TGF-β, an important cytokine that plays a key role in many diseases regulates a wide array of cellular and physiologic processes via several TGF-β-driven signaling cascades, including the SMAD and non-SMAD-driven pathways. However, the detailed mechanisms by which TGF-β induces such diverse responses remain poorly understood. In particular, compared to the SMAD-dependent pathway, SMAD-independent pathways such as the ERK/MAPK pathway, which is critical in cancer progression, are less characterized. Here, we develop an integrated mechanistic model of the TGF-β-triggered ERK activation pathway and its crosstalk with the SMAD pathway, an analysis of which demonstrates how SMAD dynamics can be significantly modulated and regulated by the ERK pathway. In particular, SMAD-mediated transcription can be altered and delayed due to expedited phosphorylation of the linker of SMAD by TGF-β-activated ERK; and enhanced ERK activity, but attenuated SMAD activity, can be achieved simultaneously by fast turnover of TGF-β receptors via lipid-rafts. Also, in silico mutations of the TGF-β pathways reveal that the dynamic characteristics of both SMAD and ERK signaling may change significantly during cancer development. Specifically, normal cells may exhibit enhanced and sustained SMAD signaling with transient ERK activation, whereas cancerous cells may produce elevated and prolonged ERK signaling with enervated SMAD activation. These distinctive differences between normal and cancerous signaling behavior provide clues concerning, and potential explanations for, the seemingly contradictory roles played by TGF-β during cancer progression. We demonstrate how crosstalk among various branch pathways of TGF-β can influence overall cellular behavior. Based on model analysis, we hypothesize that aberrant molecular alterations drive changes in the intensity and duration of SMAD and ERK signaling during cancer progression and ultimately lead to an imbalance between the SMAD and ERK pathways in favor of tumor promotion. Thus, to treat cancer patients with a genetic signature of oncogenic Ras effectively may require at least a combination therapy to restore both the expression of TGF-β receptors and the GTPase activity of Ras.

Natural gas at remote locations would greatly benefit from on-site processing using modular technologies such as dehydroaromatization (DHA). This work models an intensified DHA process to increase product yield and methane conversion by coupling the reactor with a chemical looping unit that effectively separates hydrogen through a redox cycle and a temperature swing adsorption process to remove the aromatics and water and recycle unconverted methane. We postulate dynamic models and steady-state surrogate models to analyze and optimize the production of the aromatic product. The optimum methane conversion of 48% and the aromatic yield of 42% occur at a recycle ratio of 0.47 and a reactor temperature of 725 degrees C.

The baroreflex is a multi-input, multi-output control physiological system that regulates blood pressure by modulating nerve activity between the brainstem and the heart. Existing computational models of the baroreflex do not explictly incorporate the intrinsic cardiac nervous system (ICN), which mediates central control of the heart function. We developed a computational model of closed-loop cardiovascular control by integrating a network representation of the ICN within central control reflex circuits. We examined central and local contributions to the control of heart rate, ventricular functions, and respiratory sinus arrhythmia (RSA). Our simulations match the experimentally observed relationship between RSA and lung tidal volume. Our simulations predicted the relative contributions of the sensory and the motor neuron pathways to the experimentally observed changes in the heart rate. Our closed-loop cardiovascular control model is primed for evaluating bioelectronic interventions to treat heart failure and renormalize cardiovascular physiology.

Recent experimental investigations of liver homeostatic renewal have identified high replication capacity hepatocyte populations as the primary maintainers of liver mass. However, the molecular and cellular processes controlling liver homeostatic renewal remain unknown. To address this problem, we developed and analyzed a mathematical model describing cellular network interactions underlying liver homeostatic renewal. Model simulation results demonstrate that without feedback control, basic homeostatic renewal is not robust to disruptions, leading to tissue loss under persistent/repetitive insults. Consequently, we extended our basic model to incorporate putative regulatory interactions and investigated how such interactions may confer robustness on the homeostatic renewal process. We utilized a Design of Experiments approach to identify the combination of feedback interactions that yields a cell network model of homeostatic renewal capable of maintaining liver mass robustly during persistent/repetitive injury. Simulations of this robust model indicate that repeated injury destabilizes liver homeostasis within several months, which differs from epidemiological observations of a much slower decay of liver function occurring over several years. To address this discrepancy, we extended the model to include feedback control by liver nonparenchymal cells. Simulations and analysis of the final multicellular feedback control network suggest that achieving robust liver homeostatic renewal requires intrinsic stability in a hepatocellular network combined with feedback control by nonparenchymal cells.

Therapeutic monoclonal antibodies (mAbs) are typically manufactured using mammalian cell cultures in fed-batch bioreactors, with increasing emphasis on meeting productivity and product quality attribute targets that depend strongly on such process variables as nutrient feed rates and bioreactor operating conditions. In this article, we identify, categorize, and address the challenges of achieving both productivity and product quality goals simultaneously, by developing a multivariable, model-based control system that can satisfy multiple production objectives in a fed-batch cell culture process. Here, we discuss model development and present theoretical concepts of observability and controllability that are essential to understanding and handling effectively these intrinsic challenges. Subsequently, we evaluate via simulation the performance of the outer-loop model predictive control and demonstrate the overall capability to satisfy complex production objectives in a laboratory scale bioreactor, as a first step toward the ultimate goal of creating an advanced control system for fed-batch mAb manufacturing processes.

COPD is an inflammatory lung disease affecting millions of people around the globe. The occasional worsening of the disease, termed exacerbation, reduces the quality of life and causes a substantial economic burden. For efficient management of exacerbations, it is desirable to be able to predict their onset before the condition worsens. Recently, Ghadipasha et al. (in prep.) developed a mathematical model of the cardio-respiratory system, which is expected to help identify trends in patient vitals that indicate the onset of exacerbations. In this paper, we modify the model to account for the changes due to metabolic rates based on physiological data. Simulation results indicate that the differences between healthy individuals and COPD patients may be more pronounced at higher activity levels compared with that at rest.

The baroreceptor reflex is a multi-input, multi-output physiological control system that regulates short-term blood pressure by modulating nerve activity between the brainstem and the heart. The computational model by Park et al. (2020) is the most recent iteration in our exploration of the system. However, the contributions of ”the little brain of the heart”, the intrinsic cardiac nervous system (ICN), to local control of the heart and to the integration of sensory information is unknown and has been overlooked in previous models. We have incorporated a high-fidelity representation of the ICN into a model of the baroreceptor reflex based on anatomical, molecular, and physiological evidence. The model consists of (1) differential equations to represent the cardiovascular system, and (2) transfer functions to represent neural control components, connected in a closed-loop control circuit. We use the model to evaluate the impact of alternative ICN network structures on overall cardiovascular control in response to mean arterial pressure and lung tidal volume perturbations. Our results show that the local circuit neurons that integrate sensory information into the ICN strengthen the response of ICN neuron activity, especially at low blood pressures, suggesting that the ICN amplifies the brainstem's response to perturbations.

The baroreceptor reflex is a multi‐input, multi‐output physiological control system that regulates short‐term blood pressure by modulating parasympathetic and sympathetic nerve activity between the brainstem and the heart. The opposing effects of parasympathetic and sympathetic nerve activity work in conjunction to maintain cardiovascular homeostasis, with imbalances in activity associated with cardiovascular disease. Recently, attention has focused on the role of the intrinsic cardiac nervous system (ICN) in local control of nervous regulation of the heart and its role in balancing parasympathetic and sympathetic nerve activity. However, it is unknown how the ICN network structure contributes to integrative control of the heart. We formulated multiple alternative network options based on the anatomical, molecular and physiological evidence. We extended a quantitative closed‐loop computational model of the baroreceptor reflex by incorporating a high‐fidelity representation of the ICN to evaluate the impact of altered ICN network structures on overall cardiovascular control. The present computational model consists of (1) a system of ordinary differential equations to represent blood flow in the cardiovascular system, and (2) transfer function representations of sensory neurons, central nervous system neuronal groups, and ICN neuronal groups, connected in a closed‐loop control circuit. We use this model to investigate, via simulation, the role of the intrinsic cardiac nervous system in integrating and modulating parasympathetic and sympathetic nerve activity in healthy and diseased states. Our results show that the local circuit neurons may modulate the ICN network response to distinct vagal inputs towards the integrative control of local cardiac function.

Engineered hydrogels are increasingly used as extracellular matrix (ECM) surrogates for probing cell function in response to ECM remodeling events related to injury or disease (e.g., degradation followed by deposition/crosslinking). Inspired by these events, this work establishes an approach for pseudo‐reversible mechanical property modulation in synthetic hydrogels by integrating orthogonal, enzymatically triggered crosslink degradation, and light‐triggered photopolymerization stiffening. Hydrogels are formed by a photo‐initiated thiol–ene reaction between multiarm polyethylene glycol and a dually enzymatically degradable peptide linker, which incorporates a thrombin‐degradable sequence for triggered softening and a matrix metalloproteinase (MMP)‐degradable sequence for cell‐driven remodeling. Hydrogels are stiffened by photopolymerization using a flexible, MMP‐degradable polymer‐peptide conjugate and multiarm macromers, increasing the synthetic matrix crosslink density while retaining degradability. Integration of these tools enables sequential softening and stiffening inspired by matrix remodeling events within loose connective tissues (Young's modulus ( E ) ≈5 to 1.5 to 6 kPa with >3x ΔE). The cytocompatibility and utility of this approach is examined with breast cancer cells, where cell proliferation shows a dependence on the timing of triggered softening. This work provides innovative tools for 3D dynamic property modulation that are synthetically accessible and cell compatible.

Four organic halide salts of interest to alloyed perovskite solar cell fabrication are characterized using attenuated total reflectance Fourier transform infrared spectroscopy (ATR‐FTIR), powder X‐ray diffraction (XRD), and thermogravimetric analysis. The chemical and crystal structures of methylammonium iodide (MAI), methylammonium bromide (MABr), and formamidinium iodide (FAI) are confirmed, and the experimental ATR‐FTIR spectrum and XRD pattern of formamidinium bromide (FABr) are presented. The enthalpy, Δ H vap , and entropy, Δ S vap , of vaporization are quantified for each salt and are used to estimate their vapor pressures in the temperature range of 150–300 °C. MAI, MABr, and FAI have similar vapor pressures in this temperature range, whereas FABr has a higher vapor pressure in the temperature range of 150–240 °C. These data provide a foundation for achieving effective control of vapor phase concentrations for vapor processing of alloyed perovskite solar cells.

EDITORIAL article Front. Bioeng. Biotechnol., 09 April 2021 | https://doi.org/10.3389/fbioe.2021.677976

The production of monoclonal antibody (mAb) therapeutics, a rapidly growing multi-billion-dollar enterprise in the biopharmaceutical industry, faces major challenges in achieving desired productivity and product quality consistently. These challenges, traditionally addressed by genetic engineering and media recipe development, are now being addressed with process systems engineering (PSE) techniques. In this perspective paper, we discuss how this alternative approach, comprising three components — process modeling, estimation, and control — is being used to address biomanufacturing challenges. We survey the state of current practice for each component, identify existing gaps, and highlight some advances needed to achieve routine implementation of fully automated systems for optimal bioprocess operations.

Rapid breakdown of hepatic glycogen stores into glucose plays an important role during intense physical exercise to maintain systemic euglycemia. Hepatic glycogenolysis is governed by several different liver-intrinsic and systemic factors such as hepatic zonation, circulating catecholamines, hepatocellular calcium signaling, hepatic neuroanatomy, and the central nervous system (CNS). Of the factors regulating hepatic glycogenolysis, the extent of lobular innervation varies significantly between humans and rodents. While rodents display very few autonomic nerve terminals in the liver, nearly every hepatic layer in the human liver receives neural input. In the present study, we developed a multi-scale, multi-organ model of hepatic metabolism incorporating liver zonation, lobular scale calcium signaling, hepatic innervation, and direct and peripheral organ-mediated communication between the liver and the CNS. We evaluated the effect of each of these governing factors on the total hepatic glucose output and zonal glycogenolytic patterns within liver lobules during simulated physical exercise. Our simulations revealed that direct neuronal stimulation of the liver and an increase in circulating catecholamines increases hepatic glucose output mediated by mobilization of intracellular calcium stores and lobular scale calcium waves. Comparing simulated glycogenolysis between human-like and rodent-like hepatic innervation patterns (extensive vs. minimal) suggested that propagation of calcium transients across liver lobules acts as a compensatory mechanism to improve hepatic glucose output in sparsely innervated livers. Interestingly, our simulations suggested that catecholamine-driven glycogenolysis is reduced under portal hypertension. However, increased innervation coupled with strong intercellular communication can improve the total hepatic glucose output under portal hypertension. In summary, our modeling and simulation study reveals a complex interplay of intercellular and multi-organ interactions that can lead to differing calcium dynamics and spatial distributions of glycogenolysis at the lobular scale in the liver.

Interactions between temperature, pressure, and deposition rate are explored for the deposition of PbI2 in a close space vapor transport (CSVT) geometry. The data presented here confirm that PbI2 deposition occurs through diffusive mass transport based on strong correlations between the deposition rate and PbI2 concentration gradient from the source and to the substrate. The calculated deposition rates from a one-dimensional diffusive mass transport model are found to be in good agreement with the experimentally-measured values. Additionally, the deposition temperature and pressure are found to strongly affect the morphology of equally-thick PbI2 films, where higher temperature produces a rougher morphology and higher pressure leads to a more open grain structure.

Monoclonal antibodies are critically important biologics as the largest class of molecules used to treat cancers, rheumatoid arthritis, and other chronic diseases. Antibody glycosylation is a critical quality attribute that has ramifications for patient safety and physiological efficacy-one that can be modified by such factors as media formulation and process conditions during production. Using a design-of-experiments approach, we examined the effect of 2-F-peracetyl fucose (2FP), uridine, and galactose on cell growth and metabolism, titer, and gene expression of key glycosylation-related proteins, and report how the glycoform distribution changed from Days 4 to 7 in a batch process used for IgG1 production from Chinese hamster ovary cells. We observed major glycosylation changes upon supplement addition, where the addition of 2FP decreased antibody fucosylation by up to 48%, galactose addition increased galactosylation by up to 21%, and uridine addition decreased fucosylation and increased galactosylation by 6% and 2%, respectively. Despite having major effects on glycosylation, neither galactose nor 2FP significantly affected cell culture growth, metabolism, or titer. Uridine improved peak cell densities by 23% but also reduced titer by ∼30%. The supplements caused significant changes in gene expression by Day 4 of the cultures where 2FP addition significantly reduced fucosyltransferase 8 and nucleotide sugar transporter gene expression (by ∼2-fold), and uridine addition significantly increased expression of UDP-GlcNAcT (SLC35A3) and B4GALT1-6 genes (by 1.5-3-fold). These gene expression data alongside glycosylation, metabolic, and growth data improve our understanding of the cellular mechanisms affected by media supplementation and suggest approaches for modifying antibody glycosylation in antibody production processes.

Macrocytic anemia is usually associated with vitamin B12 or folate deficiency. However, folate deficiency was rarely reported as a cause of hemolytic anemia. We present a case of a young man with a history of alcohol abuse who initially presented with an acute on chronic abdominal pain and was found to have jaundice and scleral icterus. His liver enzymes were unremarkable, and his abdominal imaging did not reveal any acute pathology. However, he was found to have a severe non-immune hemolytic anemia secondary to folate deficiency.

Genes that establish the circadian clock have differential expression with respect to solar time in central and peripheral tissues. Here, we find circadian-time-induced differential expression in a large number of genes not associated with circadian rhythms in two brain regions lacking overt circadian function: the dorsal vagal complex (DVC) and the central nucleus of the amygdala (CeA). These regions primarily engage in autonomic, homeostatic, and emotional regulation. However, we find striking diurnal shifts in gene expression in these regions of male Sprague Dawley rats with no obvious patterns that could be attributed to function or region. These findings have implications for the design of gene expression studies as well as for the potential effects of xenobiotics on these regions that regulate autonomic and emotional states.

In manufacturing monoclonal antibodies (mAbs), it is crucial to be able to predict how process conditions and supplements affect productivity and quality attributes, especially glycosylation. Supplemental inputs, such as amino acids and trace metals in the media, are reported to affect cell metabolism and glycosylation; quantifying their effects is essential for effective process development. We aim to present and validate, through a commercially relevant cell culture process, a technique for modeling such effects efficiently. While existing models can predict mAb production or glycosylation dynamics under specific process configurations, adapting them to new processes remains challenging, because it involves modifying the model structure and often requires some mechanistic understanding. Here, a modular modeling technique for adapting an existing model for a fed-batch Chinese hamster ovary (CHO) cell culture process without structural modifications or mechanistic insight is presented. Instead, data is used, obtained from designed experimental perturbations in media supplementation, to train and validate a supplemental input effect model, which is used to "patch" the existing model. The combined model can be used for model-based process development to improve productivity and to meet product quality targets more efficiently. The methodology and analysis are generally applicable to other CHO cell lines and cell types.

ADVERTISEMENT RETURN TO ISSUEEditorialNEXTSigning Off of I&ECR TogetherLorenz T. Biegler*Lorenz T. Biegler*E-mail: [email protected] More by Lorenz T. Bieglerhttp://orcid.org/0000-0003-3875-4441 and Babatunde A. OgunnaikeBabatunde A. OgunnaikeMore by Babatunde A. Ogunnaikehttp://orcid.org/0000-0002-8246-070XCite this: Ind. Eng. Chem. Res. 2020, 59, 52, 22311–22312Publication Date (Web):December 30, 2020Publication History Published online30 December 2020Published inissue 30 December 2020https://pubs.acs.org/doi/10.1021/acs.iecr.0c05896https://doi.org/10.1021/acs.iecr.0c05896editorialACS PublicationsCopyright © 2020 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views747Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (465 KB) Get e-AlertscloseSUBJECTS:Chemical engineering and industrial chemistry,Optimization,Physical and chemical processes,Process systems,Students Get e-Alerts

Central coordination of cardiovascular function is accomplished, in part, by the baroreceptor reflex, a multi-input multi-output physiological control system that regulates the activity of the parasympathetic and sympathetic nervous systems via interactions among multiple brainstem nuclei. Recent single-cell analyses within the brain revealed that individual neurons within and across brain nuclei exhibit distinct transcriptional states contributing to neuronal function. Such transcriptional heterogeneity complicates the task of understanding how neurons within and across brain nuclei organize and function to process multiple inputs and coordinate cardiovascular functions within the larger context of the baroreceptor reflex. However, prior analysis of brainstem neurons revealed that single-neuron transcriptional heterogeneity reflects an adaptive response to synaptic inputs and that neurons organize into distinct subtypes with respect to synaptic inputs received. Based on these results, we hypothesize that adaptation of neuronal subtypes support robust biological function through graded cellular responses. We test this hypothesis by examining the functional impact of neuronal adaptation on parasympathetic activity within the context of short-term baroreceptor reflex regulation. In this work, we extend existing quantitative closed-loop models of the baroreceptor reflex by incorporating into the model distinct input-driven neuronal subtypes and neuroanatomical groups that modulate parasympathetic activity. We then use this extended model to investigate, via simulation, the functional role of neuronal adaptation under conditions of health and systolic heart failure. Simulation results suggest that parasympathetic activity can be modulated appropriately by the coordination of distinct neuronal subtypes to maintain normal cardiovascular functions under systolic heart failure conditions. Moreover, differing degrees of adaptation of these neuronal subtypes contribute to cardiovascular behaviors corresponding to distinct clinical phenotypes of heart failure, such as exercise intolerance. Further, our results suggest that an imbalance between sympathetic and parasympathetic activity regulating ventricular contractility contributes to exercise intolerance in systolic heart failure patients, and restoring this balance can improve the short-term cardiovascular performance of these patients.