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A peroxygenase from Chaetomium globosum catalyzes the selective oxygenation of testosteroneKiebist, Jan, Schmidtke, Kai-Uwe, Zimmermann, Jörg, Kellner, Harald, Jehmlich, Nico, Ullrich, René, Zänder, Daniel, Hofrichter, Martin, Scheibner, Katrin 03 April 2017 (has links)
Unspecific peroxygenases (UPO, EC 1.11.2.1) secreted by fungi open an efficient way to selectively oxyfunctionalize diverse organic substrates, including less-activated hydrocarbons, by transferring peroxide-borne oxygen. We investigated a cell-free approach to incorporate epoxy and hydroxyl functionalities directly into the bulky molecule testosterone by a novel unspecific peroxygenase (UPO) that is produced by the ascomycetous fungus Chaetomium globosum in a complex medium rich in carbon and nitrogen. Purification by fast protein liquid chromatography revealed two enzyme fractions with the same molecular mass (36 kDa) and with specific activity of 4.4 to 12 U mg−1. Although the well-known UPOs of Agrocybe aegerita (AaeUPO) and Marasmius rotula (MroUPO) failed to convert testosterone in a comparative study, the UPO of C. globosum (CglUPO) accepted testosterone as substrate and converted it with total turnover number (TTN) of up to 7000 into two oxygenated products: the 4,5-epoxide of testosterone in β-configuration and 16α-hydroxytestosterone. The reaction performed on a 100 mg scale resulted in the formation of about 90 % of the epoxide and 10 % of the hydroxylation product, both of which could be isolated with purities above 96 %. Thus, CglUPO is a promising biocatalyst for the oxyfunctionalization of bulky steroids and it will be a useful tool for the synthesis of pharmaceutically relevant steroidal molecules.
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Diabetes-linked transcription factor HNF4α regulates metabolism of endogenous methylarginines and β-aminoisobutyric acid by controlling expression of alanine-glyoxylate aminotransferase 2Burdin, Dmitry V., Kolobov, Alexey A., Brocker, Chad, Soshnev, Alexey A., Samusik, Nikolay, Demyanov, Anton v., Brilloff, Silke, Jarzebska, Natalia, Martens-Lobenhoffer, Jens, Mieth, Maren, Maas, Renke, Bornstein, Stefan R., Bode-Böger, Stefanie M., Gonzalez, Frank, Weiss, Norbert, Rodionov, Roman N. 21 July 2017 (has links)
Elevated levels of circulating asymmetric and symmetric dimethylarginines (ADMA and SDMA) predict and potentially contribute to end organ damage in cardiovascular diseases. Alanine-glyoxylate aminotransferase 2 (AGXT2) regulates systemic levels of ADMA and SDMA, and also of beta-aminoisobutyric acid (BAIB)-a modulator of lipid metabolism. We identified a putative binding site for hepatic nuclear factor 4 α (HNF4α) in AGXT2 promoter sequence. In a luciferase reporter assay we found a 75% decrease in activity of Agxt2 core promoter after disruption of the HNF4α binding site. Direct binding of HNF4α to Agxt2 promoter was confirmed by chromatin immunoprecipitation assay. siRNA-mediated knockdown of Hnf4a led to an almost 50% reduction in Agxt2 mRNA levels in Hepa 1–6 cells. Liver-specific Hnf4a knockout mice exhibited a 90% decrease in liver Agxt2 expression and activity, and elevated plasma levels of ADMA, SDMA and BAIB, compared to wild-type littermates. Thus we identified HNF4α as a major regulator of Agxt2 expression. Considering a strong association between human HNF4A polymorphisms and increased risk of type 2 diabetes our current findings suggest that downregulation of AGXT2 and subsequent impairment in metabolism of dimethylarginines and BAIB caused by HNF4α deficiency might contribute to development of cardiovascular complications in diabetic patients.
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New determinants of olfactory habituationSinding, Charlotte, Valadier, François, Al-Hassani, Viviana, Feron, Gilles, Tromelin, Anne, Kontaris, Ioannis, Hummel, Thomas 27 July 2017 (has links)
Habituation is a filter that optimizes the processing of information by our brain in all sensory modalities. It results in an unconscious reduced responsiveness to continuous or repetitive stimulation. In olfaction, the main question is whether habituation works the same way for any odorant or whether we habituate differently to each odorant? In particular, whether chemical, physical or perceptual cues can limit or increase habituation. To test this, the odour intensity of 32 odorants differing in physicochemical characteristics was rated by 58 participants continuously during 120s. Each odorant was delivered at a constant concentration. Results showed odorants differed significantly in habituation, highlighting the multifactoriality of habituation. Additionally habituation was predicted from 15 physico-chemical and perceptual characteristics of the odorants. The analysis highlighted the importance of trigeminality which is highly correlated to intensity and pleasantness. The vapour pressure, the molecular weight, the Odor Activity Value (OAV) and the number of double bonds mostly contributed to the modulation of habituation. Moreover, length of the carbon chain, number of conformers and hydrophobicity contributed to a lesser extent to the modulation of habituation. These results highlight new principles involved in the fundamental process of habituation, notably trigeminality and the physicochemical characteristics associated.
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Clinical impact of duodenal pancreatic heterotopia – Is there a need for surgical treatment?Betzler, Alexander, Mees, Soeren Torge, Pump, Josefine, Schölch, Sebastian, Zimmermann, Carolin, Aust, Daniela E., Weitz, Jürgen, Welsch, Thilo, Distler, Marius 27 July 2017 (has links)
Background
Pancreatic heterotopia (PH) is defined as ectopic pancreatic tissue outside the normal pancreas and its vasculature and duct system. Most frequently, PH is detected incidentally by histopathological examination. The aim of the present study was to analyze a large single-center series of duodenal PH with respect to the clinical presentation.
Methods
A prospective pancreatic database was retrospectively analyzed for cases of PH of the duodenum. All pancreatic and duodenal resections performed between January 2000 and October 2015 were included and screened for histopathologically proven duodenal PH. PH was classified according to Heinrich’s classification (Type I acini, ducts, and islet cells; Type II acini and ducts; Type III only ducts).
Results
A total of 1274 pancreatic and duodenal resections were performed within the study period, and 67 cases of PH (5.3%) were identified. The respective patients were predominantly male (72%) and either underwent pancreatoduodenectomy (n = 60); a limited pancreas resection with partial duodenal resection (n = 4); distal pancreatectomy with partial duodenal resection (n = 1); total pancreatectomy (n = 1); or enucleation (n = 1). Whereas 65 patients (83.5%) were asymptomatic, 11 patients (18.4%) presented with symptoms related to PH (most frequently with abdominal pain [72%] and duodenal obstruction [55%]). Of those, seven patients (63.6%) had chronic pancreatitis in the heterotopic pancreas. The risk of malignant transformation into adenocarcinoma was 2.9%.
Conclusions
PH is found in approximately 5% of pancreatic or duodenal resections and is generally asymptomatic. Chronic pancreatitis is not uncommon in heterotopic pancreatic tissue, and even there is a risk of malignant transformation. PH should be considered for the differential diagnosis of duodenal lesions and surgery should be considered, especially in symptomatic cases.
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Response inhibition in Attention deficit disorder and neurofibromatosis type 1 – clinically similar, neurophysiologically differentBluschke, Annet, von der Hagen, Maja, Papenhagen, Katharina, Roessner, Veit, Beste, Christian 15 November 2017 (has links)
There are large overlaps in cognitive deficits occurring in attention deficit disorder (ADD) and neurodevelopmental disorders like neurofibromatosis type 1 (NF1). This overlap is mostly based on clinical measures and not on in-depth analyses of neuronal mechanisms. However, the consideration of such neuronal underpinnings is crucial when aiming to integrate measures that can lead to a better understanding of the underlying mechanisms. Inhibitory control deficits, for example, are a hallmark in ADD, but it is unclear how far there are similar deficits in NF1. We thus compared adolescent ADD and NF1 patients to healthy controls in a Go/Nogo task using behavioural and neurophysiological measures. Clinical measures of ADD-symptoms were not different between ADD and NF1. Only patients with ADD showed increased Nogo errors and reductions in components reflecting response inhibition (i.e. Nogo-P3). Early perceptual processes (P1) were changed in ADD and NF1. Clinically, patients with ADD and NF1 thus show strong similarities. This is not the case in regard to underlying cognitive control processes. This shows that in-depth analyses of neurophysiological processes are needed to determine whether the overlap between ADD and NF1 is as strong as assumed and to develop appropriate treatment strategies.
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Sulfated Hyaluronan Derivatives Modulate TGF-β1:Receptor Complex Formation: Possible Consequences for TGF-β1 SignalingHintze, Vera, Samsonov, Sergey, Rother, Sandra, Vogel, Sarah, Köhling, Sebastian, Moeller, Stephanie, Schnabelrauch, Matthias, Rademann, Jörg, Hempel, Ute, Pisabarro, M. Teresa, Scharnweber, Dieter 10 November 2017 (has links)
Glycosaminoglycans are known to bind biological mediators thereby modulating their biological activity. Sulfated hyaluronans (sHA) were reported to strongly interact with transforming growth factor (TGF)-β1 leading to impaired bioactivity in fibroblasts. The underlying mechanism is not fully elucidated yet. Examining the interaction of all components of the TGF-β1:receptor complex with sHA by surface plasmon resonance, we could show that highly sulfated HA (sHA3) blocks binding of TGF-β1 to its TGF-β receptor-I (TβR-I) and -II (TβR-II). However, sequential addition of sHA3 to the TβR-II/TGF-β1 complex led to a significantly stronger recruitment of TβR-I compared to a complex lacking sHA3, indicating that the order of binding events is very important. Molecular modeling suggested a possible molecular mechanism in which sHA3 could potentially favor the association of TβR-I when added sequentially. For the first time bioactivity of TGF-β1 in conjunction with sHA was investigated at the receptor level. TβR-I and, furthermore, Smad2 phosphorylation were decreased in the presence of sHA3 indicating the formation of an inactive signaling complex. The results contribute to an improved understanding of the interference of sHA3 with TGF-β1:receptor complex formation and will help to further improve the design of functional biomaterials that interfere with TGF-β1-driven skin fibrosis.
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On the effects of multimodal information integration in multitaskingStock, Ann-Kathrin, Gohil, Krutika, Huster, René J., Beste, Christian 14 November 2017 (has links)
There have recently been considerable advances in our understanding of the neuronal mechanisms underlying multitasking, but the role of multimodal integration for this faculty has remained rather unclear. We examined this issue by comparing different modality combinations in a multitasking (stop-change) paradigm. In-depth neurophysiological analyses of event-related potentials (ERPs) were conducted to complement the obtained behavioral data. Specifically, we applied signal decomposition using second order blind identification (SOBI) to the multi-subject ERP data and source localization. We found that both general multimodal information integration and modality-specific aspects (potentially related to task difficulty) modulate behavioral performance and associated neurophysiological correlates. Simultaneous multimodal input generally increased early attentional processing of visual stimuli (i.e. P1 and N1 amplitudes) as well as measures of cognitive effort and conflict (i.e. central P3 amplitudes). Yet, tactile-visual input caused larger impairments in multitasking than audio-visual input. General aspects of multimodal information integration modulated the activity in the premotor cortex (BA 6) as well as different visual association areas concerned with the integration of visual information with input from other modalities (BA 19, BA 21, BA 37). On top of this, differences in the specific combination of modalities also affected performance and measures of conflict/effort originating in prefrontal regions (BA 6).
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Reliability in adolescent fMRI within two years – a comparison of three tasksVetter, Nora C., Steding, Julius, Jurk, Sarah, Ripke, Stephan, Mennigen, Eva, Smolka, Michael N. 16 November 2017 (has links)
Longitudinal developmental fMRI studies just recently began to focus on within-subject reliability using the intraclass coefficient (ICC). It remains largely unclear which degree of reliability can be achieved in developmental studies and whether this depends on the type of task used. Therefore, we aimed to systematically investigate the reliability of three well-classified tasks: an emotional attention, a cognitive control, and an intertemporal choice paradigm. We hypothesized to find higher reliability in the cognitive task than in the emotional or reward-related task. 104 healthy mid-adolescents were scanned at age 14 and again at age 16 within M = 1.8 years using the same paradigms, scanner, and scanning protocols. Overall, we found both variability and stability (i.e. poor to excellent ICCs) depending largely on the region of interest (ROI) and task. Contrary to our hypothesis, whole brain reliability was fair for the cognitive control task but good for the emotional attention and intertemporal choice task. Subcortical ROIs (ventral striatum, amygdala) resulted in lower ICCs than visual ROIs. Current results add to the yet sparse overall ICC literature in both developing samples and adults. This study shows that analyses of stability, i.e. reliability, are helpful benchmarks for longitudinal studies and their implications for adolescent development.
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Tuning the Sensitivity of the PDR5 Promoter-Based Detection of Diclofenac in Yeast BiosensorsSchuller, Astrid, Rödel, Gerhard, Ostermann, Kai 15 November 2017 (has links)
The commonly used drug diclofenac is an important environmental anthropogenic pollutant. Currently, detection of diclofenac is mainly based on chemical and physical methods. Here we describe a yeast biosensor that drives the diclofenac-dependent expression of a recombinant fluorescent protein from the authentic promoter of the PDR5 gene. This key component of the pleiotropic drug response encodes a multidrug transporter that is involved in cellular detoxification. We analyse the effects on diclofenac sensitivity of artificial PDR5 promoter derivatives in wild-type and various yeast mutant strains. This approach enabled us to generate sensor strains with elevated drug sensitivity.
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Amoeboid-mesenchymal migration plasticity promotes invasion only in complex heterogeneous microenvironmentsTalkenberger, Katrin, Cavalcanti-Adam, Elisabetta Ada, Voss-Böhme, Anja, Deutsch, Andreas 30 November 2017 (has links)
During tissue invasion individual tumor cells exhibit two interconvertible migration modes, namely mesenchymal and amoeboid migration. The cellular microenvironment triggers the switch between both modes, thereby allowing adaptation to dynamic conditions. It is, however, unclear if this amoeboid-mesenchymal migration plasticity contributes to a more effective tumor invasion. We address this question with a mathematical model, where the amoeboid-mesenchymal migration plasticity is regulated in response to local extracellular matrix resistance. Our numerical analysis reveals that extracellular matrix structure and presence of a chemotactic gradient are key determinants of the model behavior. Only in complex microenvironments, if the extracellular matrix is highly heterogeneous and a chemotactic gradient directs migration, the amoeboid-mesenchymal migration plasticity allows a more widespread invasion compared to the non-switching amoeboid and mesenchymal modes. Importantly, these specific conditions are characteristic for in vivo tumor invasion. Thus, our study suggests that in vitro systems aiming at unraveling the underlying molecular mechanisms of tumor invasion should take into account the complexity of the microenvironment by considering the combined effects of structural heterogeneities and chemical gradients on cell migration.
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