Native aggregation as a cause of origin of temporary cellular structures needed for all forms of cellular activity, signaling and transformations

According to the hypothesis explored in this paper, native aggregation is genetically controlled (programmed) reversible aggregation that occurs when interacting proteins form new temporary structures through highly specific interactions. It is assumed that Anfinsen's dogma may be extended to protein aggregation: composition and amino acid sequence determine not only the secondary and tertiary structure of single protein, but also the structure of protein aggregates (associates). Cell function is considered as a transition between two states (two states model), the resting state and state of activity (this applies to the cell as a whole and to its individual structures). In the resting state, the key proteins are found in the following inactive forms: natively unfolded and globular. When the cell is activated, secondary structures appear in natively unfolded proteins (including unfolded regions in other proteins), and globular proteins begin to melt and their secondary structures become available for interaction with the secondary structures of other proteins. These temporary secondary structures provide a means for highly specific interactions between proteins. As a result, native aggregation creates temporary structures necessary for cell activity

Mathematical modelling of clostridial acetone-butanol-ethanol fermentation

Clostridial acetone-butanol-ethanol (ABE) fermentation features a remarkable shift in the cellular metabolic activity from acid formation, acidogenesis, to the production of industrial-relevant solvents, solventogensis. In recent decades, mathematical models have been employed to elucidate the complex interlinked regulation and conditions that determine these two distinct metabolic states and govern the transition between them. In this review, we discuss these models with a focus on the mechanisms controlling intra- and extracellular changes between acidogenesis and solventogenesis. In particular, we critically evaluate underlying model assumptions and predictions in the light of current experimental knowledge. Towards this end, we briefly introduce key ideas and assumptions applied in the discussed modelling approaches, but waive a comprehensive mathematical presentation. We distinguish between structural and dynamical models, which will be discussed in their chronological order to illustrate how new biological information facilitates the ‘evolution’ of mathematical models. Mathematical models and their analysis have significantly contributed to our knowledge of ABE fermentation and the underlying regulatory network which spans all levels of biological organization. However, the ties between the different levels of cellular regulation are not well understood. Furthermore, contradictory experimental and theoretical results challenge our current notion of ABE metabolic network structure. Thus, clostridial ABE fermentation still poses theoretical as well as experimental challenges which are best approached in close collaboration between modellers and experimentalists

A multiscale systems perspective on cancer, immunotherapy, and Interleukin-12

Monoclonal antibodies represent some of the most promising molecular targeted immunotherapies. However, understanding mechanisms by which tumors evade elimination by the immune system of the host presents a significant challenge for developing effective cancer immunotherapies. The interaction of cancer cells with the host is a complex process that is distributed across a variety of time and length scales. The time scales range from the dynamics of protein refolding (i.e., microseconds) to the dynamics of disease progression (i.e., years). The length scales span the farthest reaches of the human body (i.e., meters) down to the range of molecular interactions (i.e., nanometers). Limited ranges of time and length scales are used experimentally to observe and quantify changes in physiology due to cancer. Translating knowledge obtained from the limited scales observed experimentally to predict patient response is an essential prerequisite for the rational design of cancer immunotherapies that improve clinical outcomes. In studying multiscale systems, engineers use systems analysis and design to identify important components in a complex system and to test conceptual understanding of the integrated system behavior using simulation. The objective of this review is to summarize interactions between the tumor and cell-mediated immunity from a multiscale perspective. Interleukin-12 and its role in coordinating antibody-dependent cell-mediated cytotoxicity is used illustrate the different time and length scale that underpin cancer immunoediting. An underlying theme in this review is the potential role that simulation can play in translating knowledge across scales

Quality and safety models and optimization as part of computer-integrated manufacturing

7 páginas, 3 figurasMathematical models are the basis of modern process engineering methods. Mathematical optimization is at the kernel of systematic and efficient tools for (1) experimental design, model development, and identification, (2) development of optimal operating procedures, and (3) implementation of those procedures by means of model-predictive controllers. Here, we review and discuss how these model-based optimization techniques can be used at the core of computer-integrated manufacturing systems for the food industry. These systems will be able to bring the operation of food processing plants closer to the best possible product quality and safety, at a reduced cost and with minimal environmental impactPeer reviewe

Characterization of Microchannels Created by Metal Microneedles: Formation and Closure

Transdermal delivery of therapeutic agents for cosmetic therapy is limited to small and lipophilic molecules by the stratum corneum barrier. Microneedle technology overcomes this barrier and offers a minimally invasive and painless route of administration. DermaRoller®, a commercially available handheld device, has metal microneedles embedded on its surface which offers a means of microporation. We have characterized the microneedles and the microchannels created by these microneedles in a hairless rat model, using models with 370 and 770 μm long microneedles. Scanning electron microscopy was employed to study the geometry and dimensions of the metal microneedles. Dye binding studies, histological sectioning, and confocal microscopy were performed to characterize the created microchannels. Recovery of skin barrier function after poration was studied via transepidermal water loss (TEWL) measurements, and direct observation of the pore closure process was investigated via calcein imaging. Characterization studies indicate that 770 μm long metal microneedles with an average base width of 140 μm and a sharp tip with a radius of 4 μm effectively created microchannels in the skin with an average depth of 152.5 ± 9.6 μm and a surface diameter of 70.7 ± 9.9 μm. TEWL measurements indicated that skin regains it barrier function around 4 to 5 h after poration, for both 370 and 770 μm microneedles. However, direct observation of pore closure, by calcein imaging, indicated that pores closed by 12 h for 370 μm microneedles and by 18 h for 770 μm microneedles. Pore closure can be further delayed significantly under occluded conditions