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141.
Hiromi González-Fuentes Katharina Riehn Martin Koethe Eberhard von Borell Ernst Luecker Ahmad Hamedy 《Parasitology research》2014,113(8):2983-2989
The aim of this study was to determine the effect of different concentrations of table salt (NaCl) and ethanol (v/v) solutions on the viability of Alaria alata mesocercariae. Furthermore, the survival of A. alata mesocercariae during simulated human gastric digestion was evaluated. For this purpose, A. alata mesocercariae migration technique (AMT) was used for the isolation of the parasite from high-positive A. alata mesocercariae meat from wild boar, raccoon, raccoon dog, and badger meat. In total, we have studied the behavior of 582 larvae under different conditions (NaCl, ethanol, and artificial gastric juice) in three independent in vitro experiments. The larvae survived at a NaCl concentration of up to 2.0 % until day 21 with a median survival time of 11 days. At 3.0 % NaCl concentration, the larvae lost their vitality after less than 24 h. In addition, it was found that ethanol concentrations from 8.0 to 70.0 % were effective at reducing survival of A. alata mesocercariae within a short period of time (<1 min). Finally, our studies have revealed that it required 120 min to reliably inactivate all A. alata mesocercariae within HCl-pepsin digestion solution with a pH of 1.5–2.0 at 37 °C. Consequently, the results showed that 3.0 % is the minimum concentration of NaCl in meat products recommended for human consumption because at lower NaCl concentration the parasite survived for a substantial period of time. Finally, the common concentrations of ethanol used for the disinfection of surfaces in household and/or laboratory, are sufficient for the inactivation of A. alata mesocercariae. 相似文献
142.
Tilman T. Rau Abbas Agaimy Anastasia Gehoff Carol Geppert Klaus Jung Katharina Knobloch Cord Langner Alessandro Lugli Irene Groenbus-Lurkin Iris D. Nagtegaal Josef Rüschoff Xavier Saegert Mario Sarbia Regine Schneider-Stock Michael Vieth Ellen C. Zwarthoff Arndt Hartmann 《Virchows Archiv : an international journal of pathology》2014,464(6):663-672
Criteria for the diagnosis of serrated colorectal lesions (hyperplastic polyp, sessile serrated adenoma without or with dysplasia—which we called mixed polyp—and traditional serrated adenoma) for which consensus has been reached should be validated for applicability in daily practice in terms of inter-observer reproducibility and their association with clinical features and (epi)genetic events. A study set was created from a consecutive series of colorectal polyps (n?=?1,926) by selecting all sessile serrated adenomas, traditional serrated adenomas and mixed polyps. We added consecutive series of hyperplastic polyps, classical adenomas and normal mucosa samples for a total of 200 specimens. With this series, we conducted an inter-observer study, encompassing ten pathologists with gastrointestinal pathology experience from five European countries, in three rounds in which all cases were microscopically evaluated. An assessment of single morphological criteria was included, and these were correlated with clinical parameters and the mutation status of KRAS, BRAF and PIK3CA and the methylation status of MLH1. Gender, age and localisation were significantly associated with certain types of lesions. Kappa statistics revealed moderate to good inter-observer agreement for polyp classification (κ = 0.56 to 0.63), but for single criteria, this varied considerably (κ = 0.06 to 0.82). BRAF mutations were frequently found in hyperplastic polyps (86 %, 62/72) and sessile serrated adenomas (80 %, 41/51). KRAS mutations occurred more frequently in traditional serrated adenomas (78 %, 7/9) and less so in classical adenomas (20 %, 10/51). Single morphological criteria for sessile serrated adenomas showed significant correlation with BRAF mutation (all p?≤?0.001), and those for classical adenomas or traditional serrated adenoma correlated significantly with KRAS mutation (all p?<?0.001). Therefore, single well-defined morphological criteria are predictive for genetic alterations in colorectal polyps. 相似文献
143.
144.
Lalini Raghoebir Katharina Biermann Marjon Buscop-van Kempen Hendrikus J. Dubbink Winand N. M. Dinjens Remko Hersmus Leendert H. J. Looijenga Marco J. Bruno Dick Tibboel Robbert J. Rottier Ron Smits 《Virchows Archiv : an international journal of pathology》2014,465(4):395-400
Colorectal cancer (CRC) can be divided into non-mucinous and mucinous subtypes, of which the latter portends to have a worse clinical prognosis. A previous study suggested a putative link between SOX2 expression observed selectively in mucinous CRC and the induction of the gastric mucin MUC5AC. In this study, we re-evaluated the expression behavior of SOX2, MUC5AC, and CDX2 in both types of CRC. We performed immunohistochemical analysis on 90 cases of non-mucinous CRCs, 57 cases of mucinous CRCs, and 15 case-matched normal intestinal mucosa. In contrast to the previously suggested link between SOX2 and mucinous CRC, we observe aberrant expression of SOX2 at equal levels in both subtypes. Fluorescence in situ hybridization (FISH) analysis shows that expression is not attributed to genomic amplification. While SOX2 and CDX2 are normally expressed in a reciprocal manner, SOX2-positive tumor cells co-express CDX2. Furthermore, we show that MUC5AC is expressed independently of SOX2. In conclusion, we show that aberrant SOX2 expression is specifically linked neither to mucinous CRCs nor to the induction of MUC5AC, in contrast to previous suggestions. 相似文献
145.
146.
147.
Samuel Sutiono Katharina Satzinger Andr Pick Jrg Carsten Volker Sieber 《RSC advances》2019,9(51):29743
Pyruvate decarboxylase (PDC) is a key enzyme for the production of ethanol at high temperatures and for cell-free butanol synthesis. Thermostable, organic solvent stable PDC was evolved from bacterial PDCs. The new variant shows >1500-fold-improved half-life at 75 °C and >5000-fold-increased half-life in the presence of 9 vol% butanol at 50 °C.Pyruvate decarboxylase (PDC) is a key enzyme for the production of ethanol at high temperatures and for cell-free butanol synthesis.For many years, bioethanol has been used widely as an additive in gasoline or as a fuel by itself.1 To avoid competition with food, production of ethanol from plant-derived starch or sugar (first generation) has shifted to lignocellulosic biomass (second generation). To date, most of the bioethanol produced industrially still utilises yeasts as the main fermentation organism.1–3 However, in recent years, several efforts have been made to use thermophilic microorganisms as the new framework.1,3 The main motivating forces behind this are the volatility of ethanol at higher temperatures, which facilitates easy product removal, reduced risk of contamination and feasibility of consolidated bioprocessing (CBP). In this process, cellulolytic ethanologenic thermophilic microorganisms are applied, thus reducing the energy consumption required for heat exchange between biomass pre-treatment, fermentation and product separation and to avoid cellulase inhibition by accumulating glucose.3,4There are two major pathways for producing ethanol from pyruvate, the central metabolite in glycolysis: non-oxidative decarboxylation via pyruvate decarboxylase (PDC) and oxidative decarboxylation via pyruvate dehydrogenase (PDH) or pyruvate ferredoxin oxidoreductase (PFOR). Non-oxidative ethanol productions are commonly found in yeasts and other ethanologenic bacteria, while PDH and PFOR routes are described in thermophilic microorganisms.3,4 PDC mode may offer advantages compared with PDH and PFOR, as it is thermodynamically more favourable and will not lead to any other organic acid by-products.3–5 In fact, all industrially relevant ethanol producing organisms use PDC. Thermostable PDCs are, therefore, suggested to play an important role in creating homo-ethanologenic, thermophilic microorganisms.5,6Until recently, there were only limited efforts described in literature for improving the thermostability of PDC. Ancestral sequence reconstruction, supposedly a powerful method of resurrecting ancient thermostable enzymes, did not yield more thermostable PDC.7 A computational Rosetta-based design resulted in several variants with improved stability, determined by differential interference contrast (DIC) microscopy; unfortunately, the work was not corroborated by kinetic activity and stability data.8 Another effort to redirect the specificity of a thermostable, acetolactate synthase to perform a PDC-like reaction by conventional directed evolution did not yield variants either, with activity similar to that of bacterial PDC.9 Thus, creating thermostable PDC variants remains as the main challenge towards second generation ethanol production by thermophilic microorganisms.Besides acting as an important enzyme for ethanol production, PDC has also been applied in the in vitro production of n-butanol (Scheme 1).10,11 Butanol together with other longer-chain alcohols, such as 1-propanol, isobutanol and isopentanol, is regarded as the next-generation biofuel, due to its closer resemblance to traditional gasoline.12 Thus, there is an increasing demand to produce longer-chain alcohols sustainably.12 Industrially, butanol is still produced from petroleum-derived propene utilizing Co-catalyst, H2, and CO via oxo synthesis and Reppe process.13 Albeit its efficiency, production of butanol from petroleum is not sustainable.Open in a separate windowScheme 1Simplified pathway to produce ethanol and 1-butanol from lignocellulosic biomass via pyruvate decarboxylase (PDC). There are two major pathways for producing 1-butanol via pyruvate: CoA-dependent or proline-dependent condensation. ADH is an alcohol dehydrogenase.In a more sustainable way, butanol can be produced via an acetone–butanol–ethanol (ABE) process, utilising Clostridium acetobutylicum.12,14 Recent work on metabolic engineering has demonstrated the possibility of producing butanol in other microorganisms.15,16 However, one of the major challenges in butanol fermentation is still the toxicity of butanol to many microorganisms at relatively low concentrations (<2 vol%).17,18 This effect, however, is less pronounced for the enzymes catalysing butanol production in vitro.10,19 Many enzymes can already tolerate higher organic solvent concentrations than the corresponding microorganisms.20 Furthermore, engineering enzyme stability towards organic solvents is less challenging than evolving microorganisms to withstand the same concentration of organic solvents.17,21 Therefore, in vitro butanol production emerges as a very promising alternative to traditional butanol fermentation. Thus, in this work, we focused on the engineering of PDC towards higher thermal stability for prospective ethanol production in thermophilic microorganisms and improved stability in butanol for applications in in vitro, artificial butanol synthesis.Prior to engineering a PDC, we characterised two new yeast PDCs from Candida glabrata (CgPDC) and Zygosaccharomyces rouxii (ZrPDC), as well as other PDCs reported in the literature, to determine the most suitable template. As presented in 22 Characterisation of bacterial PDCs showed similar findings to the previous report, with PDC from Acetobacter pasteurianus (ApPDC) demonstrating the highest kinetic stability (T501 h) and melting temperature (Tm).22T501 h is defined as the temperature at which 50% of the enzymes remained active after 1 h incubation, while Tm is defined as the temperature at which 50% of the enzymes are in an unfolded state.23 In general, bacterial PDCs showed higher activity at 25 °C and overall stability (T501 h and Tm) than newly characterised CgPDC and ZrPDC.Summary of kinetic characterisations and thermostability of WT PDCs and variants
Open in a separate windowa T 50 1 h is defined as the temperature at which the enzyme gives 50% remaining activity after 1 h incubation (Fig. S1).23bMelting temperature was determined using Thermofluor assay (Fig. S1).cThe Hill coefficient was determined according to the equation: . Cg is Candida glabrata, Zr is Zygosaccharomyces rouxii, Ap is Acetobacter pasteurianus, Zm is Zymomonas mobilis and Zp is Zymobacter palmae.Another PDC that was reported to have improved stability, called 5TMA (Rosetta-designed ZmPDC), was also characterised in this study to fill the gap remaining due to the lack of data on activity and kinetic stability in the original study.8 It was claimed that 5TMA did not show any loss of molar ellipticity, measured by circular dichroism and that it was stable at 60 °C, observed by DIC microscopy. However, our kinetic stability studies based on activity suggested otherwise. We observed that 5TMA was less stable than wild-type (WT) ZmPDC, the parental PDC, in respect to T501 h and Tm (8 It is worth mentioning that during our T501 h experiment, we observed that 5TMA did not show any aggregation in contrast to other WT PDCs. This could explain why the authors did not observe a phase transition in DIC of 5TMA, but did for WT ZmPDC.Our previous work on evolving thermostable, branched-chain α-keto acid decarboxylase from Lactococcus lactis (LlKdcA) showed that improved thermostability was also translated to increased stability against isobutanol.24 The direct relationship between thermostability and organic solvent stability has also been described in other enzyme classes.21,25,26 Therefore, to save time and expense in finding PDC variants with increased thermostability and butanol-stability, we developed a simple screening platform to screen only for improved thermostability. For library development, staggered extensions process (StEP) was utilised.27 StEP has been shown in previous work to be a robust and relatively easy approach for increasing thermostability.27 Three PDCs from Zymomonas mobilis (ZmPDC), Zymobacter palmae (ZpPDC) and ApPDC with relatively similar stability and activity, were chosen as parental templates.After screening about 800 colonies, we obtained several variants that showed improved thermostability in comparison with our control (WT ApPDC). The most thermostable variant (renamed PDC-Var. 1) was selected, and the mutations were determined by DNA sequencing. PDC-Var. 1 showed the highest sequence similarity to ApPDC (98%), bearing 13 substitutions (Fig. S2 and S3†). In comparison with ApPDC, the most thermostable PDC reported to date, PDC-Var. 1 exhibited increases of 8.2 °C and 7.0 °C in T501 h and Tm, respectively. Surprisingly, PDC-Var. 1 also showed improved activity in comparison with WT ApPDC, without significant change in Km (28 We later used this new variant as a new template to further increase its thermostability.In a previous work with LlKdcA, we successfully improved its thermal and isobutanol-stability by introducing seven amino acid substitutions (Var. 7M.D).24 As ApPDC and LlKdcA belong to the same α-keto acid decarboxylase family, we intended to transfer the seven beneficial substitutions of Var. 7M.D to our new PDC-Var. 1. A similar screening procedure was applied. From the seven libraries, only one variant showed improved stability. We named the new variant PDC-Var. 2, which displays a change at position 441 of PDC-Var. 1 from isoleucine to valine (Fig. S3†).24 PDC-Var. 2 exhibited T501 h and Tm of 78.5 °C and 82.0 °C, respectively, meaning an improvement of 5.4 °C and 5.0 °C compared with PDC-Var. 1 or an increase of 13.6 °C and 12.0 °C compared with WT ApPDC.To check the stability of PDC-Var. 2 in comparison with WT ApPDC for ethanol fermentation applications via thermophilic microorganisms, both enzymes were incubated at 65 °C, 70 °C and 75 °C (Fig. 1). At 65 °C, WT ApPDC showed a first-order deactivation kinetics, with a half-life of 57 min, while PDC-Var. 2 showed a half-life of 18 h. This improvement represented an almost 19-fold increase. At higher temperatures, the stability effect of PDC-Var. 2 became even more apparent. At 70 °C, WT ApPDC completely lost its activity after 10 min of incubation, while PDC-Var. 2 retained 25% of initial activity after 24 h incubation. At 75 °C, WT ApPDC was completely deactivated after 2 min, while PDC-Var. 2 retained more than 20% of initial activity after 12 h incubation. Based on a first-order kinetic deactivation, WT ApPDC exhibited half-lives of 1.2 min and 10.8 s at 70 °C and 75 °C, respectively. For PDC-Var. 2, the half-lives at 70 °C and 75 °C are 10.7 h and 7.3 h, respectively. As such, the improved stability of PDC-Var. 2 corresponded to a 522-fold and a 2438-fold increased half-life at 70 °C and 75 °C (Fig. 1), respectively. PDC-Var. 2 also demonstrated improved stability towards ethanol by tolerating ethanol up to 40 vol% at 50 °C in comparison with WT ApPDC that showed stability up to only 22 vol% (Fig. S4†). We stress that this new improved characteristic is important for ethanol production in vitro.19Open in a separate windowFig. 1Kinetic stability of WT ApPDC in comparison with PDC-Var. 2 at 65 °C (A), 70 °C (B) and 75 °C (C). Thermal denaturations of the WT and PDC-Var. 2 followed first order kinetics at any given temperature. Half-lives of WT ApPDC are 57 min, 1.2 min and 10.8 s at 65, 70 and 75 °C, respectively. Half-lives of Variant 2 are 18, 10.7 and 7.3 h at 65, 70 and 75 °C, respectively. Standard deviations are shown from three independent technical replications.Biotechnological production of butanol is challenging, mainly due to its high toxicity for microbial cells. Until now, no microorganism has been found in nature that can grow at butanol concentrations higher than 4 vol%.29 Recently, production schemes were proposed that utilise the solubility limit of butanol in water (9 vol% at 50 °C).10,11 Using solvent-stable enzymes and hands-on in vitro enzyme cascade, cell-free butanol production within a two-phase water/butanol system can be envisioned. Some enzymes from thermophilic microorganisms can already tolerate higher alcohol concentrations, such as aldolase from Saccharolobus solfataricus (previously known as Sulfolobus solfataricus), which was shown to retain full activity in a two-phase system.19At 50 °C, the most thermostable WT PDC, ApPDC, showed stability up to only 5.6 vol% butanol after incubation for 1 h (Fig. 2A). In 7 vol% butanol, WT ApPDC was completely deactivated. As expected, PDC-Var. 2 demonstrated exceptional stability, by retaining more than 70% of its initial activity in 9 vol% butanol after 1 h incubation at 50 °C (Fig. 2A). Further kinetic stability studies revealed that WT ApPDC was completely deactivated after 30 s incubation at 9 vol% butanol at 50 °C (Fig. 2B). PDC-Var. 2, however, maintained more than 40% of its initial activity after 24 h incubation and 15% of its initial activity after 48 h incubation (Fig. 2B). This corresponds to a half-life of 15 h and thus an over 5000-fold increase in half-life in comparison with WT ApPDC.Open in a separate windowFig. 2Stability of WT ApPDC and PDC-Var. 2 in the presence of butanol. (A) Stability of the WT ApPDC and the variant after incubation in different concentrations of butanol for 1 at 50 °C. Lines are drawn to ease reading. (B) Stability of the WT ApPDC and the variant over time in 9 vol% butanol at 50 °C. Standard deviations are shown from three independent technical replications.When a higher temperature is desired, e.g. 60 °C, as indicated by previous work, WT ApPDC could retain 50% of its activity only up to 2 vol% of butanol at 60 °C, while PDC-Var. 2 started to lose 50% of initial activity in the presence of 8 vol% butanol (Fig. S5†).10,11 Hence, with this new improved process stability and high activity (3,5 Improved butanol stability of PDC-Var. 2 should drive forward the already developed in vitro butanol production, either via CoA dependent or proline-facilitated aldehyde condensation pathways (Scheme 1).10,11 Additionally, improved thermostability and stability in the presence of butanol of PDC-Var. 2 will facilitate simpler product removal at high temperatures in cell-free butanol synthesis. 相似文献
Enzyme | V max (U mg−1) | K m (mM) | T 50 1 h a (°C) | T m b (°C) |
---|---|---|---|---|
CgPDC | 22.2 ± 0.4 | 9.1 ± 0.2 h: 2.02c | 49.6 | 55.5 |
ZrPDC | 16.7 ± 0.4 | 11.6 ± 0.4 h: 2.39c | 42.9 | 50.5 |
ApPDC | 80.3 ± 0.6 | 1.9 ± 0.1 | 64.9 | 70.0 |
ZmPDC | 92.5 ± 0.7 | 1.3 ± 0.1 | 62.4 | 66.5 |
ZpPDC | 79.7 ± 0.4 | 0.8 ± 0.1 | 61.2 | 65.0 |
5NPU7 | 20.7 ± 0.8 | 4.8 ± 0.4 h: 1.28c | 51.9 | 55.5 |
5TMA8 | 87.0 ± 0.7 | 1.8 ± 0.1 | 54.7 | 59.5 |
PDC-Var. 1 | 91.7 ± 0.7 | 2.1 ± 0.1 | 73.1 | 77.0 |
PDC-Var. 2 | 71.6 ± 0.7 | 1.5 ± 0.1 | 78.5 | 82.0 |
148.
Katharina Hess Saad H. Alzahrani Jackie F. Price Mark W. Strachan Natalie Oxley Rhodri King Tobias Gamlen Verena Schroeder Paul D. Baxter Ramzi A. Ajjan 《Diabetologia》2014,57(8):1737-1741
Aims/hypothesis
Plasminogen activator inhibitor-1 (PAI-1) has been regarded as the main antifibrinolytic protein in diabetes, but recent work indicates that complement C3 (C3), an inflammatory protein, directly compromises fibrinolysis in type 1 diabetes. The aim of the current project was to investigate associations between C3 and fibrinolysis in a large cohort of individuals with type 2 diabetes.Methods
Plasma levels of C3, C-reactive protein (CRP), PAI-1 and fibrinogen were analysed by ELISA in 837 patients enrolled in the Edinburgh Type 2 Diabetes Study. Fibrin clot lysis was analysed using a validated turbidimetric assay.Results
Clot lysis time correlated with C3 and PAI-1 plasma levels (r?=?0.24, p?<?0.001 and r?=?0.22, p?<?0.001, respectively). In a multivariable regression model involving age, sex, BMI, C3, PAI-1, CRP and fibrinogen, and using log-transformed data as appropriate, C3 was associated with clot lysis time (regression coefficient 0.227 [95% CI 0.161, 0.292], p?<?0.001), as was PAI-1 (regression coefficient 0.033 [95% CI 0.020, 0.064], p?<?0.05) but not fibrinogen (regression coefficient 0.003 [95% CI ?0.046, 0.051], p?=?0.92) or CRP (regression coefficient 0.024 [95% CI ?0.008, 0.056], p?=?0.14). No correlation was demonstrated between plasma levels of C3 and PAI-1 (r?=??0.03, p?=?0.44), consistent with previous observations that the two proteins affect different pathways in the fibrinolytic system.Conclusions/interpretation
Similarly to PAI-1, C3 plasma levels are independently associated with fibrin clot lysis in individuals with type 2 diabetes. Therefore, future studies should analyse C3 plasma levels as a surrogate marker of fibrinolysis potential in this population. 相似文献149.
150.
G Stübiger E Aldover-Macasaet W Bicker G Sobal A Willfort-Ehringer K Pock V Bochkov K Widhalm O Belgacem 《Atherosclerosis》2012,224(1):177-186
ObjectivesPhospholipids (PLs) are increasingly recognized as key molecules with potential diagnostic value in acute inflammation, CVD and atherosclerosis. We introduce a pioneer mass spectrometry (MS)-based approach aiming to investigate the relationship of specific plasma PL-subsets with atherogenic blood parameters in young patients with familial hyperlipidemia representing high-CVD-risk groups.MethodsPlasma of carefully phenotyped FH and FCH patients as well as normolipidemic subjects (age 13 ± 5 years, n = 20) was used. Clinical parameters were assessed using standard laboratory techniques and lipids were subjected to a direct targeted monitoring using LC-ESI-SRM- and MALDI-QIT-TOF-MS/MS, respectively. Statistical analysis was performed to evaluate correlations between PL data and the clinical parameters.ResultsMost characteristically significant differences of SM/PC and PC/LPC ratios and positive correlations between SM vs. LDL-C (r = 0.946; p = 0.004) and LPC vs. VLDL-C (r = 0.669; p = 0.218) were observed in FH in contrast to the other study groups. OxPC levels were found in the range of ~2–20 μmol/L with predominance of short-chain aldehydic species (e.g. SOVPC). A positive correlation of OxPCs with IMT (r = 0.952; p = 0.052) and HDL-C (r = 0.893; p = 0.016) but negative correlation with OxLDL (r = ?0.910; p = 0.096) was observed.ConclusionsOur study was a first attempt to use a MALDI-QIT-TOF-MS/MS based clinical lipidomics approach to investigate atherogenic dyslipidemia in young patients with familial hyperlipidemia. This technique represents a promising platform for clinical screening of lipid biomarkers in the future. 相似文献