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- Elsevier (2)
Staphylococcus aureussuperantigens (SAgs) are among the most potent T cell mitogensknown.They stimulate large fractions of T cells by cross-linking their T cell receptor withmajor histocompatibility complex class-II molecules on antigen presenting cells, resulting in Tcell proliferation and massive cytokine release. To date, 26 different SAgs have been described in thespeciesS. aureus; they comprise the toxic shock syndrome toxin (TSST-1), as well as 25 staphylococcalenterotoxins (SEs) or enterotoxin-like proteins (SEls). SAgs can cause staphylococcal food poisoningand toxic shock syndrome and contribute to the clinical symptoms of staphylococcal infection. Inaddition, there is growing evidence that SAgs are involved in allergic diseases. This review providesan overview on recent epidemiological data on the involvement ofS. aureusSAgs and anti-SAg-IgEin allergy, demonstrating that being sensitized to SEs—in contrast to inhalant allergens—is associatedwith a severe disease course in patients with chronic airway inflammation. The mechanisms by whichSAgs trigger or amplify allergic immune responses, however, are not yet fully understood. Here, wediscuss known and hypothetical pathways by which SAgs can drive an atopic disease
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.
Background: Stroke patients are at risk of acquiring secondary infections due to stroke-induced immune suppression (SIIS). Immunosuppressive cells comprise myeloid-derived suppressor cells (MDSCs) and immunosuppressive interleukin 10 (IL-10)-producing monocytes. MDSCs represent a small but heterogeneous population of monocytic, polymorphonuclear (or granulocytic), and early progenitor cells (“early” MDSC), which can expand extensively in pathophysiological conditions. MDSCs have been shown to exert strong immune-suppressive effects. The role of IL-10-producing immunosuppressive monocytes after stroke has not been investigated, but monocytes are impaired in oxidative burst and downregulate human leukocyte antigen—DR isotype (HLA-DR) on the cell surface.
Objectives: The objective of this work was to investigate the regulation and function of MDSCs as well as the immunosuppressive IL-10-producing monocytes in experimental and human stroke.
Methods: This longitudinal, monocentric, non-interventional prospective explorative study used multicolor flow cytometry to identify MDSC subpopulations and IL-10 expression in monocytes in the peripheral blood of 19 healthy controls and 27 patients on days 1, 3, and 5 post-stroke. Quantification of intracellular STAT3p and Arginase-1 by geometric mean fluorescence intensity was used to assess the functionality of MDSCs. In experimental stroke induced by electrocoagulation in middle-aged mice, monocytic (CD11b+Ly6G−Ly6Chigh) and polymorphonuclear (CD11b+Ly6G+Ly6Clow) MDSCs in the spleen were analyzed by flow cytometry.
Results: Compared to the controls, stroke patients showed a relative increase in monocytic MDSCs (percentage of CD11b+ cells) in whole blood without evidence for an altered function. The other MDSC subgroups did not differ from the control. Also, in experimental stroke, monocytic, and in addition, polymorphonuclear MDSCs were increased. The numbers of IL-10-positive monocytes did not differ between the patients and controls. However, we provide a new insight into monocytic function post-stroke since we can report that a differential regulation of HLA-DR and PD-L1 was found depending on the IL-10 production of monocytes. IL-10-positive monocytes are more activated post-stroke, as indicated by their increased HLA-DR expression.
Conclusions: MDSC and IL-10+ monocytes can induce immunosuppression within days after stroke.
Abstract
Introduction
Transabdominal ultrasound (US) and magnetic resonance imaging (MRI) are commonly used for the examination of the pancreas in clinical routine. We therefore were interested in the concordance of these two imaging methods for the size measurement of the pancreas and how age, gender, and body mass index (BMI) affect the organ size.
Methods
A total of 342 participants from the Study of Health in Pomerania underwent whole‐body MRI and transabdominal US on the same day, and the diameter of the pancreatic head, body, and tail were measured. The agreement between US and MRI measurements was assessed by Bland and Altman plots. Intraclass correlation coefficients were used to compare observers. A multivariable regression model was applied using the independent variables age, gender, and body mass index.
Results
Compared to MRI, abdominal US returned smaller values for each segment of the pancreas, with a high level of inconsistency between these two methods. The mean difference was 0.39, 0.18, and 0.54 cm for the head, body, and tail, respectively. A high interobserver variability was detected for US. Multivariable analysis showed that pancreatic size in all three segments increased with BMI in both genders whereas pancreatic head and tail size decreased with age, an effect more marked in women.
Conclusions
Agreement of pancreatic size measurements is poor between US and MRI. These limitations should be considered when evaluating morphologic features for pathologic conditions or setting limits of normal size. Adjustments for BMI, gender, and age may also be warranted.
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.
Abstract
Aims
Pinus uncinata is the major treeline‐forming species in the Pyrenees. Yet, the role of its reproduction and dispersal as drivers of treeline dynamics remains unknown. Here we quantify seed production, dispersal and germination changes along the elevation gradient to assess whether they may constrain the foreseen treeline advance in the Pyrenees.
Location
Central Pyrenees, Catalonia, NE Spain.
Methods
We established four plots along an elevation gradient from the closed subalpine forest to the krummholz zone at five study sites. In each plot, we collected cones from five to six trees, measured their length, and triggered their opening in the laboratory to count the number of empty seeds and the number and weight of full seeds. We used the collected seeds in a germination experiment under controlled conditions in growth chambers. Additionally, we installed seed traps along the forest–alpine grassland transition to measure seed rain for three consecutive years in three of the study sites.
Results
The number of full seeds per cone decreased along the elevation gradient and was correlated with cone length. However, the proportion of full seeds per cone and their weight did not differ between elevation positions. Seed rain decreased drastically with elevation and no seeds arrived into the alpine grassland traps consistently across study years. Although germination success did not significantly differ between elevation provenances (i.e., elevation position of origin), we found significant differences in germination dynamics between study sites and between elevation provenances within sites.
Conclusions
Our results indicate that whereas the viability of Pinus uncinata seeds is not limited by elevation, seed production and dispersal are constraining the ongoing rates of treeline advance in the Pyrenees.
Herein, we report the synthesis of a series of push–pull imines by considering cyclic diamino substituent at the C‐centre and fluoroaryl substituent at the N‐centre. This has been achieved by a selective aromatic nucleophilic substitution of different fluoroarenes by N‐H‐substituted N‐heterocyclic imines (NHIs) at ambient conditions without any additional reagent. Solid‐state molecular structure analysis reveals the elongation of the central C–N bond of the imine functionality, which is consistent with the push–pull nature of these imines. The push–pull nature of these imines is further validated by computational studies.
Abstract
Purpose
This study aims to assess the implementation of published research, contraindications, and warnings on the prescription of dual renin‐angiotensin‐hormone system (RAS) blockade in ambulatory care in Germany.
Methods
Cohort study based on health claims data of 6.7 million subjects from 2008 to 2015. Yearly prevalence and incidence for dual RAS blockade with (a) angiotensin‐converting enzyme inhibitors and angiotensin‐receptor blockers (ACEI + ARB) and (b) aliskiren and ACEI or ARB (aliskiren + ACEI/ARB) were calculated. We assessed prescriber specialty and associations between discontinuing dual RAS blockade with specialist (internal medicine, cardiology, nephrology) visits and hospital discharge in the previous year.
Results
A total of 2 984 517 patients were included (age 51.4 ± SD 18.4 y, 48.5% male). Prescription rates for ACEI + ARB decreased from 0.6% (n = 17 907) to 0.4% (n = 12 237) and for aliskiren + ACEI/ARB from 0.23% (n = 6634) to 0.03% (n = 818). Incident prescriptions decreased from 0.23% (n = 6705) to 0.19% (n = 5055) (ACE + ARB) and from 0.1% (n = 2796) to 0.005% (n = 142) (aliskiren + ACE/ARB); 59% of ACEI + ARB and 48% of aliskiren + ACE/ARB combinations were prescribed only by one physician. Of those, 73% (ACEI + ARB) and 58% (aliskiren + ACE/ARB) were primary care providers (PCPs). Discontinuing dual RAS blockade was associated with specialist care and hospital discharge in the previous year (specialist care: RR 1.4, 95% CI, 1.3‐1.6; hospital visit: RR 1.5, 95% CI, 1.3‐1.6).
Conclusions
Our results suggest a delayed uptake of treatment recommendation for ACEI + ARB and a higher impact of Dear Doctor letters addressing PCPs directly compared with published research, contraindications, and warnings. Targeted continuous medical education, practice software alerts, and stronger involvement of pharmacists might improve the implementation of medication safety recommendations in ambulatory care.
Bacillus subtilis has been extensively used as a microbial cell factory for industrial enzymes due to its excellent capacities for protein secretion and large-scale fermentation. This bacterium is also an attractive host for biopharmaceutical production. However, the secretion potential of this organism is not fully utilized yet, mostly due to a limited understanding of critical rearrangements in the membrane proteome upon high-level protein secretion. Recently, it was shown that bottlenecks in heterologous protein secretion can be resolved by genome minimization. Here, we present for the first time absolute membrane protein concentrations of a genome-reduced B. subtilis strain (“midiBacillus”) expressing the immunodominant Staphylococcus aureus antigen A (IsaA). We quantitatively characterize the membrane proteome adaptation of midiBacillus during production stress on the level of molecules per cell for more than 400 membrane proteins, including determination of protein concentrations for ∼61% of the predicted transporters. We demonstrate that ∼30% of proteins with unknown functions display a significant increase in abundance, confirming the crucial role of membrane proteins in vital biological processes. In addition, our results show an increase of proteins dedicated to translational processes in response to IsaA induction. For the first time reported, we provide accumulation rates of a heterologous protein, demonstrating that midiBacillus secretes 2.41 molecules of IsaA per minute. Despite the successful secretion of this protein, it was found that there is still some IsaA accumulation occurring in the cytosol and membrane fraction, leading to a severe secretion stress response, and a clear adjustment of the cell’s array of transporters. This quantitative dataset offers unprecedented insights into bioproduction stress responses in a synthetic microbial cell.
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.
AbstractFluctuations of electron cyclotron emission (ECE) signals are analyzed for differently heated Wendelstein 7-X plasmas. The fluctuations appear to travel predominantly on flux surfaces and are used as ‘tracers’ in multivariate time series. Different statistical techniques are assessed to reveal the coupling and information entropy-based coupling analysis are conducted. All these techniques provide evidence that the fluctuation analysis allows one to check the consistency of magneto-hydrodynamic (MHD) equilibrium calculations. Expanding the suite of techniques applied in fusion data analysis, partial mutual information (PMI) analysis is introduced. PMI generalizes traditional partial correlation (Frenzel and Pompe Phys. Rev. Lett.
99 204101) and also Schreiber’s transfer entropy (Schreiber 2000 Phys. Rev. Lett.
85 461). The main additional capability of PMI is to allow one to discount for specific spurious data. Since PMI analysis allows one to study the effect of common drivers, the influence of the electron cyclotron resonance heating on the mutual dependencies of simultaneous ECE measurements was assessed. Additionally, MHD mode activity was found to be coupled in a limited volume in the plasma core for different plasmas. The study reveals an experimental test for equilibrium calculations and ECE radiation transport.
An Ultrasensitive Fluorescence Assay for the Detection of Halides and Enzymatic Dehalogenation
(2020)
Abstract
Halide assays are important for the study of enzymatic dehalogenation, a topic of great industrial and scientific importance. Here we describe the development of a very sensitive halide assay that can detect less than a picomole of bromide ions, making it very useful for quantifying enzymatic dehalogenation products. Halides are oxidised under mild conditions using the vanadium‐dependent chloroperoxidase from Curvularia inaequalis, forming hypohalous acids that are detected using aminophenyl fluorescein. The assay is up to three orders of magnitude more sensitive than currently available alternatives, with detection limits of 20 nM for bromide and 1 μM for chloride and iodide. We demonstrate that the assay can be used to determine specific activities of dehalogenases and validate this by comparison to a well‐established GC‐MS method. This new assay will facilitate the identification and characterisation of novel dehalogenases and may also be of interest to those studying other halide‐producing enzymes.
In summer 2017, the World Health Organization published 10 facts on asthma, which is known as a major non-communicable disease of high clinical and scientific importance with currently several hundred million people—with many children among them—suffering from air passages inflammation and narrowing. Importantly, the World Health Organization sees asthma as being underdiagnosed and undertreated. Consequently, much more efforts in clinical disease management and research need to be spent on reducing the asthma-related health burden. Particularly, for young approximately 6 months aged patients presenting recurrent bronchitic respiratory symptoms, many parents anxiously ask the doctors for risk prognosis for their children's future life. Therefore, we urgently need to reevaluate if the current diagnostic and treatment measures are in concordance with our yet incomplete knowledge of pathomechanisms on exacerbation. To contribute to this increasing concern worldwide, we established a multicentric pediatric exacerbation study network, still recruiting acute exacerbated asthmatics (children >6 years) and preschool asthmatics/wheezers (children <6 years) since winter 2018 in Germany. The current study that has a currently population comprising 176 study participants aims to discover novel holistic entry points for achieving a better understanding of the poorly understood plasticity of involved molecular pathways and to define biomarkers enabling improved diagnostics and therapeutics. With this study description, we want to present the study design, population, and few ongoing experiments for novel biomarker research.
Clinical Trial Registration: German Clinical Trials Register (Deutsches Register für Klinische Studien, DRKS): DRKS00015738.
Aims
Averaged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear.
Methods and results
An individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration (n = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events.
Conclusion
Averaged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints.
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.
Entropy Ratio and Entropy Concentration Coefficient, with Application to the COVID-19 Pandemic
(2020)
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.
Abstract
Environmentally‐friendly processes for the manufacturing of valuable industrial compounds like ω‐hydroxy fatty acids (ω‐OHFAs) are highly desirable. Herein, we present such an approach by establishing a two‐step enzymatic cascade reaction for the production of 2,15,16‐trihydroxy hexadecanoic acid (THA). Starting with the easily accessible natural compound ustilagic acid (UA) that is secreted by the corn smut fungus Ustilago maydis, the recombinantly expressed esterase BS2 from Bacillus subtilis and the commercial β‐glucosidase from almonds were applied yielding 86 % product. Both hydrolases do not require expensive cofactors, making the process economically attractive. Additionally, no harmful solvents are required, so that the product THA can be labelled natural to be used in food and cosmetic products.
Abstract
This paper focuses on the expectation formation process of professional forecasters by relying on survey data on forecasts regarding gross domestic product growth, consumer price index inflation and 3‐month interest rates for a broad set of countries. We examine the interrelation between macroeconomic forecasts and also the impact of uncertainty on forecasts by allowing for cross‐country interdependencies and time variation in the coefficients. We find that professional forecasts are often in line with the Taylor rule and identify significant expectation spillovers from monetary policy in the USA.
Abstract
This article takes a novel look at the relationship between government activity, partisan preferences and varieties of capitalism. Evidence from panel regressions for 25 EU countries from 1990 to 2014 suggests that there are major divides among European countries in terms of the drivers of government activity, that is, government spending and government regulation. The European divide appears to be even more pronounced between liberal and coordinated economic systems than between the classical geographical divide of east and west, which is typically used in most contributions. While both divides apply to the determinants of government activity in general, a reversal of the classical partisan effect for the east is to be found only in specific cases and, is most likely in government spending in liberal eastern countries.
The role of glutathione peroxidases (GPx) in cancer and their influence on tumor prognosisand the development of anticancer drug resistance has been extensively and controversially discussed.The aim of this study was to evaluate the influence of GPx1 expression on anticancer drug cytotoxicity.For this purpose, a GPx1 knockout of the near-haploid human cancer cell line HAP-1 was generatedand compared to the native cell line with regards to morphology, growth and metabolic rates,and oxidative stress defenses. Furthermore, the IC50values of two peroxides and 16 widely usedanticancer drugs were determined in both cell lines. Here we report that the knockout of GPx1 in HAP-1cells has no significant effect on cell size, viability, growth and metabolic rates. Significant increasesin the cytotoxic potency of hydrogen peroxide andtert-butylhydroperoxide, the anticancer drugscisplatin and carboplatin as well as the alkylating agents lomustine and temozolomide were found.While a concentration dependent increases in intracellular reactive oxygen species (ROS) levelswere observed for both HAP-1 cell lines treated with either cisplatin, lomustine or temozolamide,no significant enhancement in ROS levels was observed in the GPx1 knockout compared to the nativecell line except at the highest concentration of temozolamide. On the other hand, a ca. 50% decreasein glutathione levels was noted in the GPx1 knockout relative to the native line, suggesting thatfactors other than ROS levels alone play a role in the increased cytotoxic activity of these drugs in theGPx1 knockout cells.
Abstract
Over the last years, there has been an enormous increase in the knowledge on koi herpesvirus (KHV), koi herpesvirus disease (KHVD), pathogenesis and virus variants. Different KHV lineages have clearly been identified, possible genomic changes during replication in different cell cultures at different temperatures but also in several hosts have been identified, a persistent stage of infection has been specified and it has been shown that infection with KHV is not host specific at all, but KHVD is. Additionally, it has been shown that it is possible to combat KHVD by immunization with inactivated and attenuated live vaccines using different delivery systems but also to benefit from alternative treatments with e.g. exopolysaccharids obtained from Arthrospira platensis.
Abstract
Head motion during magnetic resonance imaging (MRI) induces image artifacts that affect virtually every brain measure. In parallel, cross‐sectional observations indicate a correlation of head motion with age, psychiatric disease status and obesity, raising the possibility of a systematic artifact‐induced bias in neuroimaging outcomes in these conditions, due to the differences in head motion. Yet, a causal link between obesity and head motion has not been tested in an experimental design. Here, we show that a change in body mass index (BMI) (i.e., weight loss after bariatric surgery) systematically decreases head motion during MRI. In this setting, reduced imaging artifacts due to lower head motion might result in biased estimates of neural differences induced by changes in BMI. Overall, our finding urges the need to rigorously control for head motion during MRI to enable valid results of neuroimaging outcomes in populations that differ in head motion due to obesity or other conditions.
Investigation of In-Vitro Adaptation toward Sodium Bituminosulfonate in Staphylococcus aureus
(2020)
Staphylococcus aureus can cause life-threatening diseases, and hospital- as well as community-associated antibiotic-resistant strains are an emerging global public health problem. Therefore, prophylactic vaccines or immune-based therapies are considered as alternative treatment opportunities. To develop such novel treatment approaches, a better understanding of the bacterial virulence and immune evasion mechanisms and their potential effects on immune-based therapies is essential. One important staphylococcal virulence factor is alpha-toxin, which is able to disrupt the epithelial barrier in order to establish infection. In addition, alpha-toxin has been reported to modulate other cell types including immune cells. Since CD4+ T cell-mediated immunity is required for protection against S. aureus infection, we were interested in the ability of alpha-toxin to directly modulate CD4+ T cells. To address this, murine naïve CD4+ T cells were differentiated in vitro into effector T cell subsets in the presence of alpha-toxin. Interestingly, alpha-toxin induced death of Th1-polarized cells, while cells polarized under Th17 conditions showed a high resistance toward increasing concentrations of this toxin. These effects could neither be explained by differential expression of the cellular alpha-toxin receptor ADAM10 nor by differential activation of caspases, but might result from an increased susceptibility of Th1 cells toward Ca2+-mediated activation-induced cell death. In accordance with the in vitro findings, an alpha-toxin-dependent decrease of Th1 and concomitant increase of Th17 cells was observed in vivo during S. aureus bacteremia. Interestingly, corresponding subsets of innate lymphoid cells and γδ T cells were similarly affected, suggesting a more general effect of alpha-toxin on the modulation of type 1 and type 3 immune responses. In conclusion, we have identified a novel alpha-toxin-dependent immunomodulatory strategy of S. aureus, which can directly act on CD4+ T cells and might be exploited for the development of novel immune-based therapeutic approaches to treat infections with antibiotic-resistant S. aureus strains.
The transcriptome of non-coding RNA (ncRNA) species is increasingly focused in Alzheimer’s disease (AD) research. NcRNAs comprise, among others, transfer RNAs, long non-coding RNAs and microRNAs (miRs), each with their own specific biological function. We used smallRNASeq to assess miR expression in the hippocampus of young (3 month old) and aged (8 month old) Tg4-42 mice, a model system for sporadic AD, as well as age-matched wildtype controls. Tg4-42 mice express N-truncated Aβ4–42, develop age-related neuron loss, reduced neurogenesis and behavioral deficits. Our results do not only confirm known miR-AD associations in Tg4-42 mice, but more importantly pinpoint 22 additional miRs associated to the disease. Twenty-five miRs were differentially expressed in both aged Tg4-42 and aged wildtype mice while eight miRs were differentially expressed only in aged wildtype mice, and 33 only in aged Tg4-42 mice. No significant alteration in the miRNome was detected in young mice, which indicates that the changes observed in aged mice are down-stream effects of Aβ-induced pathology in the Tg4-42 mouse model for AD. Targets of those miRs were predicted using miRWalk. For miRs that were differentially expressed only in the Tg4-42 model, 128 targets could be identified, whereas 18 genes were targeted by miRs only differentially expressed in wildtype mice and 85 genes were targeted by miRs differentially expressed in both mouse models. Genes targeted by differentially expressed miRs in the Tg4-42 model were enriched for negative regulation of long-term synaptic potentiation, learning or memory, regulation of trans-synaptic signaling and modulation of chemical synaptic transmission obtained. This untargeted miR sequencing approach supports previous reports on the Tg4-42 mice as a valuable model for AD. Furthermore, it revealed miRs involved in AD, which can serve as biomarkers or therapeutic targets.
Abstract
Objectives
Visual shade selection is the most commonly used method in dentistry and a challenge for every dentist. However, differences to natural tooth color and the differences of each shade guide are well known. The aim of this paper is to investigate the suitability of two different color scales for determining the color of no‐match templates.
Materials and methods
Volunteers (N = 76) selected a shade color of a no‐match template with two shade guides (VITA Classical shade guide (VC) and VITA Linearguide 3D‐Master (V3D LG), both Vita Zahnfabrik). The neutral grey background was laterally illuminated with a color differentiation lamp (Dialite, Eickhorst GmbH). For the volunteers’ accuracy, the triangle's area was used which are emerge by the color coordinates of a template (LTaTbT) and the color coordinates of the two decisions (L1a1b1 and L2a2b2). Statistical software was used to evaluate the differences in ΔE00 with α = .01.
Results
A deviation in the median of ΔE00 of 7.6 (V3D LG, first choice) to 6.6 (VC, second choice) was detected, while U test showed no significant differences in the median for both color scales. But the triangle's area generated by both shade decisions and tooth color with V3D LG was significant smaller (14.2) then VC (19.2) (P ≤ .001).
Conclusions
When comparing both results no significant difference in the subject's shade selection and the shade guides was detected. The new evaluation strategy using the size of the triangle's areas proves the superiority of the V3D LG due to a better distribution of the tooth color shades within the color space.
Abstract
Two decades after the discovery of adult‐born neurons in the brains of decapod crustaceans, the deutocerebral proliferative system (DPS) producing these neural lineages has become a model of adult neurogenesis in invertebrates. Studies on crayfish have provided substantial insights into the anatomy, cellular dynamics, and regulation of the DPS. Contrary to traditional thinking, recent evidence suggests that the neurogenic niche in the crayfish DPS lacks self‐renewing stem cells, its cell pool being instead sustained via integration of hemocytes generated by the innate immune system. Here, we investigated the origin, division and migration patterns of the adult‐born neural progenitor (NP) lineages in detail. We show that the niche cell pool is not only replenished by hemocyte integration but also by limited numbers of symmetric cell divisions with some characteristics reminiscent of interkinetic nuclear migration. Once specified in the niche, first generation NPs act as transit‐amplifying intermediate NPs that eventually exit and produce multicellular clones as they move along migratory streams toward target brain areas. Different clones may migrate simultaneously in the streams but occupy separate tracks and show spatio‐temporally flexible division patterns. Based on this, we propose an extended DPS model that emphasizes structural similarities to pseudostratified neuroepithelia in other arthropods and vertebrates. This model includes hemocyte integration and intrinsic cell proliferation to synergistically counteract niche cell pool depletion during the animal's lifespan. Further, we discuss parallels to recent findings on mammalian adult neurogenesis, as both systems seem to exhibit a similar decoupling of proliferative replenishment divisions and consuming neurogenic divisions.
Trade of cattle between farms forms a complex trade network. We investigate partitions of this network for cattle trade in Germany. These partitions are groups of farms with similar properties and they are inferred directly from the trade pattern between farms. We make use of a rather new method known as stochastic block modeling (SBM) in order to divide the network into smaller units. SBM turns out to outperform the more established community detection method in the context of disease control in terms of trade restriction. Moreover, SBM is also superior to geographical based trade restrictions and could be a promising approach for disease control.
Trade of cattle between farms forms a complex trade network. We investigate partitions of this network for cattle trade in Germany. These partitions are groups of farms with similar properties and they are inferred directly from the trade pattern between farms. We make use of a rather new method known as stochastic block modeling (SBM) in order to divide the network into smaller units. SBM turns out to outperform the more established community detection method in the context of disease control in terms of trade restriction. Moreover, SBM is also superior to geographical based trade restrictions and could be a promising approach for disease control.
One of the most common mutations in the serine protease inhibitor Kazal type 1 (SPINK1) gene is the N34S variant which is strongly associated with chronic pancreatitis. Although it is assumed that N34S mutation constitutes a high-risk factor, the underlying pathologic mechanism is still unknown. In the present study, we investigated the impact of physiological stress factors on SPINK1 protein structure and trypsin inhibitor function using biophysical methods. Our circular dichroism spectroscopy data revealed differences in the secondary structure of SPINK1 and N34S mutant suggesting protein structural changes induced by the mutation as an impairment that could be disease-relevant. We further confirmed that both SPINK1 (KD of 0.15 ± 0.06 nM) and its N34S variant (KD of 0.08 ± 0.02 nM) have similar binding affinity and inhibitory effect towards trypsin as shown by surface plasmon resonance and trypsin inhibition assay studies, respectively. We found that stress conditions such as altered ion concentrations (i.e. potassium, calcium), temperature shifts, as well as environmental pH lead to insignificant differences in trypsin inhibition between SPINK1 and N34S mutant. However, we have shown that the environmental pH induces structural changes in both SPINK1 constructs in a different manner. Our findings suggest protein structural changes in the N34S variant as an impairment of SPINK1 and environmental pH shift as a trigger that could play a role in disease progression of pancreatitis.
Mussel farming, compared to marine finfish aquaculture, represents an environmentally friendly alternative for a high quality protein source and can at the same time be a measure to remove excess nutrients in eutrophic areas. As such, it is considered as a promising “blue growth” potential and promoted within the European Union. To expand mussel aquaculture, new regions have to be considered because there are multiple marine usages, and spatial limitations occur in coastal areas. The brackish Baltic Sea might be considered for expansion of mussel aquaculture. This study focusses on estimated production potential, economic profitability and nutrient remediation potential of mussel farming at different salinities. Four experimental mussel farms were set up along the German Baltic coast at salinities ranging from 7 to 17 psu. Collected growth data was used to calibrate and validate a Dynamic Energy Budget model and to predict the potential mussel production at 12 sites along the German coast. The estimated production and nutrient removal was used to assess economic profitability, assuming two usages of the harvest: human consumption and mussel meal production. Measured mussel specific growth rates increased with salinity from 0.05 mm d–1 in Greifswald Bay to 0.11 mm d–1 in Kiel Fjord. Within 6 months, a 1-ha farm could produce from 1 t (Darss-Zingst-Bodden-Chain) to 51 t (Flensburg) fresh mussels and remove 1.1 to 27.7 kg P and 24.7 to 612.7 kg N, respectively. Mussel farms at sites west of Rostock at salinities >10 psu could produce 5 cm mussels within 18 months, but only farms at Flensburg, Eckernförde and Kiel Fjord became profitable at a farm size of 4 ha (160,000 m3) at current market prices of 2.2 € kg–1. Regardless of the farm size, none of the farm sites could operate profitable if fresh mussels were sold for animal feeding at sales price of 0.06 € kg–1. Yearly nutrient removal costs at a small-scale farm (1 ha) ranged between 162 € (Flensburg) and 4,018 € (Darss-Zingst-Bodden-Chain) kg–1 nitrogen, and 3,580 € and 88,750 € kg–1 phosphorus, respectively.
Direct monitoring of drug‐induced mechanical response of individual cells by atomic force microscopy
(2020)
Abstract
Mechanical characteristics of individual cells play a vital role in many biological processes and are considered as indicators of the cells’ states. Disturbances including methyl‐β‐cyclodextrin (MβCD) and cytochalasin D (cytoD) are known to significantly affect the state of cells, but little is known about the real‐time response of single cells to these drugs in their physiological condition. Here, nanoindentation‐based atomic force microscopy (AFM) was used to measure the elasticity of human embryonic kidney cells in the presence and absence of these pharmaceuticals. The results showed that depletion of cholesterol in the plasma membrane with MβCD resulted in cell stiffening whereas depolymerization of the actin cytoskeleton by cytoD resulted in cell softening. Using AFM for real‐time measurements, we observed that cells mechanically responded right after these drugs were added. In more detail, the cell´s elasticity suddenly increased with increasing instability upon cholesterol extraction while it is rapidly decreased without changing cellular stability upon depolymerizing actin cytoskeleton. These results demonstrated that actin cytoskeleton and cholesterol contributed differently to the cell mechanical characteristics.
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.
Long-chain aliphatic amines such as (S,Z)-hepta- dec-9-en-7-amine and 9-aminoheptadecane were synthesized from ricinoleic acid and oleic acid, respectively, by whole-cell cascade reactions using the combination of an alcohol dehydrogenase (ADH) from Micrococcus luteus, an engi- neered amine transaminase from Vibrio fluvialis (Vf-ATA), and a photoactivated decarboxylase from Chlorella variabilis NC64A (Cv-FAP) in a one-pot process. In addition, long chain aliphatic esters such as 10-(heptanoyloxy)dec-8-ene and octyl- nonanoate were prepared from ricinoleic acid and oleic acid, respectively, by using the combination of the ADH, a Baeyer– Villiger monooxygenase variant from Pseudomonas putida KT2440, and the Cv-FAP. The target compounds were produced at rates of up to 37 U g1 dry cells with conversions up to 90 %. Therefore, this study contributes to the preparation of industrially relevant long-chain aliphatic chiral amines and esters from renewable fatty acid resources.
Patients with high-risk neuroblastoma treated with continuous long-term infusion of anti-GD2 antibody dinutuximab beta (DB) in combination with IL-2 show an acceptable safety profile. Here, we compared treatment tolerance with and without IL-2. Ninety-nine patients with high-risk neuroblastoma received up to five cycles of DB given as long-term infusion (10 mg/m2/d, 100 mg/m2; per cycle) with IL-2 (53 patients; regimen A; 6 × 106 IU/m2/d; 60 × 106 IU/m2/cycle) and without IL-2 (46 patients; regimen B) in a single-center compassionate use program. Clinical parameters (body temperature, vital signs, Lansky performance score), laboratory values [C-reactive protein, IFN-γ, IL-6, and IL-18 (cycle 1)], and requirement of i.v. co-medication (e.g., morphine, metamizole) were systematically assessed. Patients with stable clinical parameters and that did not require co-medication were defined as potential “outpatient candidates.” Patients showed higher levels of body temperature and CRP in regimen A compared to B. However, IL-6 serum concentrations were similar in pts of both cohorts in the first cycle. Patients receiving regimen B showed a shorter time to achieve normal vital parameters and required less co-medication compared to patients in regimen A that resulted in a shorter median time period to discharge and to achieve a potential outpatient status (6d regimen A and 3–5d regimen B after start of antibody infusion, respectively). This study shows that omitting IL-2 from immunotherapy with DB allows reduced co-medication and hospitalization time and therefore results in improved quality of life in patients with high-risk neuroblastoma.
Abstract
Platelets are small anucleate blood cells with a life span of 7 to 10 days. They are main regulators of hemostasis. Balanced platelet activity is crucial to prevent bleeding or occlusive thrombus formation. Growing evidence supports that platelets also participate in immune reactions, and interaction between platelets and leukocytes contributes to both thrombosis and inflammation. The ubiquitin‐proteasome system (UPS) plays a key role in maintaining cellular protein homeostasis by its ability to degrade non‐functional self‐, foreign, or short‐lived regulatory proteins. Platelets express standard and immunoproteasomes. Inhibition of the proteasome impairs platelet production and platelet function. Platelets also express major histocompatibility complex (MHC) class I molecules. Peptide fragments released by proteasomes can bind to MHC class I, which makes it also likely that platelets can activate epitope specific cytotoxic T lymphocytes (CTLs). In this review, we focus on current knowledge on the significance of the proteasome for the functions of platelets as critical regulators of hemostasis as well as modulators of the immune response.
Acidobacteria represents one of the most dominant bacterial groups across diverse ecosystems. However, insight into their ecology and physiology has been hampered by difficulties in cultivating members of this phylum. Previous cultivation efforts have suggested an important role of trace elements for the proliferation of Acidobacteria, however, the impact of these metals on their growth and metabolism is not known. In order to gain insight into this relationship, we evaluated the effect of trace element solution SL10 on the growth of two strains (5B5 and WH15) of Acidobacteria belonging to the genus Granulicella and studied the proteomic responses to manganese (Mn). Granulicella species had highest growth with the addition of Mn, as well as higher tolerance to this metal compared to seven other metal salts. Variations in tolerance to metal salt concentrations suggests that Granulicella sp. strains possess different mechanisms to deal with metal ion homeostasis and stress. Furthermore, Granulicella sp. 5B5 might be more adapted to survive in an environment with higher concentration of several metal ions when compared to Granulicella sp. WH15. The proteomic profiles of both strains indicated that Mn was more important in enhancing enzymatic activity than to protein expression regulation. In the genomic analyses, we did not find the most common transcriptional regulation of Mn homeostasis, but we found candidate transporters that could be potentially involved in Mn homeostasis for Granulicella species. The presence of such transporters might be involved in tolerance to higher Mn concentrations, improving the adaptability of bacteria to metal enriched environments, such as the decaying wood-rich Mn environment from which these two Granulicella strains were isolated.
Non-alcoholic fatty liver disease (NAFLD) is gaining in importance and is linked to obesity.
Especially, the development of fibrosis and portal hypertension in NAFLD patients requires treatment.
Transgenic TGR(mREN2)27 rats overexpressing mouse renin spontaneously develop NAFLD with
portal hypertension but without obesity. This study investigated the additional role of obesity in this
model on the development of portal hypertension and fibrosis. Obesity was induced in twelve-week
old TGR(mREN2)27 rats after receiving Western diet (WD) for two or four weeks. Liver fibrosis
was assessed using standard techniques. Hepatic expression of transforming growth factor-β1
(TGF-β1), collagen type Iα1, α-smooth muscle actin, and the macrophage markers Emr1, as well as
the chemoattractant Ccl2, interleukin-1β (IL1β) and tumor necrosis factor-α (TNFα) were analyzed.
Assessment of portal and systemic hemodynamics was performed using the colored microsphere
technique. As expected, WD induced obesity and liver fibrosis as confirmed by Sirius Red and Oil Red
O staining. The expression of the monocyte-macrophage markers, Emr1, Ccl2, IL1β and TNFα were
increased during feeding of WD, indicating infiltration of macrophages into the liver, even though this
increase was statistically not significant for the EGF module-containing mucin-like receptor (Emr1)
mRNA expression levels. Of note, portal pressure increased with the duration of WD compared
to animals that received a normal chow. Besides obesity, WD feeding increased systemic vascular
resistance reflecting systemic endothelial and splanchnic vascular dysfunction. We conclude that
transgenic TGR(mREN2)27 rats are a suitable model to investigate NAFLD development with liver
fibrosis and portal hypertension. Tendency towards elevated expression of Emr1 is associated with
macrophage activity point to a significant role of macrophages in NAFLD pathogenesis, probably
due to a shift of the renin–angiotensin system towards a higher activation of the classical pathway.The hepatic injury induced by WD in TGR(mREN2)27 rats is suitable to evaluate different stages of
fibrosis and portal hypertension in NAFLD with obesity
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?
Glutathione (GSH) was initially identified and characterized for its redox properties andlater for its contributions to detoxification reactions. Over the past decade, however, the essentialcontributions of glutathione to cellular iron metabolism have come more and more into focus. GSH isindispensable in mitochondrial iron-sulfur (FeS) cluster biosynthesis, primarily by co-ligating FeSclusters as a cofactor of the CGFS-type (class II) glutaredoxins (Grxs). GSH is required for the exportof the yet to be defined FeS precursor from the mitochondria to the cytosol. In the cytosol, it is anessential cofactor, again of the multi-domain CGFS-type Grxs, master players in cellular iron and FeStrafficking. In this review, we summarize the recent advances and progress in this field. The mosturgent open questions are discussed, such as the role of GSH in the export of FeS precursors frommitochondria, the physiological roles of the CGFS-type Grx interactions with BolA-like proteins andthe cluster transfer between Grxs and recipient proteins
Abstract
Background and aims: Intestinal adaptation in short bowel syndrome (SBS) includes morphologic processes and functional mechanisms. This study investigated whether digestive enzyme expression in the duodenum and colon is upregulated in SBS patients. Method: Sucrase‐isomaltase (SI), lactase‐phlorizin hydrolase (LPH), and neutral Aminopeptidase N (ApN) were analyzed in duodenal and colonic biopsies from nine SBS patients in a late stage of adaptation as well as healthy and disease controls by immunoelectron microscopy (IEM), Western blots, and enzyme activities. Furthermore, proliferation rates and intestinal microbiota were analyzed in the mucosal specimen. Results: We found significantly increased amounts of SI, LPH, and ApN in colonocytes in most SBS patients with large variation and strongest effect for SI and ApN. Digestive enzyme expression was only partially elevated in duodenal enterocytes due to a low proliferation level measured by Ki‐67 staining. Microbiome analysis revealed high amounts of Lactobacillus resp. low amounts of Proteobacteria in SBS patients with preservation of colon and ileocecal valve. Colonic expression was associated with a better clinical course in single cases. Conclusion: In SBS patients disaccharidases and peptidases can be upregulated in the colon. Stimulation of this colonic intestinalization process by drugs, nutrients, and pre‐ or probiotics might offer better therapeutic approaches.
Abstract
Aim
Species–area relationships (SARs) are fundamental scaling laws in ecology although their shape is still disputed. At larger areas, power laws best represent SARs. Yet, it remains unclear whether SARs follow other shapes at finer spatial grains in continuous vegetation. We asked which function describes SARs best at small grains and explored how sampling methodology or the environment influence SAR shape.
Location
Palaearctic grasslands and other non‐forested habitats.
Taxa
Vascular plants, bryophytes and lichens.
Methods
We used the GrassPlot database, containing standardized vegetation‐plot data from vascular plants, bryophytes and lichens spanning a wide range of grassland types throughout the Palaearctic and including 2,057 nested‐plot series with at least seven grain sizes ranging from 1 cm2 to 1,024 m2. Using nonlinear regression, we assessed the appropriateness of different SAR functions (power, power quadratic, power breakpoint, logarithmic, Michaelis–Menten). Based on AICc, we tested whether the ranking of functions differed among taxonomic groups, methodological settings, biomes or vegetation types.
Results
The power function was the most suitable function across the studied taxonomic groups. The superiority of this function increased from lichens to bryophytes to vascular plants to all three taxonomic groups together. The sampling method was highly influential as rooted presence sampling decreased the performance of the power function. By contrast, biome and vegetation type had practically no influence on the superiority of the power law.
Main conclusions
We conclude that SARs of sessile organisms at smaller spatial grains are best approximated by a power function. This coincides with several other comprehensive studies of SARs at different grain sizes and for different taxa, thus supporting the general appropriateness of the power function for modelling species diversity over a wide range of grain sizes. The poor performance of the Michaelis–Menten function demonstrates that richness within plant communities generally does not approach any saturation, thus calling into question the concept of minimal area.
Electrochemical characterisation of the redox behaviour of quinoide components in membrane models
(2020)
The leading idea of this thesis is to study the effects of (i) membrane composition and (ii) membrane environment (aqueous phases) on the redox properties of membrane-confined redox active compounds. For solutions, it is known since long, how strong solvents affect the redox properties of dissolved redox active species. However, for membranes this question has not yet been addressed, although it can be supposed that such effects may be important to understand the role of membrane-confined redox active compounds in biological systems. To interrogate this problem, a monolayer model was chosen. It consists of a lipid monolayer with embedded menaquinones on mercury electrodes. Since ion transfer across membranes is also a crucial question, in the first part of this project, 2,2-diphenyl-1-picrylhydrazyl (DPPH) was studied as a new redox probe for transferring anions and cation between an organic and an aqueous phase. The important findings of this thesis are: (i) accessing the ion pair equilibrium constant of anions and cations with DPPH redox probe as a model study using the three-phase electrochemistry, (ii) the redox potentials of menaquinone-4, -7, and -9 in 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) monolayers and the acidity constants of menaquinones (MK’s) in membranes monolayer model, and (iii) the effects of membrane composition and the aqueous environment on the thermodynamics and kinetics of MK’s in membrane models.
Abstract
Non‐native invasive species are threatening ecosystems and biodiversity worldwide. High genetic variation is thought to be a critical factor for invasion success. Accordingly, the global invasion of a few clonal lineages of the gastropod Potamopyrgus antipodarum is thus both puzzling and has the potential to help illuminate why some invasions succeed while others fail. Here, we used SNP markers and a geographically broad sampling scheme (N = 1617) including native New Zealand populations and invasive North American and European populations to provide the first widescale population genetic assessment of the relationships between and among native and invasive P. antipodarum. We used a combination of traditional and Bayesian molecular analyses to demonstrate that New Zealand populations harbour very high diversity relative to the invasive populations and are the source of the two main European genetic lineages. One of these two European lineages was in turn the source of at least one of the two main North American genetic clusters of invasive P. antipodarum, located in Lake Ontario. The other widespread North American group had a more complex origin that included the other European lineage and two New Zealand clusters. Altogether, our analyses suggest that just a small handful of clonal lineages of P. antipodarum were responsible for invasion across continents. Our findings provide critical information for prevention of additional invasions and control of existing invasive populations and are of broader relevance towards understanding the establishment and evolution of asexual populations and the forces driving biological invasion.
Membrane monocarboxylate transporter 1 (SLC16A1/MCT1) plays an important role in
hepatocyte homeostasis, as well as drug handling. However, there is no available information
about the impact of liver pathology on the transporter levels and function. The study was aimed to
quantify SLC16A1 mRNA (qRT-PCR) and MCT1 protein abundance (liquid chromatography–tandem
mass spectrometry (LC¬¬–MS/MS)) in the livers of patients diagnosed, according to the standard
clinical criteria, with hepatitis C, primary biliary cirrhosis, primary sclerosing hepatitis, alcoholic liver
disease (ALD), and autoimmune hepatitis. The stage of liver dysfunction was classified according to
Child–Pugh score. Downregulation of SLC16A1/MCT1 levels was observed in all liver pathology
states, significantly for ALD. The progression of liver dysfunction, from Child–Pugh class A to C,
involved the gradual decline in SLC16A1 mRNA and MCT1 protein abundance, reaching a clinically
significant decrease in class C livers. Reduced levels of MCT1 were associated with significant
intracellular lactate accumulation. The MCT1 transcript and protein did not demonstrate significant
correlations regardless of the liver pathology analyzed, as well as the disease stage, suggesting
posttranscriptional regulation, and several microRNAs were found as potential regulators of MCT1
abundance. MCT1 membrane immunolocalization without cytoplasmic retention was observed in all
studied liver pathologies. Overall, the study demonstrates that SLC16A1/MCT1 is involved in liver
pathology, especially in ALD
This paper presents continuous, high resolution fossil pollen and microcharcoal records from Bo Langvlei, a lake in the Wilderness Embayment on South Africa’s southern Cape coast. Spanning the past ~1300 years and encompassing the Medieval Climate Anomaly (MCA; c. AD 950–1250) and the Little Ice Age (LIA; c. AD 1300–1850), these records provide a rare southern African perspective on past temperature, moisture and vegetation change during these much debated periods of the recent geological past. Considered together with other records from the Wilderness Embayment, we conclude that conditions in the region during the MCA chronozone were – in the context of the last 1300 years – likely relatively dry (reduced levels of Afrotemperate forest pollen) and perhaps slightly cooler (increased percentages of Stoebe-type pollen) than present. The most significant phase of forest expansion, and more humid conditions, occurred during the transition between the MCA and the most prominent cooling phase of the LIA. The LIA is clearly identified at this locality as a period of cool, dry conditions between c. AD 1600 and 1850. The mechanisms driving the changes observed in the Bo Langvlei pollen record appear to be generally linked to changes in temperature, and changes in the influence of tropical circulation systems. During warmer periods, moisture availability was higher at Bo Langvlei, and rainfall was perhaps less seasonal. During colder periods, precipitation resulting from tropical disturbances was more restricted, resulting in drier conditions. While increased precipitation has been reported during the LIA from Verlorenvlei in the Western Cape as a result of an equatorward displacement of the westerly storm-track at this time, the opposing response at Bo Langvlei suggests that any increased influence of westerlies was insufficient to compensate for the concurrent reduction in tropical/local rainfall in the region.
Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease which is often
caused by recurrent emboli. These are also frequently found in patients with myeloproliferative
diseases. While myeloproliferative diseases can be caused by gene defects, the genetic predisposition
to CTEPH is largely unexplored. Therefore, the objective of this study was to analyse these genes
and further genes involved in pulmonary hypertension in CTEPH patients. A systematic screening
was conducted for pathogenic variants using a gene panel based on next generation sequencing.
CTEPH was diagnosed according to current guidelines. In this study, out of 40 CTEPH patients
4 (10%) carried pathogenic variants. One patient had a nonsense variant (c.2071A>T p.Lys691*)
in the BMPR2 gene and three further patients carried the same pathogenic variant (missense variant,
c.1849G>T p.Val617Phe) in the Janus kinase 2 (JAK2) gene. The latter led to a myeloproliferative
disease in each patient. The prevalence of this JAK2 variant was significantly higher than expected
(p < 0.0001). CTEPH patients may have a genetic predisposition more often than previously thought.
The predisposition for myeloproliferative diseases could be an additional risk factor for CTEPH
development. Thus, clinical screening for myeloproliferative diseases and genetic testing may be
considered also for CTEPH patients.
Abstract
Background
Knowledge of molar incisor hypomineralization (MIH) has relevance for paediatric dentists.
Aim
To assess final‐year German dental students’ knowledge, attitudes, and beliefs regarding MIH.
Materials and methods
A previously validated questionnaire was posted to the 31 German dental schools. Demographic covariates as well as knowledge regarding
diagnosis and prevalence, and attitudes and beliefs around aetiology and management were collected.
Results
Twenty‐two (71%) dental schools responded and a total of 877 students participated. Most (97%) were familiar with MIH and 88% were aware of the diagnostic criteria for MIH; however, only 42% knew how to implement them. One‐third were able to identify MIH and 16% reported diagnostic confidence when doing so; 90% assumed the MIH prevalence to be <10%. Two‐thirds of the respondents implicated genetic components as the main aetiological factor of MIH. Resin composite (60%) and preformed metal crowns (46%) were the dental materials most often suggested for restorative management. Almost all (98%) respondents were interested in receiving more clinical training.
Conclusion
German students were familiar with MIH; however, they reported low levels of knowledge and confidence regarding its prevalence and diagnosis. Standardized nationwide, up‐to‐date curricula should be implemented to educate future dentists in Germany.
Abstract
Caveolae position CaV3.2 (T‐type Ca2+ channel encoded by the α‐3.2 subunit) sufficiently close to RyR (ryanodine receptors) for extracellular Ca2+ influx to trigger Ca2+ sparks and large‐conductance Ca2+‐activated K+ channel feedback in vascular smooth muscle. We hypothesize that this mechanism of Ca2+ spark generation is affected by age. Using smooth muscle cells (VSMCs) from mouse mesenteric arteries, we found that both Cav3.2 channel inhibition by Ni2+ (50 µM) and caveolae disruption by methyl‐ß‐cyclodextrin or genetic abolition of Eps15 homology domain‐containing protein (EHD2) inhibited Ca2+ sparks in cells from young (4 months) but not old (12 months) mice. In accordance, expression of Cav3.2 channel was higher in mesenteric arteries from young than old mice. Similar effects were observed for caveolae density. Using SMAKO Cav1.2−/− mice, caffeine (RyR activator) and thapsigargin (Ca2+ transport ATPase inhibitor), we found that sufficient SR Ca2+ load is a prerequisite for the CaV3.2‐RyR axis to generate Ca2+ sparks. We identified a fraction of Ca2+ sparks in aged VSMCs, which is sensitive to the TRP channel blocker Gd3+ (100 µM), but insensitive to CaV1.2 and CaV3.2 channel blockade. Our data demonstrate that the VSMC CaV3.2‐RyR axis is down‐regulated by aging. This defective CaV3.2‐RyR coupling is counterbalanced by a Gd3+ sensitive Ca2+ pathway providing compensatory Ca2+ influx for triggering Ca2+ sparks in aged VSMCs.
Abstract
Aim
This study analysed the comparative cost of feeding donor human milk to preterm infants compared to mother's own milk and formula.
Methods
A document and process analysis and a time measurement study were carried out at the milk bank of the Level 1 Perinatal Center of the University Hospital of Greifswald, Germany, from April to June 2017. The cost analysis data were provided by the University's financial department.
Results
The total cost per year was €92 085.02 for 300 litres of donor human milk: 27% of this was material costs, 51% was personnel costs, and 22% was other overheads. The average cost per litre was €306.95, and staff time was 492 minutes per litre. The total marginal cost for each additional litre of donor human milk, formula or unpasteurised mother´s milk was €82.88, €10.28 and €38.42, respectively. Pasteurising a litre of donor milk cost €3.51.
Conclusion
Providing preterm infants with donor milk was much more expensive than using formula or mother's own milk, but the cost of pasteurisation was minimal.
Objective
This study provides a comprehensive overview of the associations of five adipokines (adiponectin, chemerin, galectin‐3, leptin, and resistin) with fat deposits, behavioral risk factors, and metabolic phenotypes.
Methods
Using multivariable linear and logistic regression models, cross‐sectional data from 4,116 participants of the population‐based Study of Health in Pomerania were analyzed.
Results
Participants with obesity showed higher chemerin, galectin‐3, and leptin but showed lower adiponectin concentrations. Independently of other fat compounds, liver fat content, visceral adipose tissue, and subcutaneous adipose tissue (SAT) were inversely associated with adiponectin. Independent positive associations of liver fat content and SAT with chemerin as well as of SAT with galectin‐3 and leptin were observed. Physically inactive participants had higher chemerin and leptin concentrations. Smokers had higher chemerin and galectin‐3 as well as lower leptin. Alcohol consumption was associated with adiponectin (positive) and resistin (inverse). All adipokines were associated with at least one lipid marker. Associations with glucose metabolism were seen for adiponectin, chemerin, galectin‐3, and leptin.
Conclusions
High adiponectin concentrations were related to favorable metabolic conditions, whereas high chemerin, galectin‐3, and leptin were associated with an unfavorable metabolic profile. High leptin seems to be primarily indicative of obesity, whereas high adiponectin and chemerin are associated with a broader range of metabolic phenotypes.
This thesis describes recent developments in multi-reflection time-of-flight mass spectrometry (MR-ToF MS) with ions exhibiting large masses and mass differences at an MR-ToF setup at the University of Greifswald. A series of in-trap manipulation techniques to selectively retain or eject ion bunches of multiple species with disparate mass-to-charge ratios is investigated. These highlight the possibility to correct long-term flight-time drifts using a reference ion species far away in mass from the species of interest and also the ability to use such a pair to perform single-reference precision mass determinations. In both cases, the results obtained with disparate-mass ion pairs are comparable to those known from operation with isobaric species.
In addition, an in-trap photoexcitation technique is developed and applied to study the dissociation behavior of atomic bismuth clusters (systems of some number of bismuth atoms). Compared to previous works by other groups, the probed cluster-size range is expanded for both ion polarities, resulting in a more comprehensive picture of the underlying dissociation pathways. The known significance of neutral-tetramer breakoff is confirmed, however, evidence is also found for the loss of larger neutral fragments.
Lastly, the principle of tandem high-resolution MR-ToF MS is introduced. This new method allows the study of the change in dissociation behavior of the cationic bismuth octamer resulting from substituting one of its atoms for lead. It is found that the lead-doping opens new preferential fragmentation pathways that outstrip the dominant tetramer breakoff for this specific precursor cluster size. As a first proof-of-principle experiment, the case of the cationic octamer shows that tandem MR-ToF MS is well-suited for the investigation of compound clusters.
Indium-cluster anions In−nare probed for delayed dissociation by photoexcitation in a multi-reflection time-of-flight device. In addition to prompt dissociation with below-microsecond decay constants, we observe reactionson timescales of several tens to hundreds of microseconds. These time-resolved decay-rate measurements reveala power-law behavior in time which can be traced back to the clusters’ energy distribution due to their productionby laser ablation in high vacuum. Modeling energy distributions from such a production allows us to connect thecluster-specific dissociation energy with the ensemble temperature through experimentally determined power-law exponents.
Objectives: Navigated transcranial magnetic stimulation (nTMS) provides significant benefits over classic TMS. Yet, the acquisition of individual structural magnetic resonance images (MRIindividual) is a time-consuming, expensive, and not feasible prerequisite in all subjects for spatial tracking and anatomical guidance in nTMS studies. We hypothesize that spatial transformation can be used to adjust MRI templates to individual head shapes (MRIwarped) and that TMS parameters do not differ between nTMS using MRIindividual or MRIwarped.
Materials and Methods: Twenty identical TMS sessions, each including four different navigation conditions, were conducted in 10 healthy subjects (one female, 27.4 ± 3.8 years), i.e., twice per subject by two researchers to additionally assess interrater reliabilities. MRIindividual were acquired for all subjects. MRIwarped were obtained through the spatial transformation of a template MRI following a 5-, 9-and 36-point head surface registration (MRIwarped_5, MRIwarped_9, MRIwarped_36). Stimulation hotspot locations, resting motor threshold (RMT), 500 μV motor threshold (500 μV-MT), and mean absolute motor evoked potential difference (MAD) of primary motor cortex (M1) examinations were compared between nTMS using either MRIwarped variants or MRIindividual and non-navigated TMS.
Results: M1 hotspots were spatially consistent between MRIindividual and MRIwarped_36 (insignificant deviation by 4.79 ± 2.62 mm). MEP thresholds and variance were also equivalent between MRIindividual and MRIwarped_36 with mean differences of RMT by −0.05 ± 2.28% maximum stimulator output (%MSO; t(19) = −0.09, p = 0.923), 500 μV-MT by −0.15 ± 1.63%MSO (t(19) = −0.41, p = 0.686) and MAD by 70.5 ± 214.38 μV (t(19) = 1.47, p = 0.158). Intraclass correlations (ICC) of motor thresholds were between 0.88 and 0.97.
Conclusions: NTMS examinations of M1 yield equivalent topographical and functional results using MRIindividual and MRIwarped if a sufficient number of registration points are used.
Polysaccharide is a major constituent of the total organic carbon that is generated by photosynthetic eukaryotes. In the marine realm, where approximately half of annual global carbon fixation occurs, algae can produce large amounts of polysaccharide during bloom events. Phytoplankton blooms are frequently seasonal phenomena, and spring blooms in particular have been a focus of study as they are predictable in space and time. This makes them much more amenable model systems in which to explore the processes that occur as organic carbon is recycled.
It is assumed that the bulk of the polysaccharides algae produce serve one of two primary functions - namely acting as an energy storage molecule, or they serve as structural polymers in the cell walls. Other polysaccharides may also have protective functions as exudates. Regardless of function in algae, the polysaccharides are a valuable energy source for heterotrophic bacteria. The combination of abundance and predictable or semi-predictable structure of the polysaccharides has led to proliferation of variations on a particular sequestration and degradation strategy among the Bacteroidetes and Gammaproteobacteria that is frequently characterised as being ‘selfish’. The strategy is based on uptake of poly- and especially oligosaccharides into the periplasm via the use of TonB-dependent transporters. Once in the periplasmic space, oligomers can be further degraded to monomers that can then be transported into the cytosol. This mechanism is beneficial to the cell as it needn’t then lose the nutritive benefit of the polysaccharide to other cells, which may or may not have manufactured their own degradative carbohydrate active enzymes (CAZymes).
The research articles that make up this thesis are thus based around attempts to find and elucidate the polysaccharide preferences of heterotrophic bacteria that become abundant following phytoplankton blooms.The first article is a study into the abundance of TonB-dependent transporter proteins in metaproteomes and metagenomes across a single spring phytoplankton bloom at the long term research station at Helgoland. This investigation identifies transporters for laminarin and alpha-glucans, the two most abundant glucose-based storage polysaccharides, are the most abundant predicted polysaccharide transporting TonB-dependent transporters during the bloom. However, as the bloom progressed, and particularly following a doubling of bacterial cell numbers, the proportion of predicted polysaccharide transporters dedicated to laminarin and alpha-glucan transport declined relative to transporters for less readily degraded mannose-, xylose-, and fucose-containing polysaccharides. The inference is that this change is an active response to the availability of the different polysaccharides, or their relative attractiveness as growth substrates during the period.
The second article is an in-depth look at one of the most abundant Bacteroidetes clades, which was previously unnamed, and has not to date been cultivated. The most abundant species in this clade grows rapidly and often peaks earlier than other heterotrophic clades. It was found to be limited in predicted polysaccharide consumption capability, having only PULs for predicted laminarin degradation. It is also detectable in many locations at higher latitudes where phytoplankton blooms are expected to occur, indicating this is a globally successful consumer of algal organic matter, and may have an outsize significance for global laminarin degradation given its high abundance.
The third article is a more holistic study of phytoplankton bloom associated Gammaproteobacteria, which have otherwise been rather ignored compared to the Bacteroidetes. Gammaproteobacteria overlap with Bacteroidetes to some extent in being clear consumers of laminarin, but fewer of them are clearly capable of consuming the more complex cell-wall derived polysaccharides. Some may, however, be producers of alginate, an otherwise mysteriously popular polysaccharide with Bacteroidetes, given that it is not known to be produced by bloom forming microalgae.
The fourth article then goes into detail on the PUL content of Bacteroidetes, based on metagenomic data. It finds five substrates, alpha- and beta-glucans, xylose and mannose rich polysaccharides, and alginate, are the most frequent predicted polysaccharide substrates for Bacteroidetes PULs among populations responding to the Helgoland spring blooms.
This thesis thus summarises multiple metagenomic and metaproteomic investigations into the polysaccharide consumption capabilities of marine heterotrophic bacteria. These bacteria have a profound impact on the overall carbon cycle in coastal regions, and are critical for understanding how changes in atmospheric carbon concentrations impact carbon turnover and storage in the world's oceans.
Introduction: It has been shown that Alzheimer’s disease (AD) is accompanied by marked structural brain changes that can be detected several years before clinical diagnosis via structural magnetic resonance (MR) imaging. In this study, we developed a structural MR-based biomarker for in vivo detection of AD using a supervised machine learning approach. Based on an individual’s pattern of brain atrophy a continuous AD score is assigned which measures the similarity with brain atrophy patterns seen in clinical cases of AD.
Methods: The underlying statistical model was trained with MR scans of patients and healthy controls from the Alzheimer’s Disease Neuroimaging Initiative (ADNI-1 screening). Validation was performed within ADNI-1 and in an independent patient sample from the Open Access Series of Imaging Studies (OASIS-1). In addition, our analyses included data from a large general population sample of the Study of Health in Pomerania (SHIP-Trend).
Results: Based on the proposed AD score we were able to differentiate patients from healthy controls in ADNI-1 and OASIS-1 with an accuracy of 89% (AUC = 95%) and 87% (AUC = 93%), respectively. Moreover, we found the AD score to be significantly associated with cognitive functioning as assessed by the Mini-Mental State Examination in the OASIS-1 sample after correcting for diagnosis, age, sex, age·sex, and total intracranial volume (Cohen’s f2 = 0.13). Additional analyses showed that the prediction accuracy of AD status based on both the AD score and the MMSE score is significantly higher than when using just one of them. In SHIP-Trend we found the AD score to be weakly but significantly associated with a test of verbal memory consisting of an immediate and a delayed word list recall (again after correcting for age, sex, age·sex, and total intracranial volume, Cohen’s f2 = 0.009). This association was mainly driven by the immediate recall performance.
Discussion: In summary, our proposed biomarker well differentiated between patients and healthy controls in an independent test sample. It was associated with measures of cognitive functioning both in a patient sample and a general population sample. Our approach might be useful for defining robust MR-based biomarkers for other neurodegenerative diseases, too.
The requirements for new technologies to serve as anticancer agents go far beyond their toxicity potential. Novel applications also need to be safe on a molecular and patient level. In a broader sense, this also relates to cancer metastasis and inflammation. In a previous study, the toxicity of an atmospheric pressure argon plasma jet in four human pancreatic cancer cell lines was confirmed and plasma treatment did not promote metastasis in vitro and in ovo. Here, these results are extended by additional types of analysis and new models to validate and define on a molecular level the changes related to metastatic processes in pancreatic cancer cells following plasma treatment in vitro and in ovo. In solid tumors that were grown on the chorion-allantois membrane of fertilized chicken eggs (TUM-CAM), plasma treatment induced modest to profound apoptosis in the tissues. This, however, was not associated with a change in the expression levels of adhesion molecules, as shown using immunofluorescence of ultrathin tissue sections. Culturing of the cells detached from these solid tumors for 6d revealed a similar or smaller total growth area and expression of ZEB1, a transcription factor associated with cancer metastasis, in the plasma-treated pancreatic cancer tissues. Analysis of in vitro and in ovo supernatants of 13 different cytokines and chemokines revealed cell line-specific effects of the plasma treatment but a noticeable increase of, e.g., growth-promoting interleukin 10 was not observed. Moreover, markers of epithelial-to-mesenchymal transition (EMT), a metastasis-promoting cellular program, were investigated. Plasma-treated pancreatic cancer cells did not present an EMT-profile. Finally, a realistic 3D tumor spheroid co-culture model with pancreatic stellate cells was employed, and the invasive properties in a gel-like cellular matrix were investigated. Tumor outgrowth and spread was similar or decreased in the plasma conditions. Altogether, these results provide valuable insights into the effect of plasma treatment on metastasis-related properties of cancer cells and did not suggest EMT-promoting effects of this novel cancer therapy.
Sphagnum growth under N saturation: interactive effects of water level and P or K fertilization
(2020)
Abstract
Sphagnum biomass is a promising material that could be used as a substitute for peat in growing media and can be sustainably produced by converting existing drainage‐based peatland agriculture into wet, climate‐friendly agriculture (paludiculture). Our study focuses on yield maximization of Sphagnum as a crop.
We tested the effects of three water level regimes and of phosphorus or potassium fertilization on the growth of four Sphagnum species (S. papillosum, S. palustre, S. fimbriatum, S. fallax). To simulate field conditions in Central and Western Europe we carried out a glasshouse experiment under nitrogen‐saturated conditions.
A constant high water table (remaining at 2 cm below capitulum during growth) led to highest productivity for all tested species. Water table fluctuations between 2 and 9 cm below capitulum during growth and a water level 2 cm below capitulum at the start but falling relatively during plant growth led to significantly lower productivity. Fertilization had no effect on Sphagnum growth under conditions with high atmospheric deposition such as in NW Germany (38 kg N, 0.3 kg P, 7.6 kg K·ha−1·year−1).
Large‐scale maximization of Sphagnum yields requires precise water management, with water tables just below the capitula and rising with Sphagnum growth. The nutrient load in large areas of Central and Western Europe from atmospheric deposition and irrigation water is high but, with an optimal water supply, does not hamper Sphagnum growth, at least not of regional provenances of Sphagnum.
The genus Sphagnum (L.) belongs to the Bryophyte plant division and includes 150 to 400 species. As all mosses Sphagnum has no roots and can hardly regulate its water uptake. As long as enough water is available Sphagnum can grow nearly unlimited while the lower, older parts die off and may accumulate as peat. Single Sphagnum species are able to build up an acrotelm as a hydrological self-regulating mechanism of a bog, a type of intact peatland (mire) only fed by precipitation. Because Sphagnum dominates nearly half of the peatlands in the world, it is one of the globally most important peat formers.
Sphagnum biomass is an important raw material for many valuable products, but in a much larger scale Sphagnum is used in its fossil state – as Sphagnum peat. With a consumption of c. 40 million m³ per year globally, Sphagnum peat is the predominant raw material for horticultural growing media. To get Sphagnum biomass it is currently collected from wild populations, to get Sphagnum peat it is extracted from bogs.
By far, more peatlands (including bogs) are subjects to drainage for agri- and silvicultural use since centuries, which harms their ecosystem services, including their typical biodiversity, carbon storage capacity, water regulation function and palaeo-environmental archive. In Europe, c. 25 % of all peatlands are used for agriculture, in Germany more than 80 %. Globally drained peatlands cover 0.4 % of land surface but produce 5 % of all anthropogenic greenhouse gas emissions.
Sphagnum farming aims to cultivate Sphagnum biomass on rewetted degraded bogs as a new agricultural crop. Sphagnum farming is paludiculture and contributes to the protection of bogs and their peat by conserving the peat body through rewetting and by offering a climate-friendly alternative to fossil peat in horticulture. Next to climate change mitigation, Sphagnum farming has benefits for nutrient retention and biodiversity conservation.
This thesis contributes to the development of Sphagnum farming by studying the conditions under which Sphagnum may reach maximal growth. Under (semi)controlled glasshouse conditions, we tested the effects of different water regimes and fertilisation levels on the productivity of various Sphagnum species. On a 1260 m² large irrigated field on cut-over bog in Lower Saxony (Germany) we studied length increase, biomass productivity and tissue nutrient content of Sphagnum over a period of 10 years. Finally, we reviewed all scientific literature and practical experiences with respect to Sphagnum farming worldwide as a first step towards a science-based implementation manual.
The main conclusions of our studies are:
1. It is possible to cultivate Sphagnum on rewetted cut-over bog and on rewetted former bog grassland.
2. The rapid establishment of a closed, highly productive Sphagnum lawn requires the deployment of a loose, >1(–5) cm thick Sphagnum layer (80–100 m³ of Sphagnum founder material per hectare) at the start of the growing season (when long frost periods are no longer probable) and adequate water supply.
3. Water table management must be very precise until a dense, well-growing Sphagnum lawn has established. For highest yields the water table should rise with Sphagnum growth and be kept a few centimetres below the Sphagnum capitula. Water supply via open irrigation ditches seems to function better than via subsurface irrigation pipes.
4. Fertilisation does not increase Sphagnum productivity on sites with high atmospheric nitrogen deposition and irrigation with phosphate-rich surface water from the agricultural surroundings. To avoid growth reduction a balanced stoichiometry is important.
5. From all studied species, Sphagnum fallax has the highest productivity. Its fast decomposition and low water holding capacity, however, may make this species less suitable for use in horticultural substrates.
6. Vascular plant cover on Sphagnum production fields can be kept low (<50 % cover) by regular mowing. Higher covers retard Sphagnum growth and reduce its quality for growing media.
7. Pathogenic fungi occurred far more in the glasshouse than in the field and have to be controlled for highest Sphagnum yields. We found Sphagnum vitality and growth rate to be stimulated by high water levels, where Sphagnum is less vulnerable to fungal or algal infection despite high nutrient loads.
8. The rate of Sphagnum biomass accumulation may remain constant over at least 4–5 years after establishing a Sphagnum production field with sufficient water supply. At dry conditions Sphagnum biomass accumulation is lower as a result of lower biomass productivity and higher decomposition rates.
Despite their very close structural similarity, CxxC/S-type (class I) glutaredoxins (Grxs) actas oxidoreductases, while CGFS-type (class II) Grxs act as FeS cluster transferases. Here weshow that the key determinant of Grx function is a distinct loop structure adjacent to theactive site. Engineering of a CxxC/S-type Grx with a CGFS-type loop switched its functionfrom oxidoreductase to FeS transferase. Engineering of a CGFS-type Grx with a CxxC/S-typeloop abolished FeS transferase activity and activated the oxidative half reaction of the oxi-doreductase. The reductive half-reaction, requiring the interaction with a second GSHmolecule, was enabled by switching additional residues in the active site. We explain howsubtle structural differences, mostly depending on the structure of one particular loop, act inconcert to determine Grx function.
Key points
Muscular dystrophy patients suffer from progressive degeneration of skeletal muscle fibres, sudden spontaneous falls, balance problems, as well as gait and posture abnormalities.
Dystrophin‐ and dysferlin‐deficient mice, models for different types of muscular dystrophy with different aetiology and molecular basis, were characterized to investigate if muscle spindle structure and function are impaired.
The number and morphology of muscle spindles were unaltered in both dystrophic mouse lines but muscle spindle resting discharge and their responses to stretch were altered.
In dystrophin‐deficient muscle spindles, the expression of the paralogue utrophin was substantially upregulated, potentially compensating for the dystrophin deficiency.
The results suggest that muscle spindles might contribute to the motor problems observed in patients with muscular dystrophy.
Abstract
Muscular dystrophies comprise a heterogeneous group of hereditary diseases characterized by progressive degeneration of extrafusal muscle fibres as well as unstable gait and frequent falls. To investigate if muscle spindle function is impaired, we analysed their number, morphology and function in wildtype mice and in murine model systems for two distinct types of muscular dystrophy with very different disease aetiology, i.e. dystrophin‐ and dysferlin‐deficient mice. The total number and the overall structure of muscle spindles in soleus muscles of both dystrophic mouse mutants appeared unchanged. Immunohistochemical analyses of wildtype muscle spindles revealed a concentration of dystrophin and β‐dystroglycan in intrafusal fibres outside the region of contact with the sensory neuron. While utrophin was absent from the central part of intrafusal fibres of wildtype mice, it was substantially upregulated in dystrophin‐deficient mice. Single‐unit extracellular recordings of sensory afferents from muscle spindles of the extensor digitorum longus muscle revealed that muscle spindles from both dystrophic mouse strains have an increased resting discharge and a higher action potential firing rate during sinusoidal vibrations, particularly at low frequencies. The response to ramp‐and‐hold stretches appeared unaltered compared to the respective wildtype mice. We observed no exacerbated functional changes in dystrophin and dysferlin double mutant mice compared to the single mutant animals. These results show alterations in muscle spindle afferent responses in both dystrophic mouse lines, which might cause an increased muscle tone, and might contribute to the unstable gait and frequent falls observed in patients with muscular dystrophy.
The benefit of regular physical activity and exercise training for the prevention of cardiovascular and metabolic diseases is undisputed. Many molecular mechanisms mediating exercise effects have been deciphered. Personalised exercise prescription can help patients in achieving their individual greatest benefit from an exercise-based cardiovascular rehabilitation programme. Yet, we still struggle to provide truly personalised exercise prescriptions to our patients. In this position paper, we address novel basic and translational research concepts that can help us understand the principles underlying the inter-individual differences in the response to exercise, and identify early on who would most likely benefit from which exercise intervention. This includes hereditary, non-hereditary and sex-specific concepts. Recent insights have helped us to take on a more holistic view, integrating exercise-mediated molecular mechanisms with those influenced by metabolism and immunity. Unfortunately, while the outline is recognisable, many details are still lacking to turn the understanding of a concept into a roadmap ready to be used in clinical routine. This position paper therefore also investigates perspectives on how the advent of ‘big data’ and the use of animal models could help unravel inter-individual responses to exercise parameters and thus influence hypothesis-building for translational research in exercise-based cardiovascular rehabilitation.
Liver diseases are important causes of morbidity and mortality worldwide. The aim of
this study was to identify differentially expressed microRNAs (miRNAs), target genes, and key
pathways as innovative diagnostic biomarkers in liver patients with different pathology and functional
state. We determined, using RT-qPCR, the expression of 472 miRNAs in 125 explanted livers from
subjects with six different liver pathologies and from control livers. ANOVA was employed to
obtain differentially expressed miRNAs (DEMs), and miRDB (MicroRNA target prediction database)
was used to predict target genes. A miRNA–gene differential regulatory (MGDR) network was
constructed for each condition. Key miRNAs were detected using topological analysis. Enrichment
analysis for DEMs was performed using the Database for Annotation, Visualization, and Integrated
Discovery (DAVID). We identified important DEMs common and specific to the different patient
groups and disease progression stages. hsa-miR-1275 was universally downregulated regardless
the disease etiology and stage, while hsa-let-7a*, hsa-miR-195, hsa-miR-374, and hsa-miR-378 were
deregulated. The most significantly enriched pathways of target genes controlled by these miRNAs
comprise p53 tumor suppressor protein (TP53)-regulated metabolic genes, and those involved in
regulation of methyl-CpG-binding protein 2 (MECP2) expression, phosphatase and tensin homolog
(PTEN) messenger RNA (mRNA) translation and copper homeostasis. Our findings show a novel
panel of deregulated miRNAs in the liver tissue from patients with different liver pathologies. These
miRNAs hold potential as biomarkers for diagnosis and staging of liver diseases.
Swine are regarded as promising biomedical models, but the dynamics of theirgastrointestinal microbiome have been much less investigated than that of humans or mice. The aimof this study was to establish an integrated multi-omics protocol to investigate the fecal microbiomeof healthy swine. To this end, a preparation and analysis protocol including integrated samplepreparation for meta-omics analyses of deep-frozen feces was developed. Subsequent data integrationlinked microbiome composition with function, and metabolic activity with protein inventories, i.e.,16S rRNA data and expressed proteins, and identified proteins with corresponding metabolites.16S rRNA gene amplicon and metaproteomics analyses revealed a fecal microbiome dominated byPrevotellaceae,Lactobacillaceae,Lachnospiraceae,RuminococcaceaeandClostridiaceae.Similar microbiomecompositions in feces and colon, but not ileum samples, were observed, showing that feces can serveas minimal-invasive proxy for porcine colon microbiomes. Longitudinal dynamics in composition,e.g., temporal decreased abundance ofLactobacillaceaeandStreptococcaceaeduring the experiment,were not reflected in microbiome function. Instead, metaproteomics and metabolomics showed arather stable functional state, as evident from short-chain fatty acids (SCFA) profiles and associatedmetaproteome functions, pointing towards functional redundancy among microbiome constituents.In conclusion, our pipeline generates congruent data from different omics approaches on the taxonomyand functionality of the intestinal microbiome of swine.
In 2017, in the Polish-German transborder area of West Pomerania, Mecklenburg-Western Pomerania, and Brandenburg, in collaboration with two centers in Warsaw, a partnership in the field of newborn screening (NBS) for severe primary immunodeficiency diseases (PID), mainly severe combined immunodeficiency (SCID), was initiated. SCID, but also some other severe PID, is a group of disorders characterized by the absence of T and/or B and NK cells. Affected infants are susceptible to life-threatening infections, but early detection gives a chance for effective treatment. The prevalence of SCID in the Polish and German populations is unknown but can be comparable to other countries (1:50,000–100,000). SCID NBS tests are based on real-time polymerase chain reaction (qPCR) and the measurement of a number of T cell receptor excision circles (TREC), kappa-deleting recombination excision circles (KREC), and beta-actin (ACTB) as a quality marker of DNA. This method can also be effective in NBS for other severe PID with T- and/or B-cell lymphopenia, including combined immunodeficiency (CID) or agammaglobulinemia. During the 14 months of collaboration, 44,287 newborns were screened according to the ImmunoIVD protocol. Within 65 positive samples, seven were classified to immediate recall and 58 requested a second sample. Examination of the 58 second samples resulted in recalling one newborn. Confirmatory tests included immunophenotyping of lymphocyte subsets with extension to TCR repertoire, lymphoproliferation tests, radiosensitivity tests, maternal engraftment assays, and molecular tests. Final diagnosis included: one case of T-BlowNK+ SCID, one case of atypical Tlow BlowNK+ CID, one case of autosomal recessive agammaglobulinemia, and one case of Nijmegen breakage syndrome. Among four other positive results, three infants presented with T- and/or B-cell lymphopenia due to either the mother's immunosuppression, prematurity, or unknown reasons, which resolved or almost normalized in the first months of life. One newborn was classified as truly false positive. The overall positive predictive value (PPV) for the diagnosis of severe PID was 50.0%. This is the first population screening study that allowed identification of newborns with T and/or B immunodeficiency in Central and Eastern Europe.
Niemann–Pick type C1 (NPC1) is a lysosomal storage disorder, inherited as an
autosomal-recessive trait. Mutations in the Npc1 gene result in malfunction of the NPC1 protein,
leading to an accumulation of unesterified cholesterol and glycosphingolipids. Beside visceral
symptoms like hepatosplenomegaly, severe neurological symptoms such as ataxia occur. Here,
we analyzed the sphingosine-1-phosphate (S1P)/S1P receptor (S1PR) axis in different brain regions
of Npc1−/− mice and evaluated specific effects of treatment with 2-hydroxypropyl-β-cyclodextrin
(HPβCD) together with the iminosugar miglustat. Using high-performance thin-layer chromatography
(HPTLC), mass spectrometry, quantitative real-time PCR (qRT-PCR) and western blot analyses, we
Int. J. Mol. Sci. 2020, 21, 4502; doi:10.3390/ijms21124502 www.mdpi.com/journal/ijms
Int. J. Mol. Sci. 2020, 21, 4502 2 of 31
studied lipid metabolism in an NPC1 mouse model and human skin fibroblasts. Lipid analyses
showed disrupted S1P metabolism in Npc1−/− mice in all brain regions, together with distinct changes
in S1pr3/S1PR3 and S1pr5/S1PR5 expression. Brains of Npc1−/− mice showed only weak treatment
effects. However, side effects of the treatment were observed in Npc1+/+ mice. The S1P/S1PR axis
seems to be involved in NPC1 pathology, showing only weak treatment effects in mouse brain. S1pr
expression appears to be affected in human fibroblasts, induced pluripotent stem cells (iPSCs)-derived
neural progenitor and neuronal differentiated cells. Nevertheless, treatment-induced side effects
make examination of further treatment strategies indispensable
For many years now, Bacillus megaterium serves as a microbial workhorse for the high-level production of recombinant proteins in the g/L-scale. However, efficient and stable production processes require the knowledge of the molecular adaptation strategies of the host organism to establish optimal environmental conditions. Here, we interrogated the osmotic stress response of B. megaterium using transcriptome, proteome, metabolome, and fluxome analyses. An initial transient adaptation consisted of potassium import and glutamate counterion synthesis. The massive synthesis of the compatible solute proline constituted the second longterm adaptation process. Several stress response enzymes involved in iron scavenging and reactive oxygen species (ROS) fighting proteins showed higher levels under prolonged osmotic stress induced by 1.8 M NaCl. At the same time, the downregulation of the expression of genes of the upper part of glycolysis resulted in the activation of the pentose phosphate pathway (PPP), generating an oversupply of NADPH. The increased production of lactate accompanied by the reduction of acetate secretion partially compensate for the unbalanced (NADH/NAD+) ratio. Besides, the tricarboxylic acid cycle (TCA) mainly supplies the produced NADH, as indicated by the higher mRNA and protein levels of involved enzymes, and further confirmed by 13C flux analyses. As a consequence of the metabolic flux toward acetyl-CoA and the generation of an excess of NADPH, B. megaterium redirected the produced acetyl-CoA toward the polyhydroxybutyrate (PHB) biosynthetic pathway accumulating around 30% of the cell dry weight (CDW) as PHB. This direct relation between osmotic stress and intracellular PHB content has been evidenced for the first time, thus opening new avenues for synthesizing this valuable biopolymer using varying salt concentrations under non-limiting nutrient conditions.
For many years now, Bacillus megaterium serves as a microbial workhorse for the high-level production of recombinant proteins in the g/L-scale. However, efficient and stable production processes require the knowledge of the molecular adaptation strategies of the host organism to establish optimal environmental conditions. Here, we interrogated the osmotic stress response of B. megaterium using transcriptome, proteome, metabolome, and fluxome analyses. An initial transient adaptation consisted of potassium import and glutamate counterion synthesis. The massive synthesis of the compatible solute proline constituted the second longterm adaptation process. Several stress response enzymes involved in iron scavenging and reactive oxygen species (ROS) fighting proteins showed higher levels under prolonged osmotic stress induced by 1.8 M NaCl. At the same time, the downregulation of the expression of genes of the upper part of glycolysis resulted in the activation of the pentose phosphate pathway (PPP), generating an oversupply of NADPH. The increased production of lactate accompanied by the reduction of acetate secretion partially compensate for the unbalanced (NADH/NAD+) ratio. Besides, the tricarboxylic acid cycle (TCA) mainly supplies the produced NADH, as indicated by the higher mRNA and protein levels of involved enzymes, and further confirmed by 13C flux analyses. As a consequence of the metabolic flux toward acetyl-CoA and the generation of an excess of NADPH, B. megaterium redirected the produced acetyl-CoA toward the polyhydroxybutyrate (PHB) biosynthetic pathway accumulating around 30% of the cell dry weight (CDW) as PHB. This direct relation between osmotic stress and intracellular PHB content has been evidenced for the first time, thus opening new avenues for synthesizing this valuable biopolymer using varying salt concentrations under non-limiting nutrient conditions.
For many years now, Bacillus megaterium serves as a microbial workhorse for the high-level production of recombinant proteins in the g/L-scale. However, efficient and stable production processes require the knowledge of the molecular adaptation strategies of the host organism to establish optimal environmental conditions. Here, we interrogated the osmotic stress response of B. megaterium using transcriptome, proteome, metabolome, and fluxome analyses. An initial transient adaptation consisted of potassium import and glutamate counterion synthesis. The massive synthesis of the compatible solute proline constituted the second longterm adaptation process. Several stress response enzymes involved in iron scavenging and reactive oxygen species (ROS) fighting proteins showed higher levels under prolonged osmotic stress induced by 1.8 M NaCl. At the same time, the downregulation of the expression of genes of the upper part of glycolysis resulted in the activation of the pentose phosphate pathway (PPP), generating an oversupply of NADPH. The increased production of lactate accompanied by the reduction of acetate secretion partially compensate for the unbalanced (NADH/NAD+) ratio. Besides, the tricarboxylic acid cycle (TCA) mainly supplies the produced NADH, as indicated by the higher mRNA and protein levels of involved enzymes, and further confirmed by 13C flux analyses. As a consequence of the metabolic flux toward acetyl-CoA and the generation of an excess of NADPH, B. megaterium redirected the produced acetyl-CoA toward the polyhydroxybutyrate (PHB) biosynthetic pathway accumulating around 30% of the cell dry weight (CDW) as PHB. This direct relation between osmotic stress and intracellular PHB content has been evidenced for the first time, thus opening new avenues for synthesizing this valuable biopolymer using varying salt concentrations under non-limiting nutrient conditions.
Abstract
Fatty acid products derived from cytochromes P450 (CYP) monooxygenase and lipoxygenase (LOX)/CYP ω/(ω‐1)‐hydroxylase pathways are a superclass of lipid mediators with potent bioactivities. Whether or not the chronic kidney disease (CKD) and hemodialysis treatments performed on end‐stage renal disease (ESRD) patients affect RBC epoxy fatty acids profiles remains unknown. Measuring the products solely in plasma is suboptimal. Since such determinations invariably ignore red blood cells (RBCs) that make up 3 kg of the circulating blood. RBCs are potential reservoirs for epoxy fatty acids that regulate cardiovascular function. We studied 15 healthy persons and 15 ESRD patients undergoing regular hemodialysis treatments. We measured epoxides derived from CYP monooxygenase and metabolites derived from LOX/CYP ω/(ω‐1)‐hydroxylase pathways in RBCs by LC–MS/MS tandem mass spectrometry. Our data demonstrate that various CYP epoxides and LOX/CYP ω/(ω‐1)‐hydroxylase products are increased in RBCs of ESRD patients, compared to control subjects, including dihydroxyeicosatrienoic acids (DHETs), epoxyeicosatetraenoic acids (EEQs), dihydroxydocosapentaenoic acids (DiHDPAs), and hydroxyeicosatetraenoic acids (HETEs). Hemodialysis treatment did not affect the majority of those metabolites. Nevertheless, we detected more pronounced changes in free metabolite levels in RBCs after dialysis, as compared with the total RBC compartment. These findings indicate that free RBC eicosanoids should be considered more dynamic or vulnerable in CKD.