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Fast, simultaneous simulation of the integrated urban wastewater system using mechanistic surrogate models.

The urban wastewater system components (sewer, treatment plant, and river) are often modelled using complex mechanistic models. Mechanistic surrogate models are introduced here as simplified models that still contain some physical knowledge. Surrogate models are faster, but are less but still sufficiently accurate, and require more data to be calibrated. The possibilities of replacing actual field data by virtual data generated with a complex mechanistic model for calibration of the surrogate model are examined. As an example, a series of tanks with variable volume is shown to approximate sufficiently well the flow propagation in the river Zwalm (Belgium) as predicted by the "de Saint-Venant" equations. The three surrogate models can be implemented in the WEST simulator, which makes a simultaneous simulation of the system possible. In this work a connection is made between the ASM1 and the new IWA River Model No. 1 (RWOM1) by using a translator between the models in such a way that both mass and elemental balances remain closed for the overall system. This approach is illustrated with a case study on the river Lambro (Italy). The dispersion process in this river with steady flow could be modelled by using a tanks in series model, while the water quality in the river was predicted to improve substantially with an increase in hydraulic capacity of the treatment plant. The simulation results with the upgraded plant still need to be checked by field data.

Belgium↗

Mechanistic bases for modelling space radiation risk and planning radiation protection of astronauts.

The approaches generally adopted for planning radiation protection in ground-based facilities cannot be applied straightforward for astronaut protection in space. Indeed in such extreme conditions, modelling methods and shielding design must be based on a detailed mechanistic knowledge of the peculiar astronauts irradiation conditions. Great help can derive from mechanistic modelling, generally aimed to better understand the intermediate steps leading from the initial energy depositions to different biological endpoints, up to organ and organism level. In the present work, criteria will be illustrated for using mechanistic approaches in developing practical tools for astronauts radioprotection, once the external field and the interaction cross sections with the spacecraft walls are known; particular attention will be given to the treatment of mixed fields. Techniques for integrating into condensed-history codes stochastic information provided by event-by-event simulations will be presented.

Aerospace Medicine↗

Exercise physiology in the 1990's: mechanistically defining the exercise model.

Definition of the exercise model via a mechanistic approach is a goal which should be of high priority among sport researchers in the 1990's, in an attempt to further qualify previous phenomenological observations of exercising man. Prolonged argument on the "theory-versus-practice" issue is one which is counter-productive in the advancement of knowledge in our discipline, and must be addressed and resolved. With specific emphasis on the neuromuscular control of movement, current research literature suggests that the components limiting to human performance may reside in the muscle, motoneurone and in the supraspinal of movement. Mechanistically defining the limits in each component, related to patterns of movement during exercise, may soon herald a reclassification of exercise types and their limits, defined by the particular system involved. Similarly, new evidence on adaptations throughout the neuromuscular system calls for a systematic study of these adaptations, how they influence structure and function of cell and organ systems, and their effects on the performance of the voluntarily exercising human. A mechanistic approach to these problems, using "simple" experimental models to more precisely define cause-effect, are justifiable and necessary in our field on the basis of the potential applicability of such information in the fields of design of exercise programmes, and the evaluation of their effectiveness, for normal and special populations. The problems associated with increased academic specialization and the communication gap which might result, are not inevitable. An enhancement of the proliferation of this knowledge and its interpretation in practical terms will result through our own awareness of the necessity of doing this, and through sensitization of our students to this issue.

Humans↗

Mechanistic aspects of the metal catalyzed alternating copolymerization of epoxides and carbon monoxide.

The cobalt-catalyzed alternating copolymerization of epoxides and CO is a novel, direct approach to aliphatic polyesters, such as poly(hydroxybutyrate) (PHB). This reaction was found to be catalyzed by Ph3Si[Co(CO)4] (4) and pyridine affording in a first step the stable mono-insertion product Ph3Si-O-CH(CH3)-CH2-CO-Co(CO)4 (5). However, a profound mechanistic understanding, especially of the role of pyridine as the key component for the polymerization reaction was missing. ATR-IR online monitoring under catalytic conditions and DFT calculations were used to show that an acylpyridinium cation is formed by cleavage of the cobalt-acyl bond of 5 in the presence of pyridine. The Lewis acid thus generated activates the next incoming epoxide monomer for ring opening through [Co(CO)4]-. The catalytic cycle is completed by a subsequent CO insertion in the new cobalt-alkyl bond. The calculations are used to explore the energetic hypersurface of the polymerization reaction and are complemented by extended experimental investigations that also support the mechanistic hypotheses.

Journal Article↗

Mechanistic Insights Into the Association Between Gut Microbiota Diversity and Atherosclerosis, Acute Coronary Syndrome, and Peripheral Arterial Disease Progression.

BACKGROUND: The gut microbiome has emerged as a potential contributor to cardiovascular diseases (CVDs), including atherosclerosis, acute coronary syndrome (ACS), and peripheral arterial disease (PAD). While observational studies link dysbiosis to CVD, causal relationships remain uncertain. METHODS: This narrative review synthesizes evidence from human observational studies, clinical interventions, and experimental models to distinguish association from mechanistic plausibility and clinical causality. Literature was searched through July 2026 in PubMed/MEDLINE, Web of Science, and Scopus. RESULTS: Microbial metabolites-including trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), bile acids, and lipopolysaccharide (LPS)-modulate endothelial function, immune cell programming, platelet activity, and plaque stability through receptor-mediated signaling and epigenetic regulation. SCFAs demonstrate potentially protective effects via GPCR and HDAC pathways, while TMAO is associated with atherothrombotic risk. However, much mechanistic evidence derives from preclinical studies. Heterogeneity from diet, geography, host characteristics, renal function, and medications substantially influences microbiota-CVD associations. CONCLUSION: The gut-vascular connection is biologically plausible, but definitive clinical causality remains unproven. Microbiome-directed therapies (dietary modulation, pre/pro/synbiotics, targeted metabolite inhibition) are investigational. Prospective, standardized, adequately powered human studies with clinically meaningful outcomes are essential before routine cardiovascular application.

Gastrointestinal Microbiome↗

Mechanistics of amoeboid locomotion: signal to forces.

Dictyostelium serves as an ideal model system for studying the molecular and structural properties of the actomyosin and microtubule systems. This organism also has been the vehicle on which the gene-targeting technique was pioneered. Dictyostelium also represents a small number of organisms whose chemotactic ligand-receptor mechanism has been well characterized. This article reviews recent advances in studies of the actin-based cytoskeletal system in Dictyostelium, focusing on the mechanistic aspects of the amoeboid motion. Special emphasis is placed on the recently identified cell-substrate-anchoring structures 'eupodia', and the measurement of single-cell migration forces. The recent advances in signal transduction cascade is also discussed with relevance to the mechanistics in amoeboid locomotion.

Amoeba↗

Workshop overview. National Toxicology Program Studies: principles of dose selection and applications to mechanistic based risk assessment.

A workshop entitled "NTP Studies: Principles of Dose Selection and Applications to Mechanistic Based Risk Assessment" was held at the 34th Annual Meeting of the Society of Toxicology in Baltimore, Maryland. The purpose of the workshop was to provide an overview of factors currently considered important in the selection of doses for NTP studies, to describe some of the confounding factors that can result from the indiscriminate use of bioassay data in quantitative risk assessment, and to suggest ways in which information from mechanistic studies or studies of biomarkers of exposure or effect might be used to better advantage in risk assessment.

Biomarkers↗

Mechanistic modeling of prokaryotic mRNA decay.

A mechanistic model of gene expression was developed to test three prevailing and sliding prokaryotic mRNA decay theories: ribosome protection of mRNA from endonucleases, 5' binding and sliding of endonucleases on mRNA, and hybrid 5' binding/ribosome protection. The discrete event simulation incorporates the molecular events that determine both cellular mRNA and protein levels. A Monte Carlo technique was used to approximate the inherent randomness of the molecular processes involved in gene expression. Each of the decay theories was tested for the ability to predict the effects of ribosome loading and translation rate on mRNA stability as well as the observed 5' to 3' directionality of mRNA decay. The modeling results show that the hybrid decay mechanism best predicts the experimentally-observed mRNA decay behaviors. The 5' binding mechanism fails to adequately predict the sensitivity of mRNA stability to changes in translation rate and ribosome loading, while the ribosome protection mechanism does not correctly predict 5' to 3' decay directionality. In addition to discriminating between the three decay theories, the simulations provide insights into hybrid decay mechanism specific details such as RNase binding and cleavage characteristics. Finally, we discuss the application of the current mechanistic model for analysing and predicting expression from more complex genetic systems.

Computer Simulation↗

The use of mechanistic data and the handling of scientific uncertainty in carcinogen risk assessments. The trichloroethylene example.

The purpose of this paper is to explore how risk assessors actually use mechanistic data in carcinogen risk assessment and to discuss how the handling of scientific uncertainty may affect the outcome of the risk assessment. The analysis is performed by comparing 29 trichloroethylene risk assessment documents in general and 2 of these, namely the ECETOC (1994, Trichloroethylene: Assessment of Human Carcinogenic Hazard, Technical Report No. 60) and the OECD/EU (1996, Initial Assessment Report for the 4th SIAM (Screening Information Data Set Initial Assessment Meeting), May 1996: Trichloroethylene, sponsor country, United Kingdom [Draft]), in more detail. It is concluded that in this example the ECETOC required less evidence for considering a carcinogenic mechanism irrelevant to humans than did the OECD/EU risk assessors. There are examples of when two risk assessors have selected different primary data for their argumentation and also examples of how one and the same primary publication was interpreted differently. Biased data selection and evaluation of primary data that correlate to the risk assessor's overall conclusions have also been identified. The general comparison of all 29 TCE risk assessment documents indicates that the assessment of scientific uncertainty in the mechanistic data affects the overall conclusions.

Animals↗

Extent of initial corneal injury as the mechanistic basis for ocular irritation: key findings and recommendations for the development of alternative assays.

Currently, there are no recognized alternative tests to eliminate the use of animals in ocular irritation testing. A major reason no replacement alternatives have been developed is that the current in vivo data set provides no perspective regarding the critical cellular and molecular changes involved in initial ocular injury, subsequent responses, and repair processes in standard in vivo tests. Without this perspective, mechanistically based replacement tests cannot be developed and validated. We have proposed that the level of ocular irritation is related to the extent of initial injury, and that regardless of the processes leading to tissue damage, the extent of initial injury is the principal factor determining the outcome of ocular irritation. This article summarizes the results from our studies of various surfactants and nonsurfactants of differing irritancy that support our hypothesis. Our findings indicate that a mechanistically based alternative to in vivo ocular irritation tests would be the microscopic or biochemical measurement of initial injury using either ex vivo or in vitro corneal equivalent systems composed of corneal epithelial, stromal keratocyte, and corneal endothelial cell layers. This work also provides a well-characterized panel of materials of varying types and irritation for use in developing and validating alternative tests.

Animal Testing Alternatives↗

Towards a mechanistic understanding of tumor invasion--lessons from the alpha6beta 4 integrin.

This review explores the mechanistic basis of carcinoma migration and invasion by focusing on the contribution of integrins. Integrins are essential for invasion not only for their ability to mediate physical interactions with extracellular matrices, but also for their ability to regulate signaling pathways that control actin dynamics and cell movement, as well as for growth and survival. Our comments center on a unique member of the integrin family, the alpha 6 beta 4 integrin, which is a receptor for the laminin family of basement membrane components. Numerous studies have implicated this integrin in the invasion of solid tumors and have provided a rationale for studying the mechanistic basis of its contribution to the invasive process. Such studies have revealed novel insights into the mechanism of carcinoma invasion that involve both the dynamics of cell migration and signaling pathways that regulate this migration.

Antigens, Neoplasm↗

A mechanistic algorithm for predicting blood:air partition coefficients of organic chemicals with the consideration of reversible binding in hemoglobin.

The objectives of the present study were (i) to develop a mechanistic algorithm for predicting blood:air partition coefficients (PCs) of volatile organic chemicals (VOCs), and (ii) to apply this algorithm to predict the rat blood:air PCs of several VOCs. The approach consisted initially of developing an algorithm to predict the blood:air PCs of VOCs solely based on the solubility phenomenon and then of extending the algorithm to include protein binding. The algorithm based on solubility phenomenon predicted blood:air PCs by dividing the estimated solubility of chemicals in blood by their saturable vapor concentrations at 37 degrees C. The rat blood:air PCs predicted using this algorithm were in close agreement with the experimental values for relatively hydrophilic VOCs such as ketones, alcohols, acetate esters, and diethyl ether (with an average ratio of 0.80 between predicted and experimental values), whereas there was a marked discrepancy in the case of relatively lipophilic VOCs such as alkanes, haloalkanes, and aromatic hydrocarbons (with an average ratio of 0.21 between predicted and experimental values). This discrepancy was hypothesized to be due to the occurrence of reversible binding of these substances in rat hemoglobin based on literature evidence of the existence of hydrophobic holes (or "xenon-binding" pockets). The association constants (Ka) for the presumed reversible hemoglobin binding of several alkanes, haloalkanes, and aromatic hydrocarbons were estimated from the difference between chemical concentration in rat erythrocytes predicted by the solubility-based algorithm and that deduced from the previously published experimental blood:air PCs for these chemicals (which presumably included contribution of hemoglobin binding in addition to "true" solubility). The Ka values estimated in this manner ranged from 504 to 4725 M-1 for the chemicals investigated in the present study. The a priori predictions of the percentage of several VOCs (diethyl ether, methyl isobutyl ketone, n-hexane, toluene, and chloroform) in rat erythrocytes obtained with the algorithm using these Ka estimates corresponded well with previously published experimental data. The mechanistic algorithm developed in the present study should be useful for predicting the "apparent" blood:air PCs of VOCs regardless of exposure concentrations, by accounting for the relative contributions of both the true chemical solubility and reversible hemoglobin binding.

Alcohols↗

Validation of in vitro methods to single out photoirritants using mechanistically based tests.

In the recent OECD draft proposal for a new guideline on acute dermal photoirritation testing, in vitro screening tests have been included as part of the sequential test strategy. These screening tests were placed directly prior to animal tests proposed. In Europe some in vitro techniques - cell culture and mechanistic tests - are under validation in a joint project of the European Center for the Validation of Alternative Methods (ECVAM) and the European Cosmetic, Toiletry, and Perfumery Association (COLIPA). Two promising cellular in vitro tests are presented and discussed as tool for the screening of photoirritancy. The first one as a general core test performed in each participating laboratory is the 3T3 mouse fibroblast Neutral Red Uptake Phototoxicity test determining the cell viability by uptake of Neutral Red as end point, whereas the second performed only by three participating laboratories was the the Red Blood Cell phototoxicity test comprising a combination of two end points, the photohaemolysis and the oxyhaemoglobin oxidation. Besides this, other mechanistic tests can be used as additional support. Identification of photoirritation is generally considered to be one area for the successful research and validation of in vitro techniques.

3T3 Cells↗

Defining functional drug-interaction domains on topoisomerase II by exploiting mechanistic differences between drug classes.

Topoisomerase II is the primary cellular target for a variety of antineoplastic drugs that are active against human cancers. These drugs exert their cytotoxic effects by stabilizing covalent topoisomerase II-cleaved DNA complexes that are fleeting intermediates in the catalytic cycle of the enzyme. Despite this common feature of drug action, a number of mechanistic differences between drug classes have been described. These mechanistic differences (including effects on DNA cleavage/religation, DNA strand passage, and adenosine triphosphate hydrolysis) were used as the basis for a series of competition experiments to determine whether different compounds share a common site of action on topoisomerase II or interact at distinct sites. Results of the present study strongly suggest that at least four structurally disparate antineoplastic drugs, etoposide, amsacrine, genistein, and the quinolone CP-115,953, share an overlapping interaction domain on the enzyme.

Amsacrine↗

The mechanistic nature of the membrane potential dependence of sodium-sugar cotransport in small intestine.

Methods are described which demonstrate the use of unidirectional influx of 14C-tetraphenylphosphonium (14C-TPP+) into isolated intestinal epithelial cells as a quantitative sensor of the magnitude of membrane potentials created by experimentally imposed ion gradients. Using this technique the quantitative relationship between membrane potential (delta psi) and Na+-dependent sugar influx was determined for these cells at various Na+ and alpha-methylglucoside (alpha-MG) concentrations. The results show a high degree of delta psi dependence for the transport Michaelis constant but a maximum velocity for transport which is independent of delta psi. No transinhibition by intracellular sugar (40 mM) can be detected. Sugar influx in the absence of Na+ is insensitive to 1.3 mM phlorizin and independent of delta psi. The mechanistic implications of these results were evaluated using the quality of fit between calculated and experimentally observed kinetic constants for rate equations derived from several transport models. The analysis shows that for models in which translocation is the potential-dependent step the free carrier cannot be neutral. If it is anionic, the transporter must be functionally asymmetric. A model in which Na+ binding is the potential-dependent step (Na+ well concept) also provides an appropriate kinetic fit to the experimental data, and must be considered as a possible mechanistic basis for function of the system.

Animals↗

Mechanistic action of pediocin and nisin: recent progress and unresolved questions.

Nisin and pediocin PA-1 are examples of bacteriocins from lactic acid bacteria (LAB) that have found practical applications as food preservatives. Like other natural antimicrobial peptides, LAB bacteriocins act primarily at the cytoplasmic membranes of susceptible microorganisms. Studies with in vivo as well as in vitro membrane systems are directed toward understanding how bacteriocins interact with membranes so as to provide a mechanistic basis for their rational applications. The dissipation of proton motive force was identified early on as the common mechanism for the lethal activity of LAB bacteriocin. Models for nisin/membrane interactions propose that the peptide forms poration complexes in the membrane through a multistep process of binding, insertion, and pore formation. This review focuses on the current knowledge of: (1) the mechanistic action of nisin and pediocin-like bacteriocins, (2) the requirement for a cell factor such as a membrane protein, (3) the influence of membrane potential, pH, and lipid composition on the specificity and efficacy of bacteriocins, and (4) the roles of specific amino acids and structural domains of the bacteriocins in their action.

Amino Acid Sequence↗

Complement in transplant rejection: diagnostic and mechanistic considerations.

After decades of neglect, complement has been rediscovered as a potent mediator and diagnostic indicator of inflammation and rejection in organ transplants. In part, this reflects a better understanding of the biology of complement, but it also reflects changes in clinical practice. The relevance of complement to clinical transplantation has increased as access to transplantation continues to be extended. Extended criteria for organ donors include older donors and non-heart beating donors. Simultaneously, the criteria for recipients have been extended to include more presensitized and blood group incompatible recipients. All of these variables can increase complement activation. As a result, several components of complement have received attention as potential diagnostic tools, and, with more sophisticated reagents, evidence of complement activation has been found in larger numbers of biopsy samples. Understanding the biology of complement is important to appreciate fully the diagnostic and mechanistic implications of complement activation in organ transplants. Mechanistically, a series of effector molecules in the complement cascade mediate proinflammatory functions that can account for chemotaxis and activation of cells of the innate immune system, such as granulocytes and monocytes. Simultaneously, many of these same complement mediators activate and disrupt the endothelial cell interface between the recipient and the transplant. In addition, there is growing appreciation that complement can stimulate B and T lymphocytes of the adaptive immune system. More recent evidence indicates that complement participates in the non-inflammatory clearance of apoptotic cells. Therefore, the complement cascade can be activated by multiple mechanisms and various components of complement can modulate the response to transplants in different directions.

Animals↗

Extraocular muscle in merosin-deficient muscular dystrophy: cation homeostasis is maintained but is not mechanistic in muscle sparing.

Extraocular muscle is uniquely spared from damage in merosin-deficient congenital muscular dystrophy. Using a murine model, we have tested the hypothesis that the maintenance of calcium homeostasis is mechanistic in extraocular muscle protection. Atomic absorption spectroscopy has demonstrated a strong correlation between the perturbation of calcium homeostasis in hindlimb muscle that is severely damaged and the absence of changes in calcium in extraocular muscle. If, as in other skeletal muscles, extraocular muscle fibers are destabilized by merosin deficiency, we would expect an increase in total muscle calcium coupled with an adaptive response in the high capacity/speed of the sarcoplasmic reticulum of the eye muscle. However, we have not observed the expected increases in total muscle calcium content, Ca2+-ATPase activity, Na+/Ca2+ exchanger content, or smooth ER Ca2+-ATPase content that are predicted by this model. Instead, these results indicate that the increased membrane permeability that characterizes, and is potentially mechanistic in, myofiber degeneration in muscular dystrophy does not occur in merosin-deficient extraocular muscle. Thus, the high-capacity calcium-scavenging systems are not primarily responsible for extraocular muscle protection in muscular dystrophy.

Animals↗