Publications by authors named "Andreas Lehmann"

68 Publications

Factors influencing the spatial and temporal distribution of microplastics at the sea surface - A year-long monitoring case study from the urban Kiel Fjord, southwest Baltic Sea.

Sci Total Environ 2020 Sep 20;736:139493. Epub 2020 May 20.

GEOMAR Helmholtz Centre of Ocean Research Kiel, Düsternbrooker Weg 20, 24105 Kiel, Germany.

Microplastics are ubiquitous to most marine environments worldwide, and their management has become one of the major challenges facing stakeholders. Here we monitored monthly, between March 2018 and March 2019, the abundance of microplastics (0.3-18.2 mm) at the sea surface within the Kiel Fjord, southwest Baltic Sea. Microplastics were sampled at eight locations, inside and outside the fjord, near potential source of microplastics, such as the outlets of storm drains or the Kiel-Bülk wastewater treatment plant, the Schwentine River mouth and the entrance of the Kiel Canal. Weather (wind, precipitations) and seawater (salinity, temperature) parameters were compared to the spatiotemporal distribution of the microplastics. We found an overall stable, and low (0.04 particles/m), microplastic load within the Kiel Fjord compared to other urban areas worldwide with comparable population densities. No relationship was found between the microplastic abundance and the environmental factors, but the few samples that yielded unusually high amount of microplastics were all preceded by rainfall and snow/ice melt. During such events, vast amounts of water, potentially contaminated with microplastics, were released into the fjord via the storm drainage system. The microplastic abundances at the wastewater plant outflow were among the lowest of our survey, likely thanks to an efficient filtering system. The results of this study highlight the importance to repeat microplastic samplings over time and space to determine with confidence baseline microplastic abundance and to detect unusual acute contamination, especially during snow and ice melting. Overall, the microplastic abundance within the Kiel Fjord was low, probably thanks to efficient waste management on land. However, improvements are still needed to filter millimetre-sized particles within the storm drainage system, which is likely a major source of microplastics into the marine environment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.scitotenv.2020.139493DOI Listing
September 2020

Dietary Factors and Neurodegenerative Disorders: An Umbrella Review of Meta-Analyses of Prospective Studies.

Adv Nutr 2020 09;11(5):1161-1173

Department of Nutrition and Food Sciences, Nutritional Epidemiology, University of Bonn, Bonn, Germany.

Diet has been hypothesized to be associated with neurodegenerative disorders. The aim was to conduct an umbrella review to summarize and evaluate the current evidence of prospective associations between any dietary factors and the incidence of neurodegenerative disorders. We conducted a systematic search in PubMed, Embase, and the Cochrane library up to November 2019 to identify systematic reviews with meta-analyses of prospective studies investigating the association between dietary factors (dietary patterns, foods and beverages, nutrients, and phytochemicals) and neurodegenerative disorders (cognitive decline, cognitive impairment, Alzheimer disease, all-cause dementia, and Parkinson disease). Summary risk ratios (SRRs) and 95% CIs were recalculated using a random effects model. We evaluated the risk of bias of identified meta-analyses and the quality of evidence for all associations. In total, 20 meta-analyses including 98 SRRs were identified. All original meta-analyses were rated as being at high risk of bias. Methodological concerns related mainly to the inappropriate synthesis, assessment, and discussion of the risk of bias of primary studies. For the recalculated meta-analyses, quality of evidence was moderate for inverse associations between higher adherence to the Mediterranean diet (SRR: 0.63; 95% CI: 0.48, 0.82; n = 4 primary studies) and higher fish intake (SRR: 0.72; 95% CI: 0.59, 0.89; n = 6) and Alzheimer disease, as well as for tea consumption and all-cause dementia (SRR: 0.74; 95% CI: 0.63, 0.88; n = 2) and Parkinson disease (SRR per 2 cups/d: 0.69; 95% CI: 0.54, 0.87; n = 5). This umbrella review provides a comprehensive overview of the available evidence on dietary factors and neurodegenerative disorders. The results indicate that the Mediterranean diet, fish, and tea could be inversely associated with neurodegenerative disorders. However, the quality of evidence was generally low, suggesting that further studies are likely to change the overall estimates. Thus, more well-conducted research, also investigating other dietary factors in association with neurodegenerative disorders, is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/advances/nmaa053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490166PMC
September 2020

Epidemiologic Risk Factors in a Comparison of a Barrett Esophagus Registry (BarrettNET) and a Case-Control Population in Germany.

Cancer Prev Res (Phila) 2020 04 17;13(4):377-384. Epub 2020 Feb 17.

Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), München, Germany.

Endoscopic screening for Barrett's esophagus as the major precursor lesion for esophageal adenocarcinoma is mostly offered to patients with symptoms of gastroesophageal reflux disease (GERD). However, other epidemiologic risk factors might affect the development of Barrett's esophagus and esophageal adenocarcinoma. Therefore, efforts to improve the efficiency of screening to find the Barrett's esophagus population "at risk" compared with the normal population are needed. In a cross-sectional analysis, we compared 587 patients with Barrett's esophagus from the multicenter German BarrettNET registry to 1976 healthy subjects from the population-based German KORA cohort, with and without GERD symptoms. Data on demographic and lifestyle factors, including age, gender, smoking, alcohol consumption, body mass index, physical activity, and symptoms were collected in a standardized epidemiologic survey. Increased age, male gender, smoking, heavy alcohol consumption, low physical activity, low health status, and GERD symptoms were significantly associated with Barrett's esophagus. Surprisingly, among patients stratified for GERD symptoms, these associations did not change. Demographic, lifestyle, and clinical factors as well as GERD symptoms were associated with Barrett's esophagus development in Germany, suggesting that a combination of risk factors could be useful in developing individualized screening efforts for patients with Barrett's esophagus and GERD in Germany.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1940-6207.CAPR-19-0474DOI Listing
April 2020

Wash-Free Multiplexed Mix-and-Read Suspension Array Fluorescence Immunoassay for Anthropogenic Markers in Wastewater.

Anal Chem 2019 10 1;91(20):12988-12996. Epub 2019 Oct 1.

Department of Analytical Chemistry; Reference Materials , Bundesanstalt für Materialforschung und -prüfung (BAM) , Richard-Willstätter-Strasse 11 , D-12489 Berlin , Germany.

Pharmaceuticals, certain food ingredients, and mammalian endogenous metabolic products in wastewater are mostly of human origin. They are anthropogenic markers. Proper knowledge of their levels in wastewater helps to track sources of pollutants in natural waters and allows for calculation of removal efficiencies in wastewater treatment plants. Here, we describe the development and application of an indirect competitive, multiplexing suspension array fluorescence immunoassay (SAFIA) for the detection of carbamazepine (CBZ), diclofenac (DCF), caffeine (CAF), and isolithocholic acid (ILA) in wastewater, covering those classes of anthropogenic markers. The assay consists of haptens covalently conjugated to fluorescence-encoded polystyrene core/silica shell microparticles to create a site for competitive binding of the antibodies (Abs). Bound Abs are then stained with fluorophore-labeled Abs. Encoding and signaling fluorescence of the particles are determined by an automated flow cytometer. For compatibility of the immunoassay with the 96-well microtiter plate format, a stop reagent, containing formaldehyde, is used. This enables a wash-free procedure while decreasing time-to-result. Detection limits of 140 ± 40 ng/L for CBZ, 180 ± 110 ng/L for CAF, 4 ± 3 ng/L for DCF, and 310 ± 70 ng/L for ILA are achieved, which meet the sensitivity criteria of wastewater analysis. We demonstrate the applicability of SAFIA to real wastewater samples from three different wastewater treatment plants, finding the results in good agreement with LC-MS/MS. Moreover, the accuracy in general exceeded that from classical ELISAs. We therefore propose SAFIA as a quick and reliable approach for wastewater analysis meeting the requirements for process analytical technology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.analchem.9b03040DOI Listing
October 2019

BarrettNET-a prospective registry for risk estimation of patients with Barrett's esophagus to progress to adenocarcinoma.

Dis Esophagus 2019 Aug;32(8)

Klinik und Poliklinik für Innere Medizin II, University Hospital rechts der Isar, Technical University of Munich.

Risk stratification in patients with Barrett's esophagus (BE) to prevent the development of esophageal adenocarcinoma (EAC) is an unsolved task. The incidence of EAC and BE is increasing and patients are still at unknown risk. BarrettNET is an ongoing multicenter prospective cohort study initiated to identify and validate molecular and clinical biomarkers that allow a more personalized surveillance strategy for patients with BE. For BarrettNET participants are recruited in 20 study centers throughout Germany, to be followed for progression to dysplasia (low-grade dysplasia or high-grade dysplasia) or EAC for >10 years. The study instruments comprise self-administered epidemiological information (containing data on demographics, lifestyle factors, and health), as well as biological specimens, i.e., blood-based samples, esophageal tissue biopsies, and feces and saliva samples. In follow-up visits according to the individual surveillance plan of the participants, sample collection is repeated. The standardized collection and processing of the specimen guarantee the highest sample quality. Via a mobile accessible database, the documentation of inclusion, epidemiological data, and pathological disease status are recorded subsequently. Currently the BarrettNET registry includes 560 participants (23.1% women and 76.9% men, aged 22-92 years) with a median follow-up of 951 days. Both the design and the size of BarrettNET offer the advantage of answering research questions regarding potential causes of disease progression from BE to EAC. Here all the integrated methods and materials of BarrettNET are presented and reviewed to introduce this valuable German registry.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/dote/doz024DOI Listing
August 2019

Ecological-economic sustainability of the Baltic cod fisheries under ocean warming and acidification.

J Environ Manage 2019 May 5;238:110-118. Epub 2019 Mar 5.

Sustainable Fishery, Department of Economics, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.

Human-induced climate change such as ocean warming and acidification, threatens marine ecosystems and associated fisheries. In the Western Baltic cod stock socio-ecological links are particularly important, with many relying on cod for their livelihoods. A series of recent experiments revealed that cod populations are negatively affected by climate change, but an ecological-economic assessment of the combined effects, and advice on optimal adaptive management are still missing. For Western Baltic cod, the increase in larval mortality due to ocean acidification has experimentally been quantified. Time-series analysis allows calculating the temperature effect on recruitment. Here, we include both processes in a stock-recruitment relationship, which is part of an ecological-economic optimization model. The goal was to quantify the effects of climate change on the triple bottom line (ecological, economic, social) of the Western Baltic cod fishery. Ocean warming has an overall negative effect on cod recruitment in the Baltic. Optimal management would react by lowering fishing mortality with increasing temperature, to create a buffer against climate change impacts. The negative effects cannot be fully compensated, but even at 3 °C warming above the 2014 level, a reduced but viable fishery would be possible. However, when accounting for combined effects of ocean warming and acidification, even optimal fisheries management cannot adapt to changes beyond a warming of +1.5° above the current level. Our results highlight the need for multi-factorial climate change research, in order to provide the best available, most realistic, and precautionary advice for conservation of exploited species as well as their connected socio-economic systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jenvman.2019.02.105DOI Listing
May 2019

Differences in drug quality between South Africa and Germany.

J Pharm Pharmacol 2018 Oct 25;70(10):1301-1314. Epub 2018 Jul 25.

Institute of Pharmaceutical Technology, Goethe University Frankfurt am Main, Frankfurt am Main, Germany.

Objectives: To examine differences in drug product quality between products marketed in developed countries and in developing countries.

Methods: The quality of drug products marketed in both Germany and South Africa by the same pharmaceutical company was compared. A fixed-dose combination tablet containing amoxicillin/clavulanic acid, and mometasone furoate nasal spray were selected to represent generic medicines requiring prescriptions, while skin lightening products (legally obtained and/or confiscated) were selected to represent pharmaceutical products that are available without a prescription. Pharmacopoeial tests included assay, content uniformity, and where applicable, dissolution in addition to a visual examination of the packaging.

Key Findings: Some differences between the product marketed in Germany and in South Africa were detected for the amoxicillin tablet formulations, although all samples still complied with regulatory requirements. The mometasone nasal spray product marketed in South Africa delivered a higher dose than was declared on the label. The composition of the skin lightening products conformed qualitatively with labelling, but in some South African samples alarmingly high amounts of hydroquinone were found.

Conclusions: Important differences in quality were detected between some German and South African products. To preclude drug products of poor or doubtful quality from entering the market in South Africa, countermeasures are needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jphp.12985DOI Listing
October 2018

Drug Quality in South Africa: A Field Test.

J Pharm Sci 2018 10 21;107(10):2720-2730. Epub 2018 Jun 21.

Goethe University Frankfurt am Main, Institute of Pharmaceutical Technology, Frankfurt, Germany. Electronic address:

To assess drug quality and pharmaceutical care in South Africa, "mystery" (i.e., anonymous) customers collected 316 samples from July to September 2016. Solid dosage forms containing amoxicillin alone or in combination with clavulanic acid as well as analgesics containing paracetamol alone or in combination with other drugs were sampled in a randomized fashion from the formal market (pharmacies) and by convenient sampling from the informal market. Visual inspection, uniformity of dosage units, and dissolution testing were performed to evaluate adherence to pharmacopoeial quality standards and to identify counterfeit, degraded, or substandard drugs. Although no counterfeited products were identified, only 55.4% (173/312) of samples were able to fulfill all pharmacopeial requirements for quality. Most of the 139 samples that failed were unable to pass the visual inspection due to inappropriate labeling and packaging. In addition, several substandard products were identified: 17 (5.4%) samples failed dissolution testing and 15 (4.8%) failed the content uniformity test. To improve drug quality and the quality of pharmaceutical care, better education of pharmaceutical professionals and monitoring of the pharmaceutical supply chain in South Africa are needed. Further field studies are necessary to evaluate risks and quality issues for other drug classes and distribution channels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.xphs.2018.06.012DOI Listing
October 2018

Meeting Report: Growth and Social Environment. Proceedings of the 25th Aschauer Soiree, held at Krobielowice, Poland, November 18th 2017.

Pediatr Endocrinol Rev 2018 Apr;15(4):319-329

Aschauhof, 24340 Altenhof, Germany, E-mail: Web: www.michael-hermanussen.de.

Twenty-two scientists met at Krobielowice, Poland, to discuss the impact of the social environment, spatial proximity, migration, poverty, but also psychological factors such as body perception and satisfaction, and social stressors such as elite sports, and teenage pregnancies, on child and adolescent growth. The data analysis included linear mixed effects models with different random effects, Monte Carlo analyses, and network simulations. The work stressed the importance of the peer group, but also included historic material, some considerations about body proportions, and growth in chronic liver, and congenital heart disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.17458/per.vol15.2018.ksh.mr.GrowthSocialEnvironmentDOI Listing
April 2018

A Prodomain Fragment from the Proteolytic Activation of Growth Differentiation Factor 11 Remains Associated with the Mature Growth Factor and Keeps It Soluble.

Biochemistry 2017 08 3;56(33):4405-4418. Epub 2017 Aug 3.

Department of Biotherapeutics and Medicinal Sciences, Biogen , 115 Broadway, Cambridge, Massachusetts 02142, United States.

Growth differentiation factor 11 (GDF11), a member of the transforming growth factor β (TGF-β) family, plays diverse roles in mammalian development. It is synthesized as a large, inactive precursor protein containing a prodomain, pro-GDF11, and exists as a homodimer. Activation requires two proteolytic processing steps that release the prodomains and transform latent pro-GDF11 into active mature GDF11. In studying proteolytic activation in vitro, we discovered that a 6-kDa prodomain peptide containing residues 60-114, PDP, remained associated with the mature growth factor. Whereas the full-length prodomain of GDF11 is a functional antagonist, PDP had no impact on activity. The specific activity of the GDF11/PDP complex (EC = 1 nM) in a SMAD2/3 reporter assay was identical to that of mature GDF11 alone. PDP improved the solubility of mature GDF11 at neutral pH. As the growth factor normally aggregates/precipitates at neutral pH, PDP can be used as a solubility-enhancing formulation. Expression of two engineered constructs with PDP genetically fused to the mature domain of GDF11 through a 2x or 3x G4S linker produced soluble monomeric products that could be dimerized through redox reactions. The construct with a 3x G4S linker retained 10% activity (EC = 10 nM), whereas the construct connected with a 2x G4S linker could only be activated (EC = 2 nM) by protease treatment. Complex formation with PDP represents a new strategy for stabilizing GDF11 in an active state that may translate to other members of the TGF-β family that form latent pro/mature domain complexes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.biochem.7b00302DOI Listing
August 2017

Engineering potent long-acting variants of the Wnt inhibitor DKK2.

Protein Eng Des Sel 2017 05;30(5):359-372

Department of Cell and Protein Sciences, Biogen, Cambridge, MA 02142, USA.

Wnt signaling pathways are required for a wide variety of biological processes ranging from embryonic development to tissue repair and regeneration. Dickkopf-2 (DKK2) is classically defined as a canonical Wnt inhibitor, though it may play a role in activating non-canonical Wnt pathways in the context of endothelial network formation after acute injury. Here we report the discovery of a fusion partner for a DKK2 polypeptide that significantly improves the expression, biochemical properties and pharmacokinetics (PK) of the DKK2 polypeptide. Specifically, human serum albumin (HSA) was identified as a highly effective fusion partner. Substitution of selected amino acid residues in DKK2 designed to decrease heparan sulfate binding by HSA-DKK2 variants, further improved the PK properties of the molecule in rodents. The HSA-DKK2 variants were monomeric, as thermally stable as wild type, and active as measured by their ability to bind to and prevent phosphorylation of the Wnt coreceptor LRP6. Our engineering efforts resulted in potent long-lived variants of the canonical Wnt inhibitor DKK2, applicable for Wnt pathway manipulation either by systematic delivery or focused administration at sites of tissue injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/protein/gzx007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425732PMC
May 2017

Temporal trends, regional variation and socio-economic differences in height, BMI and body proportions among German conscripts, 1956-2010.

Public Health Nutr 2017 02 15;20(3):391-403. Epub 2016 Sep 15.

1Institute of Evolutionary Medicine,University of Zurich,Winterthurerstrasse 190,CH-8057 Zurich,Switzerland.

Objective: We analyse temporal trends and regional variation among the most recent available anthropometric data from German conscription in the years 2008-2010 and their historical contextualization since 1956. Design/setting/subjects The overall sample included German conscripts (N 13 857 313) from 1956 to 2010.

Results: German conscripts changed from growing in height to growing in breadth. Over the analysed 54 years, average height of 19-year-old conscripts increased by 6·5 cm from 173·5 cm in 1956 (birth year 1937) to 180·0 cm in 2010 (birth year 1991). This increase plateaued since the 1990s (1970s birth years). The increase in average weight, however, did not lessen during the last two decades but increased in two steps: at the end of the 1980s and after 1999. The weight and BMI distributions became increasingly right-skewed, the prevalence of overweight and obesity increased from 11·6 % and 2·1 % in 1984 to 19·9 % and 8·5 % in 2010, respectively. The north-south gradient in height (north = taller) persisted during our observations. Height and weight of conscripts from East Germany matched the German average between the early 1990s and 2009. Between the 1980s and the early 1990s, the average chest circumference increased, the average difference between chest circumference when inhaling and exhaling decreased, as did leg length relative to trunk length.

Conclusions: Measuring anthropometric data for military conscripts yielded year-by-year monitoring of the health status of young men at a proscribed age. Such findings contribute to a more precise identification of groups at risk and thus help with further studies and to target interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S1368980016002408DOI Listing
February 2017

Enzyme-linked immunosorbent assay (ELISA) for the anthropogenic marker isolithocholic acid in water.

J Environ Manage 2016 Nov 18;182:612-619. Epub 2016 Aug 18.

Bundesanstalt für Materialforschung und -prüfung (BAM), 12205 Berlin, Germany; Technische Universität Berlin, 10623 Berlin, Germany. Electronic address:

Bile acids are promising chemical markers to assess the pollution of water samples with fecal material. This study describes the optimization and validation of a direct competitive enzyme-linked immunosorbent assay for the bile acid isolithocholic acid (ILA). The quantification range of the optimized assay was between 0.09 and 15 μg/L. The assay was applied to environmental water samples. Most studies until now were focused on bile acid fractions in the particulate phase of water samples. In order to avoid tedious sample preparation, we undertook to evaluate the dynamics and significance of ILA levels in the aqueous phase. Very low concentrations in tap and surface water samples made a pre-concentration step necessary for this matrix as well as for wastewater treatment plant (WWTP) effluent. Mean recoveries for spiked water samples were between 97% and 109% for tap water and WWTP influent samples and between 102% and 136% for WWTP effluent samples. 90th percentiles of intra-plate and inter-plate coefficients of variation were below 10% for influents and below 20% for effluents and surface water. ILA concentrations were quantified in the range of 33-72 μg/L in influent, 21-49 ng/L in effluent and 18-48 ng/L in surface water samples. During wastewater treatment the ILA levels were reduced by more than 99%. ILA concentrations of influents determined by ELISA and LC-MS/MS were in good agreement. However, findings in LC-ELISA experiments suggest that the true ILA levels in concentrated samples are lower due to interfering effects of matrix compounds and/or cross-reactants. Yet, the ELISA will be a valuable tool for the performance check and comparison of WWTPs and the localization of fecal matter input into surface waters.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jenvman.2016.08.023DOI Listing
November 2016

Stunted Growth. Proceedings of the 23rd Aschauer Soiree, Held at Aschauhof, Germany, November 7th 2015.

Pediatr Endocrinol Rev 2016 Jun;13(4):756-67

Twenty-four scientists met at Aschauhof, Altenhof, Germany, to discuss the associations between child growth and development, and nutrition, health, environment and psychology. Meta-analyses of body height, height variability and household inequality, in historic and modern growth studies published since 1794, highlighting the enormously flexible patterns of child and adolescent height and weight increments throughout history which do not only depend on genetics, prenatal development, nutrition, health, and economic circumstances, but reflect social interactions. A Quality of Life in Short Stature Youth Questionnaire was presented to cross-culturally assess health-related quality of life in children. Changes of child body proportions in recent history, the relation between height and longevity in historic Dutch samples and also measures of body height in skeletal remains belonged to the topics of this meeting. Bayesian approaches and Monte Carlo simulations offer new statistical tools for the study of human growth.
View Article and Find Full Text PDF

Download full-text PDF

Source
June 2016

Impaired gonadal and somatic development corroborate vulnerability differences to the synthetic estrogen ethinylestradiol among deeply diverged anuran lineages.

Aquat Toxicol 2016 Aug 5;177:503-14. Epub 2016 Jul 5.

Leibniz-Institute of Freshwater Ecology and Inland Fisheries (IGB), Müggelseedamm 301 & 310, D-12587 Berlin, Germany. Electronic address:

Amphibians are undergoing a global decline. One poorly investigated reason could be the pollution of aquatic habitats by endocrine disrupting compounds (EDCs). We tested the susceptibility to the synthetically stabilized estrogen 17α-ethinylestradiol (EE2) in three deeply diverged anuran species, differing in sex determination systems, types of gonadogenesis and larval ecologies. To understand whether data from the amphibian model Xenopus laevis (Pipidae) are analogous and applicable to only distantly related non-model amphibians, tadpoles of X. laevis, Hyla arborea (Hylidae) and Bufo viridis (Bufonidae) were simultaneously exposed to 50, 500 and 5000ng/L EE2 from hatching until completion of metamorphosis, using a flow-through-system under identical experimental conditions. Comparing molecularly established genetic with histologically assessed phenotypic sex in all species, we have recently shown that EE2 provoked numerous genetic-male-to-phenotypic-female sex reversals and mixed sex individuals, confirming overall its expected feminizing effect. In the present study, we focus on the influence of EE2 on gonadal and somatic development. Anatomy and histology revealed several species-specific effects. In both non-model species, H. arborea and B. viridis, high numbers of anatomically impaired gonads were observed. In H. arborea, exposed to 5000ng/L EE2, numerous underdeveloped gonads were detected. Whereas EE2 did not alter snout-to-vent length and body weight of X. laevis metamorphs, H. arborea showed a treatment-dependent decrease, while B. viridis exhibited an increase in body weight and snout-to-vent length. Apart from a concentration-dependent occurrence of yellowish skin color in several H. arborea, no organ-specific effects were detected. Since EE2 ubiquitously occurs in many aquatic ecosystems and affects sexual and somatic development, among EDCs, it may indeed contribute to amphibian decline. The inter-species variation in developmental EE2-effects corroborates species-specific vulnerability differences towards EDCs between deeply diverged amphibian groups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.aquatox.2016.07.001DOI Listing
August 2016

Identification of Phosphorylation Sites Regulating sst3 Somatostatin Receptor Trafficking.

Mol Endocrinol 2016 Jun 21;30(6):645-59. Epub 2016 Apr 21.

Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, D-07747 Jena, Germany.

The human somatostatin receptor 3 (sst3) is expressed in about 50% of all neuroendocrine tumors and hence a promising target for multireceptor somatostatin analogs. The sst3 receptor is unique among ssts in that it exhibits a very long intracellular C-terminal tail containing a huge number of potential phosphate acceptor sites. Consequently, our knowledge about the functional role of the C-terminal tail in sst3 receptor regulation is very limited. Here, we have generated a series of phosphorylation-deficient mutants that enabled us to determine crucial sites for its agonist-induced β-arrestin mobilization, internalization, and down-regulation. Based on this information, we generated phosphosite-specific antibodies for C-terminal Ser(337)/Thr(341), Thr(348), and Ser(361) that enabled us to investigate the temporal patterns of sst3 phosphorylation and dephosphorylation. We found that the endogenous ligand somatostatin induced a rapid and robust phosphorylation that was completely blocked by the sst3 antagonist NVP-ACQ090. The stable somatostatin analogs pasireotide and octreotide promoted clearly less phosphorylation compared with somatostatin. We also show that sst3 phosphorylation occurred within seconds to minutes, whereas dephosphorylation of the sst3 receptor occurred at a considerable slower rate. In addition, we also identified G protein-coupled receptor kinases 2 and 3 and protein phosphatase 1α and 1β as key regulators of sst3 phosphorylation and dephosphorylation, respectively. Thus, we here define the C-terminal phosphorylation motif of the human sst3 receptor that regulates its agonist-promoted phosphorylation, β-arrestin recruitment, and internalization of this clinically relevant receptor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/me.2015-1244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414643PMC
June 2016

Sex reversal assessments reveal different vulnerability to endocrine disruption between deeply diverged anuran lineages.

Sci Rep 2016 Mar 31;6:23825. Epub 2016 Mar 31.

Leibniz-Institute of Freshwater Ecology and Inland Fisheries (IGB), Müggelseedamm 301 &310, D-12587 Berlin, Germany.

Multiple anthropogenic stressors cause worldwide amphibian declines. Among several poorly investigated causes is global pollution of aquatic ecosystems with endocrine disrupting compounds (EDCs). These substances interfere with the endocrine system and can affect the sexual development of vertebrates including amphibians. We test the susceptibility to an environmentally relevant contraceptive, the artificial estrogen 17α-ethinylestradiol (EE2), simultaneously in three deeply divergent systematic anuran families, a model-species, Xenopus laevis (Pipidae), and two non-models, Hyla arborea (Hylidae) and Bufo viridis (Bufonidae). Our new approach combines synchronized tadpole exposure to three EE2-concentrations (50, 500, 5,000 ng/L) in a flow-through-system and pioneers genetic and histological sexing of metamorphs in non-model anurans for EDC-studies. This novel methodology reveals striking quantitative differences in genetic-male-to-phenotypic-female sex reversal in non-model vs. model species. Our findings qualify molecular sexing in EDC-analyses as requirement to identify sex reversals and state-of-the-art approaches as mandatory to detect species-specific vulnerabilities to EDCs in amphibians.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep23825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814869PMC
March 2016

What does the mean menarcheal age mean?-An analysis of temporal pattern in variability in a historical swiss population from the 19th and 20th centuries.

Am J Hum Biol 2016 09 30;28(5):705-13. Epub 2016 Mar 30.

Biochemistry and Biology; Human Biology, University of Potsdam, Maulbeerallee 2a 14469, Potsdam, Germany.

Objectives: Age at menarche is one of the most important factors when observing growth and development. The aim of this study was to assess the temporal pattern in variability of menarcheal age for a historic Swiss population from the 19th and 20th centuries.

Methods: Medical health records from the Bernese women's hospital (Switzerland) were analyzed. From 10,081 women of a historical Swiss population (born from 1815 to 1954), menarcheal age was calculated. A possible decline in average menarcheal age and variance and skewness were analyzed with the use of descriptive statistics, generalized additive models, and correlation.

Results: Mean menarcheal age declined from 17.34 years (n = 358) around 1830 to 13.80 years (n = 141) around 1950. Within-cohort variance decreased from 7.5 to 2.1 year(2) . Skewness was negatively correlated with birth year (r = -0.58).

Conclusion: This study provided evidence for a secular trend in various statistical parameters for age at menarche since the 19th century. Furthermore, the results of the analysis of temporal pattern in variability revealed that the secular trend in menarcheal age happened in two phases. Am. J. Hum. Biol. 28:705-713, 2016. © 2016 Wiley Periodicals, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajhb.22854DOI Listing
September 2016

Stability engineering of anti-EGFR scFv antibodies by rational design of a lambda-to-kappa swap of the VL framework using a structure-guided approach.

MAbs 2015 4;7(6):1058-71. Epub 2015 Sep 4.

a Molecular Therapeutics Program, Fox Chase Cancer Center , Philadelphia , PA.

Phage-display technology facilitates rapid selection of antigen-specific single-chain variable fragment (scFv) antibodies from large recombinant libraries. ScFv antibodies, composed of a VH and VL domain, are readily engineered into multimeric formats for the development of diagnostics and targeted therapies. However, the recombinant nature of the selection strategy can result in VH and VL domains with sub-optimal biophysical properties, such as reduced thermodynamic stability and enhanced aggregation propensity, which lead to poor production and limited application. We found that the C10 anti-epidermal growth factor receptor (EGFR) scFv, and its affinity mutant, P2224, exhibit weak production from E. coli. Interestingly, these scFv contain a fusion of lambda3 and lambda1 V-region (LV3 and LV1) genes, most likely the result of a PCR aberration during library construction. To enhance the biophysical properties of these scFvs, we utilized a structure-based approach to replace and redesign the pre-existing framework of the VL domain to one that best pairs with the existing VH. We describe a method to exchange lambda sequences with a more stable kappa3 framework (KV3) within the VL domain that incorporates the original lambda DE-loop. The resulting scFvs, C10KV3_LV1DE and P2224KV3_LV1DE, are more thermodynamically stable and easier to produce from bacterial culture. Additionally, C10KV3_LV1DE and P2224KV3_LV1DE retain binding affinity to EGFR, suggesting that such a dramatic framework swap does not significantly affect scFv binding. We provide here a novel strategy for redesigning the light chain of problematic scFvs to enhance their stability and therapeutic applicability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/19420862.2015.1088618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966335PMC
August 2016

PyIgClassify: a database of antibody CDR structural classifications.

Nucleic Acids Res 2015 Jan 11;43(Database issue):D432-8. Epub 2014 Nov 11.

Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA

Classification of the structures of the complementarity determining regions (CDRs) of antibodies is critically important for antibody structure prediction and computational design. We have previously performed a clustering of antibody CDR conformations and defined a systematic nomenclature consisting of the CDR, length and an integer starting from the largest to the smallest cluster in the data set (e.g. L1-11-1). We present PyIgClassify (for Python-based immunoglobulin classification; available at http://dunbrack2.fccc.edu/pyigclassify/), a database and web server that provides access to assignments of all CDR structures in the PDB to our classification system. The database includes assignments to the IMGT germline V regions for heavy and light chains for several species. For humanized antibodies, the assignment of the frameworks is to human germlines and the CDRs to the germlines of mice or other species sources. The database can be searched by PDB entry, cluster identifier and IMGT germline group (e.g. human IGHV1). The entire database is downloadable so that users may filter the data as needed for antibody structure analysis, prediction and design.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gku1106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383924PMC
January 2015

The influence of deliberate practice on musical achievement: a meta-analysis.

Front Psychol 2014 25;5:646. Epub 2014 Jun 25.

Hanover Music Lab, Hanover University of Music, Drama and Media Hanover, Germany.

Deliberate practice (DP) is a task-specific structured training activity that plays a key role in understanding skill acquisition and explaining individual differences in expert performance. Relevant activities that qualify as DP have to be identified in every domain. For example, for training in classical music, solitary practice is a typical training activity during skill acquisition. To date, no meta-analysis on the quantifiable effect size of deliberate practice on attained performance in music has been conducted. Yet the identification of a quantifiable effect size could be relevant for the current discussion on the role of various factors on individual difference in musical achievement. Furthermore, a research synthesis might enable new computational approaches to musical development. Here we present the first meta-analysis on the role of deliberate practice in the domain of musical performance. A final sample size of 13 studies (total N = 788) was carefully extracted to satisfy the following criteria: reported durations of task-specific accumulated practice as predictor variables and objectively assessed musical achievement as the target variable. We identified an aggregated effect size of r c = 0.61; 95% CI [0.54, 0.67] for the relationship between task-relevant practice (which by definition includes DP) and musical achievement. Our results corroborate the central role of long-term (deliberate) practice for explaining expert performance in music.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fpsyg.2014.00646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073287PMC
July 2014

Carboxyl-terminal receptor domains control the differential dephosphorylation of somatostatin receptors by protein phosphatase 1 isoforms.

PLoS One 2014 17;9(3):e91526. Epub 2014 Mar 17.

Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany.

We have recently identified protein phosphatase 1β (PP1β) as G protein-coupled receptor (GPCR) phosphatase for the sst2 somatostatin receptor using siRNA knockdown screening. By contrast, for the sst5 somatostatin receptor we identified protein phosphatase 1γ (PP1γ) as GPCR phosphatase using the same approach. We have also shown that sst2 and sst5 receptors differ substantially in the temporal dynamics of their dephosphorylation and trafficking patterns. Whereas dephosphorylation and recycling of the sst2 receptor requires extended time periods of ∼30 min, dephosphorylation and recycling of the sst5 receptor is completed in less than 10 min. Here, we examined which receptor domains determine the selection of phosphatases for receptor dephosphorylation. We found that generation of tail-swap mutants between sst2 and sst5 was required and sufficient to reverse the patterns of dephosphorylation and trafficking of these two receptors. In fact, siRNA knockdown confirmed that the sst5 receptor carrying the sst2 tail is predominantly dephosphorylated by PP1β, whereas the sst2 receptor carrying the sst5 tail is predominantly dephosphorylated by PP1γ. Thus, the GPCR phosphatase responsible for dephosphorylation of individual somatostatin receptor subtypes is primarily determined by their different carboxyl-terminal receptor domains. This phosphatase specificity has in turn profound consequences for the dephosphorylation dynamics and trafficking patterns of GPCRs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0091526PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956607PMC
January 2015

Carboxyl-terminal multi-site phosphorylation regulates internalization and desensitization of the human sst2 somatostatin receptor.

Mol Cell Endocrinol 2014 Apr 22;387(1-2):44-51. Epub 2014 Feb 22.

Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, 07747 Jena, Germany. Electronic address:

The somatostatin receptor 2 (sst2) is the pharmacological target of somatostatin analogs that are widely used in the diagnosis and treatment of human neuroendocrine tumors. We have recently shown that the stable somatostatin analogs octreotide and pasireotide (SOM230) stimulate distinct patterns of sst2 receptor phosphorylation and internalization. Like somatostatin, octreotide promotes the phosphorylation of at least six carboxyl-terminal serine and threonine residues namely S341, S343, T353, T354, T356 and T359, which in turn leads to a robust receptor endocytosis. Unlike somatostatin, pasireotide stimulates a selective phosphorylation of S341 and S343 of the human sst2 receptor followed by a partial receptor internalization. Here, we show that exchange of S341 and S343 by alanine is sufficient to block pasireotide-driven internalization, whereas mutation of T353, T354, T356 and T359 to alanine is required to strongly inhibited both octreotide- and somatostatin-induced internalization. Yet, combined mutation of T353, T354, T356 and T359 is not sufficient to prevent somatostatin-driven β-arrestin mobilization and receptor desensitization. Replacement of all fourteen carboxyl-terminal serine and threonine residues by alanine completely abrogates sst2 receptor internalization and β-arrestin mobilization in HEK293 cells. Together, our findings demonstrate for the first time that agonist-selective sst2 receptor internalization is regulated by multi-site phosphorylation of its carboxyl-terminal tail.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mce.2014.02.009DOI Listing
April 2014

The potential of current- and wind-driven transport for environmental management of the Baltic Sea.

Ambio 2014 Feb;43(1):94-104

Estonian Academy of Sciences, Kohtu 6, 10130, Tallinn, Estonia,

The ever increasing impact of the marine industry and transport on vulnerable sea areas puts the marine environment under exceptional pressure and calls for inspired methods for mitigating the impact of the related risks. We describe a method for preventive reduction of remote environmental risks caused by the shipping and maritime industry that are transported by surface currents and wind impact to the coasts. This method is based on characterizing systematically the damaging potential of the offshore areas in terms of potential transport to vulnerable regions of an oil spill or other pollution that has occurred in a particular area. The resulting maps of probabilities of pollution to be transported to the nearshore and the time it takes for the pollution to reach the nearshore are used to design environmentally optimized fairways for the Gulf of Finland, Baltic Proper, and south-western Baltic Sea.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13280-013-0486-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888654PMC
February 2014

Fine-tuning somatostatin receptor signalling by agonist-selective phosphorylation and dephosphorylation: IUPHAR Review 5.

Br J Pharmacol 2014 Apr;171(7):1591-9

Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany.

The biological actions of somatostatin are mediated by a family of five GPCRs, named sst1 to sst5 . Somatostatin receptors exhibit equally high-binding affinities to their natural ligand somatostatin-14 and largely overlapping distributions. The overexpression of somatostatin receptors in human tumours is the molecular basis for diagnostic and therapeutic application of the stable somatostatin analogues octreotide, lanreotide and pasireotide. The efficiency of somatostatin receptor signalling is tightly regulated and ultimately limited by the coordinated phosphorylation and dephosphorylation of intracellular carboxyl-terminal serine and threonine residues. Here, we review and discuss recent progress in the generation and application of phosphosite-specific antibodies for human sst2 and sst5 receptors. These phosphosite-specific antibodies are unique tools to monitor the spatial and temporal dynamics of receptors phosphorylation and dephosphorylation. Using a combined approach of phosphosite-specific antibodies and siRNA knock-down screening, relevant kinases and phosphatases were identified. Emerging evidence suggests distinct mechanisms of agonist-selective fine-tuning for individual somatostatin receptors. The recently uncovered differences in phosphorylation and dephosphorylation of these receptors may hence be of physiological significance in mediating responses to acute, persistent or repeated stimuli in a variety of target tissues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bph.12551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3966740PMC
April 2014

Comparative analysis of different transection techniques in minor and major hepatic resections: a prospective cohort study.

Int J Surg 2013 28;11(9):826-33. Epub 2013 Aug 28.

Department of Surgery, Technische Universität München, Ismaninger Str. 22, 81675 Munich, Germany. Electronic address:

Background: In liver surgery different transection techniques are available without clear evidence regarding indication and advantage for each technique. The aim of this study was to identify the most superior liver transection technique between the different techniques (stapler, water-jet and electrocautery). Comparative analyses were performed for minor and major hepatectomies.

Methods: In a single-center study, all liver resections performed between July 2007 and July 2012 were prospectively recorded and analysed.

Results: 366 liver resections were included according to predefined eligibility criteria. No clear benefit for one particular technique in minor or major hepatectomy could be shown. Cost-effectiveness analysis revealed disadvantages for stapler-hepatectomies. However, minor hepatectomies were performed with significantly lower morbidity (p < 0.001), lower operating time (p = 0.001), fewer need of transfusion (p < 0.0001) and shorter ICU stay (p = 0.001) than major hepatectomies.

Conclusions: If possible, minor hepatectomies should be chosen. Competing techniques, selected according to surgeon's preference, revealed no significant differences in primary outcome measures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijsu.2013.08.010DOI Listing
July 2014

Computational de novo design and characterization of a protein that selectively binds a highly hyperpolarizable abiological chromophore.

J Am Chem Soc 2013 Sep 5;135(37):13914-26. Epub 2013 Sep 5.

Department of Chemistry, University of Pennsylvania , Philadelphia, Pennsylvania 19104-6323, United States.

This work reports the first example of a single-chain protein computationally designed to contain four α-helical segments and fold to form a four-helix bundle encapsulating a supramolecular abiological chromophore that possesses exceptional nonlinear optical properties. The 109-residue protein, designated SCRPZ-1, binds and disperses an insoluble hyperpolarizable chromophore, ruthenium(II) [5-(4'-ethynyl-(2,2';6',2″-terpyridinyl))-10,20-bis(phenyl)porphinato]zinc(II)-(2,2';6',2″-terpyridine)(2+) (RuPZn) in aqueous buffer solution at a 1:1 stoichiometry. A 1:1 binding stoichiometry of the holoprotein is supported by electronic absorption and circular dichroism spectra, as well as equilibrium analytical ultracentrifugation and size exclusion chromatography. SCRPZ-1 readily dimerizes at micromolar concentrations, and an empirical redesign of the protein exterior produced a stable monomeric protein, SCRPZ-2, that also displayed a 1:1 protein:cofactor stoichiometry. For both proteins in aqueous buffer, the encapsulated cofactor displays photophysical properties resembling those exhibited by the dilute RuPZn cofactor in organic solvent: femtosecond, nanosecond, and microsecond time scale pump-probe transient absorption spectroscopic data evince intensely absorbing holoprotein excited states having large spectral bandwidth that penetrate deep in the near-infrared energy regime; the holoprotein electronically excited triplet state exhibits a microsecond time scale lifetime characteristic of the RuPZn chromophore. Hyper-Rayleigh light scattering measurements carried out at an incident irradiation wavelength of 1340 nm for these holoproteins demonstrate an exceptional dynamic hyperpolarizabilty (β1340 = 3100 × 10(-30) esu). X-ray reflectivity measurements establish that this de novo-designed hyperpolarizable protein can be covalently attached with high surface density to a silicon surface without loss of the cofactor, indicating that these assemblies provide a new approach to bioinspired materials that have unique electro-optic functionality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ja4067404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787832PMC
September 2013

Development of species-, strain- and antibiotic biosynthesis-specific quantitative PCR assays for Pantoea agglomerans as tools for biocontrol monitoring.

J Microbiol Methods 2012 Sep 13;90(3):315-20. Epub 2012 Jun 13.

Agroscope Changins-Wädenswil ACW, Plant Protection Division, CH-8820 Wädenswil, Switzerland.

Pantoea agglomerans is a cosmopolitan plant epiphytic bacterium that includes some of the most effective biological antagonists against the fire blight pathogen Erwinia amylovora, a major threat to pome fruit production worldwide. Strain E325 is commercially available as Bloomtime Biological™ in the USA and Canada. New quantitative PCR (qPCR) assays were developed for species- and strain -specific detection in the environment, and for detection of indigenous strains carrying the biocontrol antibacterial peptide biosynthesis gene paaA. The qPCR assays were highly specific, efficient and sensitive, detecting fewer than three cells per reaction or 700 colony forming units per flower, respectively. The qPCR assays were tested on field samples, giving first indications to the incidence of P. agglomerans E325 related strains, total P. agglomerans and pantocin A producing bacteria in commercial orchards. These assays will facilitate monitoring the environmental behavior of biocontrol P. agglomerans after orchard application for disease protection, proprietary strain-tracking, and streamlined screening for discovery of new biocontrol strains.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mimet.2012.06.004DOI Listing
September 2012

Perioperative use of levosimendan: best practice in operative settings.

J Cardiothorac Vasc Anesth 2013 Apr 30;27(2):361-6. Epub 2012 May 30.

Department of Anesthesiology and Intensive Care Medicine, Medical University of Graz, Graz, Austria.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.jvca.2012.04.007DOI Listing
April 2013
-->