26 research outputs found
External mass transfer in a laser sintered structured reactor for continuous hydrogenation of alkynes
No full textThis work presents a study on the continuous operation of a structured reactor for alkyne hydrogenation in the field of Process Intensification. The reactor consists of a laser sintered metal structure characterized by a regular geometry, coated with a layer of ZnO/Al2O3 and impregnated with palladium nanoparticles. The partial hydrogenation of 2-methyl-3-butyn-2-ol with co-current gas-liquid upward flow was used as the test reaction system. A plug flow reactor model was applied to study the mass transfer phenomena under the reacting conditions. The reaction kinetics with the Pd/ZnO-based catalyst were simplified using a power rate law expression. The results in terms of the overall mass transfer coefficient Kov were modelled with a predictive Sherwood number correlation whose parameters were estimated by means of an optimization procedure. The structured reactor shows an overall mass transfer coefficient ranging between 0.2 and 1.2 s−1 depending on the operating conditions. The model is able to predict the impact of temperature (333–363 K), pressure (3.0–7.0 bar), gas velocity (0.005–0.024 m s−1) and liquid velocity (0.025–0.085 m s−1) on the overall mass transfer coefficient with a maximum deviation of 15%.</p
Model-based scale-up of a continuously operated consolidated bioprocess based on a microbial consortium for the production of ethanol
No full textThis work demonstrated that consolidated bioprocessing is a promising concept for conversion of lignocellulose to ethanol at industrial scale. CBP offers great cost saving potential, is feasible to be operated continuously and may be scaled up due to extensive knowledge of the process from a chemical engineering point of view.
Cost savings of up to 27.5% of the total costs compared to conventional bioethanol production from lignocellulose, as stated by a techno-economic assessment, make continuous CBP the strongest lever to reduce processing costs of lignocellulosic ethanol. A cost sensitivity analysis identified scale and yield as the main cost-pushers from a process point of view, whereas the price level of the plant location has the highest impact on the investment conditions.
To prove the feasibility of continuous CBP, and therefore the mentioned cost savings, experiments with a maximum titer of 3.258±0.007 g/L, a productivity of 0.025 g/(L*h) and constant enzyme production over 750h were conducted. Furthermore, the continuous experiments showed that experiments with identical volumetric oxygen transfer rate k_L a, but different oxygen fluxes per membrane area, showed titer differences of ca. 80% (1.83 g/L vs 3.26 g/L) in favor of setups with the large membrane surface.
A rigorous process model was developed for continuously operated CBP. 9 species were considered (oxygen, glucose, total concentration Trichoderma reesei, secondary mycelia concentration of T. reesei, enzymes, cellulose, cellobiose, yeast density and ethanol). 8 of these 9 species needed to be modelled spatially resolved to account properly for mass transfer limitations. The fungal biofilm thickness d_f was found to be a critical parameter with an optimum for every membrane configuration. Smaller d_f reduced the fungal biofilm volume and thus, the enzyme production and larger d_f increased the diffusion path length causing shortage in nutrient supply as well as lower enzyme concentrations in the bulk. The enzyme synthesis rate of the secondary mycelia was fitted by reducing it by ca. 40% (0.67 FPU/(mL*d) vs 1.152 (FPU/(mL*d) compared to batch models.
With the process model as centerpiece, a scale-up framework consisting of the model and a set of non-dimensional parameters was developed to scale CBP from 2.7L laboratory scale to 130L pilot scale. The majority of the non-dimensional parameters could be kept constant during scale-up as requested by the similarity paradigm. Necessary changes were simulated with the model. Again, the fungal biofilm thickness d_f proved to be a relevant parameter for scale-up considerations. In general, the relative loss of biofilm volume is compensated by longer residence times since the residence time has by far the least impact on the process economics.
Finally, popular rate-controlled separation techniques were investigated regarding their potential with CBP, since they offer the potential to reduce yeast inhibition, to avoid separation limitations by the azeotrope and they are not bound to the vapor-liquid-equilibrium of highly diluted ethanol-water mixtures. However, most of the mechanisms fail to handle the solids of the fermentation broth. Pervaporation, being the most promising concept for in-situ product removal, would be a cost-saving alternative to distillation for batch operation, but is limited by an unfavorable vapor-liquid equilibrium due to low bulk concentrations during continuous operation.GR-KR
Techno-economic assessment of bioethanol production from lignocellulose by consortium-based consolidated bioprocessing at industrial scale
No full textLignocellulose-based biofuels are of major importance to mitigate the impact of international traffic and transport on climate change while sustaining agricultural land for food supply. Highly integrated systems like consolidated bioprocessing (CBP), where enzyme production, enzymatic hydrolysis and fermentation of the released sugars are carried out in one reactor, offer the highest potential to save costs and to make lignocellulosebased biofuels economically competitive. The work described here showed that CBP based on a microbial consortium operated at full-scale (2000 t/d) saves up to 27.5 % of the total ethanol production costs compared to conventional ethanol production from lignocellulose in individual process steps. The cost savings are mainly achieved through lower CAPEX due to less apparatus requirements because of the integrated process, as well as through lower OPEX since no glucose is needed for enzyme production. A comparison with literature estimations of cost savings of CBP based on genetically modified microorganisms results in approximately the same range. As a result of a detailed sensitivity analysis, scale and yield were identified as the main cost-pushers from a process point of view, whereas the price level of the plant location has the highest impact on the investment conditions. In the EU, CBP yields enough margin for profitable production and the possibility to decentralize biomass valorization, whereas in the world's largest ethanol market, the U.S, profitable production of lignocellulosic ethanol can only be achieved by CBP combined with other cost saving techniques, such as utilization of cost-free waste feedstocks, since ethanol has undergone a considerable price slump.GR-KR
Circadian variation in gastric vagal afferent mechanosensitivity
No full textFood intake is coordinated to cellular metabolism by clock gene expression with a master clock in the suprachiasmatic nucleus synchronized by light exposure. Gastric vagal afferents play a role in regulating food intake, but it is unknown whether they exhibit circadian variation in their mechanosensitivity. We aimed to determine whether gastric vagal afferents express clock genes and whether their response to mechanical stimuli oscillates throughout the light/dark cycle. Nodose ganglia were collected from 8-week-old female C57BL/6 mice every 3 h starting at lights off (1800 h) to quantify Bmal1, Per1, Per2, and Nr1d1 mRNA by qRT-PCR. Additionally in vitro single-fiber recordings of gastric vagal mechanoreceptors were taken at all time points. Per1, Per2, Bmal1, and Nr1d1 mRNA is expressed in the nodose ganglia and levels oscillated over a 24 h period. In mice fed ad libitum, gastric content was 3 times higher at 0000 h and 0300 h than 1200 h. The response of tension receptors to 3 g stretch was reduced by up to 70% at 2100 h, 0000 h, and 0300 h compared with 1200 h. Gastric mucosal receptor response to stroking with a 50 mg von Frey hair was 3 times greater at 1200 h and 1500 h than the response at 0000 h. Similar findings were obtained in mice fasted for 6 h or maintained in darkness for 3 d before study. Therefore, these changes do not result from food intake or the light/dark cycle. Thus, gastric vagal mechanoreceptors display circadian rhythm, which may act to control food intake differentially at different times of the day.Stephen J. Kentish, Claudine L. Frisby, David J. Kennaway, Gary A. Wittert, and Amanda J. Pag
Alternative splicing and extensive RNA editing of human TPH2 transcripts.
No full textBrain serotonin (5-HT) neurotransmission plays a key role in the regulation of mood and has been implicated in a variety of neuropsychiatric conditions. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of 5-HT. Recently, we discovered a second TPH isoform (TPH2) in vertebrates, including man, which is predominantly expressed in brain, while the previously known TPH isoform (TPH1) is primarly a non-neuronal enzyme. Overwhelming evidence now points to TPH2 as a candidate gene for 5-HT-related psychiatric disorders. To assess the role of TPH2 gene variability in the etiology of psychiatric diseases we performed cDNA sequence analysis of TPH2 transcripts from human post mortem amygdala samples obtained from individuals with psychiatric disorders (drug abuse, schizophrenia, suicide) and controls. Here we show that TPH2 exists in two alternatively spliced variants in the coding region, denoted TPH2a and TPH2b. Moreover, we found evidence that the pre-mRNAs of both splice variants are dynamically RNA-edited in a mutually exclusive manner. Kinetic studies with cell lines expressing recombinant TPH2 variants revealed a higher activity of the novel TPH2B protein compared with the previously known TPH2A, whereas RNA editing was shown to inhibit the enzymatic activity of both TPH2 splice variants. Therefore, our results strongly suggest a complex fine-tuning of central nervous system 5-HT biosynthesis by TPH2 alternative splicing and RNA editing. Finally, we present molecular and large-scale linkage data evidencing that deregulated alternative splicing and RNA editing is involved in the etiology of psychiatric diseases, such as suicidal behaviour
Post-stenotic aortic dilatation.
No full textAortic stenosis is the most common valvular heart disease affecting up to 4% of the elderly population. It can be associated with dilatation of the ascending aorta and subsequent dissection. Post-stenotic dilatation is seen in patients with AS and/or aortic regurgitation, patients with a haemodynamically normal bicuspid aortic valve and following aortic valve replacement. Controversy exists as to whether to replace the aortic root and ascending aorta at the time of aortic valve replacement, an operation that potentially carries a higher morbidity and mortality. The aetiology of post-stenotic aortic dilatation remains controversial. It may be due to haemodynamic factors caused by a stenotic valve, involving high velocity and turbulent flow downstream of the stenosis, or due to intrinsic pathology of the aortic wall. This may involve an abnormality in the process of extracellular matrix remodelling in the aortic wall including inadequate synthesis, degradation and transport of extracellular matrix proteins. This article reviews the aetiology, pathology and management of patients with post-stenotic aortic dilatation
Two New Loci for Body-Weight Regulation Identified in a Joint Analysis of Genome-Wide Association Studies for Early-Onset Extreme Obesity in French and German Study Groups
No full textMeta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85610 x 10(-8) in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84 x 10(-7)), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at similar to 1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults
Inhibiting ADAM17 enhances the efficacy of olaparib in ovarian cancer spheroids
No full textAbstract Acquired or de novo resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) is a major challenge to ovarian cancer treatment. Therefore, strategies to overcome PARPi resistance are critical to improve prognosis. The purpose of this study is to evaluate whether inhibition of ADAM17 sensitizes ovarian cancer to treatment with olaparib, a PARPi, thereby bypassing resistance mechanisms and improving treatment response. Thus, we analyzed the effect of olaparib in combination with the ADAM17 inhibitor GW280264X in ovarian cancer using a 2D monolayer and a 3D spheroid model followed by a multicontent readout (viability, caspase activation and cytotoxicity). To emphasize the translational aspect of our work, we performed corresponding experiments on primary cells derived from ovarian cancer patients initially screened for their mutation status of the breast cancer gene (BRCA 1/2). In 2D, we observed a significant reduction in cell viability and a subsequent increase in apoptosis of the combined treatment (olaparib + GW280264X) compared with olaparib mono-treatment. The combined treatment allows a substantial dose reduction of olaparib rendering a strong synergistic effect. Using a 3D spheroid model from primary cells, we confirmed the 2D monoculture results and demonstrated not only increased caspase activity under the combined treatment but also a substantial gain in cytotoxicity compared to the mono-treatment. Our study proposes ADAM17 inhibition sensitizing ovarian cancer to olaparib treatment and improving treatment response
Nicotine dependence is associated with an increased risk of developing chronic, non-communicable inflammatory disease: a large-scale retrospective cohort study
No full textIntroductionChronic, non-communicable inflammatory diseases (CIDs) affect a large portion of the population, imposing a significant morbidity, encompassing a substantial mortality. Thus, they are a major medical burden with a high unmet need. CIDs develop over the span of several years, and the risk of developing CIDs has been linked to genetic and environmental factors. Thus, modification of environmental factors is a promising approach for the prevention of CIDs. Among modifiable environmental factors that have been linked to the CID risk is nicotine dependence. However, for only few CIDs, compelling evidence suggests that nicotine dependence increases (e.g., rheumatoid arthritis and asthma) or decreases (e.g., pemphigus) the CID risk. For most CIDs, there are inconsistent, scant, or no reports on the risk of CID associated with nicotine dependence.MethodsTo address this gap, we leveraged TriNetX, analyzing data from over 120 million electronic health records (EHRs). Using propensity score matching (PSM) to control for age, sex, ethnicity, and other CID risk factors, we contrasted the risk of developing any or any of the 38 CIDs in 881,192 EHRs from individuals with nicotine dependence to PSM-matched unexposed counterparts.ResultsThe analytical pipeline was validated by demonstrating an increased risk of individuals exposed to nicotine dependence for subsequent diagnosis of myocardial infarction, malignant neoplasm of the lung, and chronic obstructive pulmonary disease. Overall, 16.8% of individuals with nicotine dependence developed CIDs, compared to 9.6% of individuals not exposed to nicotine dependence (hazard ratio 2.12, confidence interval 2.10–2.14, p < 0.0001). Investigating single CIDs, nicotine dependence imposed increased risks for 23 of the 38 investigated diseases, i.e., dermatomyositis, granulomatosis with polyangiitis, pyoderma gangrenosum, and immune thrombocytopenic purpura. The sex-stratified analysis revealed few sex-specific differences in CID risk.DiscussionOur study emphasizes the importance of preventive measures targeting nicotine addiction to reduce the global burden of CIDs
Nicotine dependence is associated with an increased risk of developing chronic, non-communicable inflammatory disease: a large-scale retrospective cohort study
No full textIntroduction Chronic, non-communicable inflammatory diseases (CIDs) affect a large portion of the population, imposing a significant morbidity, encompassing a substantial mortality. Thus, they are a major medical burden with a high unmet need. CIDs develop over the span of several years, and the risk of developing CIDs has been linked to genetic and environmental factors. Thus, modification of environmental factors is a promising approach for the prevention of CIDs. Among modifiable environmental factors that have been linked to the CID risk is nicotine dependence. However, for only few CIDs, compelling evidence suggests that nicotine dependence increases (e.g., rheumatoid arthritis and asthma) or decreases (e.g., pemphigus) the CID risk. For most CIDs, there are inconsistent, scant, or no reports on the risk of CID associated with nicotine dependence. Methods To address this gap, we leveraged TriNetX, analyzing data from over 120 million electronic health records (EHRs). Using propensity score matching (PSM) to control for age, sex, ethnicity, and other CID risk factors, we contrasted the risk of developing any or any of the 38 CIDs in 881,192 EHRs from individuals with nicotine dependence to PSM-matched unexposed counterparts. Results The analytical pipeline was validated by demonstrating an increased risk of individuals exposed to nicotine dependence for subsequent diagnosis of myocardial infarction, malignant neoplasm of the lung, and chronic obstructive pulmonary disease. Overall, 16.8% of individuals with nicotine dependence developed CIDs, compared to 9.6% of individuals not exposed to nicotine dependence (hazard ratio 2.12, confidence interval 2.10-2.14, p < 0.0001). Investigating single CIDs, nicotine dependence imposed increased risks for 23 of the 38 investigated diseases, i.e., dermatomyositis, granulomatosis with polyangiitis, pyoderma gangrenosum, and immune thrombocytopenic purpura
