distinct relief heterogeneity, which was associated with increased vegetation diversity. Vegetation characteristics on sites with day calling activity of males showed more similarity with breeding sites than with sites only used for nocturnal calling, supporting the assumption that diurnal calling indicates the occurrence of females. Favoured vegetation structure was best provided by mowing in the preceding year. Low-intensity grazing was less effective in reducing litter and sedge cover, especially when conducted late in the season. In the absence of management, meadows rapidly overgrow and dense litter accumulates from dead plant material in eutrophic floodplains, which increases walking resistance for Corncrakes and may impede prey accessibility. Plant species richness and forb cover declined after land use cessation. Male Corncrakes abandoned calling sites on meadows unmanaged for longer periods.
Besides the availability of suitable nesting sites, food supply and nest predation risk are also related to vegetation structure and may indirectly influence the habitat quality. Faecal samples of Corncrakes consisted mainly of beetles and their larvae, followed by snails, spiders and earthworms. Invertebrate biomass, sampled with pitfall-traps, was twice as high, the numbers of large ground beetles even five times higher on previously unmanaged than on managed meadows. Invertebrate abundance was highest in the first and second years after land use abandonment, but strongly decreased afterwards to a similar level like under annual management. Therefore, unmown refuge strips for Corncrake protection and alternating mowing also enhance invertebrate prey resources in floodplain meadows.
Mammals caused the majority of all observed artificial ground nest predations. Nest predation risk was higher on previously unmanaged than on managed sites. Unmanaged meadows probably attract mammalian predators, because they provide a more favourable vegetation structure for foraging and harbour high numbers of small rodents, increasing also the risk of incidental nest predations. These findings suggest that an annual removal of vegetation, if conducted late in the season to protect grassland birds may reduce predation risk of ground nests in the subsequent year.
Whereas during 1998-2000 half of the study area was managed by the end of July, land use was delayed on meadows occupied by Corncrakes until at least 15 July or 15 August during 2012-2015. On meadows mown between 15 July and 15 August refuge strips were applied. The majority of Corncrake broods were started in the second half of May and mowing postponement until 15 August allows 80% of chicks to fledge without disturbance in the study area. In 65% of broods chicks reach independence (> 14 days old) until 15 July and can be protected by Corncrake friendly mowing because then they are large enough to successfully escape during mowing. Both adults and chicks survived in 10 m wide refuge strips. Because most birds tried to leave the unmown block for the first time when it was up to 30 m wide and only 15 to 30 m wide strips served as temporary habitat for unfledged chicks from mowing to departure, 10 m should be considered as the absolute minimum width for refuge strips.
The strong reduction of land use especially during July should have allowed more chicks to survive until fledging in 2012-2015 than 1998-2000. Besides the protection of nests and higher chick survival, the decline of mowing intensity increased the extent of habitat available for second breeding attempts. In 2012-2015, broods were initiated until late July in the study area. Male Corncrakes showed continuous arrival and departure during the breeding season. Similar departure rates were estimated by a multi-state occupancy model and for radio-tracked males in the same study area and periods, which both left their home ranges spontaneous and due to the impact of mowing. Compared to 1998-2000, total departure of males during June and July was reduced by 50% in 2012-2015, when more calling sites were protected from mowing. Although male Corncrakes show high intra-seasonal dispersal due to their sequential polygamous breeding system, postponed land use should have increased mating opportunities and re-nesting at first breeding sites.
Therefore, future directions of Corncrake conservation in eutrophic floodplains should address the increase of annual late mowing to protect broods and maintain favourable habitat conditions by creating a more flexible mowing regime adjusted to actual occurrence of Corncrakes. This requires expert advice to farmers based on an intense monitoring of calling Corncrakes. Repeated nocturnal surveys during May and June are highly recommended because low detection probability in combination with constant departure substantially underestimated the number of males present. Additionally, diurnal calling activity could improve the identification of breeding sites and timing could be used to estimate chick age in July to select sites for Corncrake friendly mowing. Because currently late mowing dates are unattractive for farmers conservation actions should along with financial compensations for mowing after 15 August promote the utilization of late-cut grass with poor nutrient quality for combustion. Energy production could provide an alternative income for farmers operating in conservation areas with delayed land use dates and will increase their acceptance of Corncrake protection measures.
In modern-day organic synthesis, transitional metal catalysis has become an essential tool-kit to access the biologically significant complex organic scaffolds. The activation profile of these sophisticated catalytic systems in cross-coupling chemistry and ring-closing processes has been well appreciated and frequently employed by the scientific community.
The present thesis is describing the results of interdisciplinary research involving medicinal chemistry and transitional metal homogeneous catalysis. A molybdenum mediated process was employed to access 32 unprecedented heterocyclic fused poly sulfur ring containing pentathiepins in moderate to good yields as a part of medicinal chemistry. Biologically significant, such as quinoxaline, pyrazine, pyridine, nicotinamide, quinoline, imdazo-pyrazine, pyrrolo-pyrazine, purine, and pyridine sulfonamide scaffolds were functionalized with pentathiepin unit via multi-step organic synthesis. Essentially, the Sonogashira cross-coupling and(Et4N)2[MoO(S4)2] mediated ring-closing steps were commonly employed in all pentathiepin syntheses. The analytically pure samples were characterized by 1H, 13C, 19F-NMR, FTIR, ESI-MS, CHNS, and X-ray single-crystal diffraction analysis. Notably, all pentathiepins exhibited an ABX3 multiplet pattern between δ: 4.2-4.5 ppm with the integration of 2H for the ethoxy functional group's methylene protons substituted on the five-membered ring of pentathiepin, which was later considered as a fingerprint for pentathiepin formation. The mechanistic investigations via control experiments suggest that the tetra sulfur ring Mo(IV) precursor (Et4N)2[MoO(S4)2] is vital along with elemental sulfur for the pentathiepin formation, and the Mo(IV) complex regenerates in the reaction. Furthermore, For the first time, the GPx1 enzyme inhibitor properties of novel fused heterocyclic pentathiepins were established, where these probes exhibited 9-12 folds higher potency than mercaptosuccinic acid. Notably, <1 µM concentration of quinoxaline, pyrazine, and quinoline fused pentathiepins were potent enough to inhibit 50% of GPx1 enzyme activity. Additionally, cytotoxicity, antimicrobial and antifungal studies were conducted for all pentathiepins. In anticancer investigations, the IC50 concentrations for all pentathiepins were ranging between 0.22 to 4.7 µM.
The second half of the thesis introduces a novel water-soluble Pd/PTABS as a potent catalyst for C-X (X = N, O, and S) cross-coupling chloroheteroarenes and halonucleosides. The novel, mild and efficient Pd/PTABS catalytic system was successfully employed at low catalytic loadings (1 mol%) for the amination (C−N), etherification (C−O), and thioetherification (C−S) of chloroheteroarenes at ambient to moderate temperatures. The Pd/PTABS catalyst is well-tolerating various heterocyclic scaffolds, and under the optimized catalytic conditions, various secondary amines, electron-rich or electron-poor phenols, thiophenols, and alkylthiols, were efficiently employed as nucleophilic coupling partners. Notably, the catalyst offered tremendous regio and chemoselectivity with excellent temperature control. Besides, novel sulfones and sulfoximines were prepared from the thioethers obtained via Pd/PTABS. The catalyst was employed efficiently for synthesizing biologically significant known drugs or drug candidates such as alogliptin (anti-diabetic agent), XRK 469 (antitumor agent), and Imuran-Azathioprine (immunosuppressive) in competitive yields. Preliminary DFT investigations were performed, and based on the DFT analysis, the electropositive character of the phosphorous atom in quaternary ammonium salts of PTABS supports the heteroatom directed C−Cl activation hypothesis.
Purpose: To assess the comparative efficacy and the long-term cost-utility of alternative minimally invasive glaucoma surgeries (MIGSs) when combined with cataract surgery in patients with primary open-angle glaucoma (POAG).
Methods: Treatment effects, as measured by the 1-year reduction in intraocular pressure (IOP), were estimated with an adjusted indirect treatment comparison. Evidence from randomized clinical trials was identified for four different MIGS methods. A disease-transition model was developed by capturing clinically relevant POAG stages and the expected natural disease evolution. Outcomes of the disease-transition model were the comparative utility [quality-adjusted life years (QALYs)], cost and cost-utility of included strategies in a lifetime horizon.
Results: Estimated 1-year IOP reductions were: cataract surgery - 2.05 mmHg (95% CI - 3.38; - 0.72), one trabecular micro-bypass stent - 3.15 mmHg (95% CI - 5.66; - 0.64), two trabecular micro-bypass stents - 4.85 mmHg (95% CI - 7.71; - 1.99) and intracanalicular scaffold - 2.25 mmHg (95% CI - 4.87; 0.37). Discounted outcomes from the disease-transition model appraised the strategy of two trabecular micro-bypass stents with cataract surgery in the moderate POAG stage as the one providing the greatest added value, with 10,955€ per additional QALY. Improved outcomes were seen when assessing MIGS in the moderate POAG stage.
Conclusions: When indirectly comparing alternative MIGS methods combined with cataract surgery, the option of two trabecular micro-bypass stents showed both a superior efficacy and long-term cost-utility from a German perspective. Moreover, outcomes of the disease-transition model suggest POAG patients to beneficiate the most from an earlier intervention in the moderate stage contrary to waiting until an advanced disease is present.
The thesis investigates the occurrence of the Early Modern European witch-hunt within the distinctively diverse society of the Grand Duchy of Lithuania. Positioned at the intersection of Latin and post-Byzantine cultures, along with Western and Eastern Christianity, this region lay on the frontlines of the Reformation and Counter-Reformation. The research aims to analyze the specific characteristics of the witch-hunt in this area, considering it a case study of social and cultural interaction within a borderland. It focuses particularly on identifying the distinctive aspects of the Lithuanian witch-hunt, examining the social and cultural roots of the witch trials, and exploring their relationship to the broader social and cultural developments of the period.
Central to this study is a detailed examination of the witch trials and an analysis of court materials. The thesis posits a socio-cultural interpretation of witch persecutions, arguing that they were culturally influenced manifestations of social tensions, enacted through legal mechanisms. The emergence of new Early Modern challenges, such as the social consequences of agrarian reform, the expansion of manorialism, and serfdom, led to novel tensions, conflicts, and responses, including accusations of witchcraft. The importation of authoritative foreign ideas about witchcraft reinvigorated, facilitated, and shaped pre-existing moderate indigenous beliefs, a process facilitated by religious struggles and Catholic post-Tridentine confessionalization. The Lithuanian legal system provided an environment conducive to an intensive witch-hunt, with witchcraft being a secular grave felony tried in highly decentralized and poorly supervised courts. However, this potential was largely unrealized. The study argues that the cultural diversity of the society played a major role in inhibiting the spread of Western witchcraft discourse, thereby limiting the extent of the witch-hunt in the Grand Duchy of Lithuania.
In contrast to its terrestrial counterpart, the metabolic degradation of marine polysaccharides is underexplored. This work aimed to functionally characterize ulvan- and xylan-degrading enzymes from marine Bacteroidetes in order to clarify the metabolic degradation pathway. For the provision of a broad polysaccharide substrate spectrum, ulvan from several different algal sources was extracted to be used in further characterization experiments. The structural differences of these ulvans could be demonstrated by enzymatic degradation with ulvan-active enzymes. In order to clarify the synergistic catalytic effects of polysaccharide sulfatases with GHs in the degradation process of ulvan, several putative sulfatases from F. agariphila were produced recombinantly in E. coli. For that, a coexpression with an FGE encoding gene was required. It could be demonstrated that several glycoside hydrolases are inhibited, if their
substrate is sulfated at the cleavage position and that a previous desulfation using one of the sulfatases enabled the further degradation. Some of the sulfatases showed an endolytic or exolytic cleavage behavior like reported for several GHs. With the combined catalytic activities, it was possible to successfully elucidate the complex ulvan degradation mechanism for the first time, which enables the use of ulvan as a biotechnological source for the production of fine chemicals and pharmaceuticals. This degradation mechanism was shown to be complemented by an alternative pathway that helps with the degradation of uronic acid-containing oligosaccharides. Here, the synergistic effects of a multimodular enzyme containing a sulfatase and rhamnosidase domain were demonstrated. Furthermore, the first dehydratase participating in the degradation of oligosaccharides was revealed. The functional characterization of putative xylan-targeting PULs from two Flavobacteriia revealed the existence of marine endolytic and exolytic xylanases. The enzymes of these PULs were produced recombinantly in E. coli and were used in biocatalysis reactions on xylan from beechwood, xylan from P. palmata or commercial xylooligosaccharide standards. Further side chain-active GHs were found to exclusively be active on either standards or xylan. The great variation of genetic equipment was demonstrated by comparing the enzyme activities of these PUL structures assuming different ecological adaptations of these organisms especially, because these PULs do not code for any putative sulfatases, which is uncommon for PULs targeting xylan. A different degradation behavior of the investigated enzymes suggested a preferred conversion of β-1,4-linked xylan, potentially present in some microalgae. The acquired insight of the metabolic ulvan and xylan utilization greatly expands the scientific knowledge about the ecologic interplays in marine environments concerning the polysaccharide utilization. It indicates the necessity of backup mechanisms for metabolic processes in order to get access to complex marine carbon sources in nature. Several small degradation cascades complement each other to break down substrate compounds to monomeric level for the use of structurally diverse polysaccharides. This expands the insights into the metabolic processes in the degradation of marine polysaccharides, which are an important part of the understanding of the ecological interactions in aquatic habitats and the ocean’s carbon cycle.
The characterization of ulvan- and xylan-active enzymes and the clarification of their substrate scopes allow to use these enzymes in future production of carbohydrate-derived chemical products for many industrial applications, making it possible to use algal waste for recycling to high value materials with even beneficial effect for the environment.
Being the victim of traumatizing events has consequences that can lead to wellknown mental disorders, such as depression. However, newest studies show that these events do not only affect the victims’ behavior, but also the expression levels of specific genes in their blood and in their brain. Latest research discovered little pieces of RNA in the cells that were long thought to be genetic junk. Nevertheless, these so-called miRNAs can regulate the expression of multiple genes, thus modulating metabolism and cell functioning. The aim of this study was to see if childhood traumatization led to a set of differentially expressed miRNA profiles in the peripheral blood. For this, we used subjects from the SHIP trend cohort, who had previously answered various questionnaires, among them the Childhood Trauma Questionnaire and the Patients Health Questionnaire-9 and analyzed the miRNAs in their blood to find out whether there was an association between the score and the dysregulation of certain miRNAs. Furthermore, we selected 5 different independent variables: PHQ-trend, CTQ score, as well as its subscales Abuse and Neglect, and Major Depressive Disorder lifetime prevalence. The analyses showed a set of up- or downregulated miRNAs in the blood. In a second step, we tried to replicate our results comparing them to results in the literature. Some of the significantly dysregulated miRNAs had previously been described as key players in the pathogenesis of MDD, a few even displaying similar results to ours. The next step was to see if the significant miRNAs had common target genes and if these had been described in the literature as having an influence on MDD, showing positive results. One last step was to see if there were also common biological pathways that were modulated by the differentially expressed miRNA. This analysis did not show promising results since there were almost no brain pathways among the results. For future studies, it will be necessary to validate our results using a clinical sample, such as GANI_MED, where the prevalence of childhood traumatization, as well as MDD, is much higher. By doing this, new possibilities of trauma treatment through modulation of epigenetic pathways could arise. If childhood traumatization leads to a set of dysregulated miRNAs that can end in a positive diagnosis of MDD in adulthood, what effects could have a targeted miRNA therapy on the pathogenesis of these psychiatric disorders?