Optimal control of a continuous bioreactor for maximized beta-carotene production

Carotenes such as β-carotene have a positive impact in human health as a precursor of vitamin A. Structural complexity of these compounds makes their chemical synthesis a difficult endeavor, facilitating the need for their biological production. Continuous operation can be used in these processes to allow for increased cell viability through the mitigation of substrate and product inhibition, thereby increasing the productivity of the carotenoid product. This work looks to examine the operating conditions necessary to achieve the maximum production of the desired carotenoid products when produced via continuous operation. First, a two-level parameter estimation method is utilized to develop a reliable kinetic model for the batch production of carotenoids via fermentation to describe the glucose consumption, metabolic product formation and depletion, and the carotenoid production in the Saccharomyces cerevisiae strain mutant SM14 with 20 g/L glucose as the carbon source. These models are then extended to the study of a novel continuous bioreactor system using a two feed configuration that gives the ability to use flowrate and glucose concentration of the feed stream as independent manipulated variables. Dynamic optimization techniques are then used to determine the optimal control actions governing the dilution rate and glucose concentration in order to maximize the carotenoid productivity during continuous operation. Finally, a model predictive control methodology utilizing state estimation via available online measurements and real time dynamic optimization is proposed to allow for the real-time control of this novel system

Comparison of adverse effects in the treatment of pulmonary hypertension with monotherapy and combination therapy

Background: Pulmonary arterial hypertension (PAH) is a serious condition characterized by an increase in pulmonary vascular resistance (PVR) that leads to right heart failure and death. The study aimed to compare the side effects of monotherapy and combination therapy in the treatment of pulmonary hypertensionMethods: This randomized control trial study was conducted at the department of pediatric cardiology, Bangabandhu Sheikh Mujib medical university, national institute of cardiovascular disease, and national heart foundation, Dhaka, Bangladesh. The study duration was 1 year, from January 2018 to December 2018. During this period, a total of 70 participants were selected for the study following the inclusion, and exclusion criteria from those diagnosed case of pulmonary hypertension with congenital heart disease admitted to the pediatric cardiology department, Bangabandhu Sheikh Mujib medical university, NICVD, NHF.Result: Maximum patients had ventricular septal defects (VSD) (34.3% in group A, and 28.6% in group B). Followed by AVSD. 20.0% in group A and 25.7% in group B. Atrial septal defect (ASD) were 14.3% in group A, and 17.1% in group B. After three, and 6 months of follow-up SpO2 per exercise, 6MWD, SpO2 post-exercise, and alanine aminotransferase showed statistically significant differences between single and combined groups. There was no statistically significant difference regarding adverse effects between the 2 groups, but group B patients had slightly higher incidence of some side effects. PASP was significantly decreased in combined group than monotherapy group.Conclusions: This study concludes that combination therapy is more successful than monotherapy in PAH with coronary heart disease (CHD). Our findings demonstrate that combining Bosentan with oral Sildenafil medication in patients with CHD-related PAH is safe, and well tolerated at 3-, and 6-month follow-ups, resulting in a significant improvement in clinical status, effort SpO2, exercise tolerance, hemodynamics, and PASP

Comparison of short-term outcome between monotherapy versus combination therapy in the treatment of pulmonary hypertension associated with congenital heart disease

Background: Pulmonary arterial hypertension (PAH) is a severe condition marked by a progressive rise in pulmonary vascular resistance (PVR), which leads to right heart failure, and mortality. Combining medications is an appealing approach for treating PAH patients. The current study sought to compare the outcomes of monotherapy, and combination therapy after a short period of follow-up. The study aimed to compare the short-term outcome of monotherapy and combination therapy in the treatment of pulmonary hypertension.Methods: This randomized control trial study was conducted at the department of pediatric cardiology, Bangabandhu Sheikh Mujib medical university, national institute of cardiovascular disease, and national heart foundation, Dhaka, Bangladesh, from January 2018 to December 2018. During this period, a total of 70 participants were selected for the study following the inclusion, and exclusion criteria. The selected participants were then divided into two groups of 35 each through random selection.Result: There were no significant differences between the two groups in terms of mean age, and sex. The 34.3% in Group A, and 28.6% in group B had ventricular septal defects (VSD, followed by AVSD at 20.0% in group A and 25.7% in Group B. After 3 and 6 months of follow-up SpO2 per exercise, 6MWD, SpO2 post-exercise, and alanine aminotransferase showed statistically significant differences between single and combined groups. There was no statistically significant difference regarding adverse effects between the two groups. PASP was significantly decreased in the combined group than monotherapy group.Conclusions: Combination therapy is more successful than monotherapy in PAH with CHD. Combining bosentan with oral sildenafil medication in patients with CHD-related PAH is safe, and well tolerated at follow-ups

Quantifying the metabolic capabilities of engineered Zymomonas mobilis using linear programming analysis

BACKGROUND: The need for discovery of alternative, renewable, environmentally friendly energy sources and the development of cost-efficient, "clean" methods for their conversion into higher fuels becomes imperative. Ethanol, whose significance as fuel has dramatically increased in the last decade, can be produced from hexoses and pentoses through microbial fermentation. Importantly, plant biomass, if appropriately and effectively decomposed, is a potential inexpensive and highly renewable source of the hexose and pentose mixture. Recently, the engineered (to also catabolize pentoses) anaerobic bacterium Zymomonas mobilis has been widely discussed among the most promising microorganisms for the microbial production of ethanol fuel. However, Z. mobilis genome having been fully sequenced in 2005, there is still a small number of published studies of its in vivo physiology and limited use of the metabolic engineering experimental and computational toolboxes to understand its metabolic pathway interconnectivity and regulation towards the optimization of its hexose and pentose fermentation into ethanol. RESULTS: In this paper, we reconstructed the metabolic network of the engineered Z. mobilis to a level that it could be modelled using the metabolic engineering methodologies. We then used linear programming (LP) analysis and identified the Z. mobilis metabolic boundaries with respect to various biological objectives, these boundaries being determined only by Z. mobilis network's stoichiometric connectivity. This study revealed the essential for bacterial growth reactions and elucidated the association between the metabolic pathways, especially regarding main product and byproduct formation. More specifically, the study indicated that ethanol and biomass production depend directly on anaerobic respiration stoichiometry and activity. Thus, enhanced understanding and improved means for analyzing anaerobic respiration and redox potential in vivo are needed to yield further conclusions for potential genetic targets that may lead to optimized Z. mobilis strains. CONCLUSION: Applying LP to study the Z. mobilis physiology enabled the identification of the main factors influencing the accomplishment of certain biological objectives due to metabolic network connectivity only. This first-level metabolic analysis model forms the basis for the incorporation of more complex regulatory mechanisms and the formation of more realistic models for the accurate simulation of the in vivo Z. mobilis physiology

SAVE: Spectral-Shift-Aware Adaptation of Image Diffusion Models for Text-guided Video Editing

Text-to-Image (T2I) diffusion models have achieved remarkable success in synthesizing high-quality images conditioned on text prompts. Recent methods have tried to replicate the success by either training text-to-video (T2V) models on a very large number of text-video pairs or adapting T2I models on text-video pairs independently. Although the latter is computationally less expensive, it still takes a significant amount of time for per-video adaption. To address this issue, we propose SAVE, a novel spectral-shift-aware adaptation framework, in which we fine-tune the spectral shift of the parameter space instead of the parameters themselves. Specifically, we take the spectral decomposition of the pre-trained T2I weights and only control the change in the corresponding singular values, i.e. spectral shift, while freezing the corresponding singular vectors. To avoid drastic drift from the original T2I weights, we introduce a spectral shift regularizer that confines the spectral shift to be more restricted for large singular values and more relaxed for small singular values. Since we are only dealing with spectral shifts, the proposed method reduces the adaptation time significantly (approx. 10 times) and has fewer resource constrains for training. Such attributes posit SAVE to be more suitable for real-world applications, e.g. editing undesirable content during video streaming. We validate the effectiveness of SAVE with an extensive experimental evaluation under different settings, e.g. style transfer, object replacement, privacy preservation, etc.Comment: 23 pages, 18 figure