Mechanistic Causation Research Articles

The Epistemology of Bacterial Virulence Factor Characterization.

The field of microbial pathogenesis seeks to identify the agents and mechanisms responsible for disease causation. Since Robert Koch introduced postulates that were used to guide the characterization of microbial pathogens, technological advances have substantially increased the capacity to rapidly identify a causative infectious agent. Research efforts currently focus on causation at the molecular level with a search for virulence factors (VFs) that contribute to different stages of the infectious process. We note that the quest to identify and characterize VFs sometimes lacks scientific rigor, and this suggests a need to examine the epistemology of VF characterization. We took this premise as an opportunity to explore the epistemology of VF characterization. In this perspective, we discuss how the characterization of various gene products that evolved to facilitate bacterial survival in the broader environment have potentially been prematurely mischaracterized as VFs that contribute to pathogenesis in the context of human biology. Examples of the reasoning that can affect misinterpretation, or at least a premature assignment of mechanistic causation, are provided. Our aim is to refine the categorization of VFs by emphasizing a broader biological view of their origin.

Modular formation of in vitro tumor models for oncological research/therapeutic drug screening.

In recognition of the lethal nature of cancer, extensive efforts have been made to understand the mechanistic causation while identifying the effective therapy modality in hope to eradicate cancerous cells with minimal damage to healthy cells. In search of such effective therapeutics, establishing pathophysiologically relevant in vitro models would be of importance in empowering our capabilities of truly identifying those potent ones with significantly reduction of the preclinical periods for rapid translation. In this regard, wealthy progresses have been achieved over past decades in establishing various in vitro and in vivo tumor models. Ideally, the tumor models should maximally recapture the key pathophysiological attributes of their native counterparts. Many of the current models have demonstrated their utilities but also showed some noticeable limitations. This book chapter will briefly review some of the mainstream platforms for in vitro tumor models followed by detailed elaboration on the modular strategies to form in vitro tumor models with complex structures and spatial organization of cellular components. Clearly, with the ability to modulate the building modules it becomes a new trend to form in vitro tumor models following a bottom-up approach, which offers a high flexibility to satisfy the needs for pathophysiological study, anticancer drug screening or design of personalized treatment.

Deepening Undergraduate Students’ Thinking about Central Dogma through Problem-Based Learning

A common belief among pre-medical and medical students is that biochemistry is not relevant to practicing medicine. The problem-based approach of case studies has been used in medical education to scaffold the application of content to clinical cases, but few studies report on a similar use in undergraduate biochemistry. Case studies in biochemistry and related disciplines have been previously reported as increasing learning motivation and supporting depth of knowledge. Additionally, students engaging in case studies outperform students in traditional instruction. The objective of this qualitative case study was to find how the timing of a medical case study within the instructional sequence in an undergraduate biochemistry course supported students in applying the central dogma of molecular biology to explain the transfer of Huntington’s disease from parent to child. The CBL+ group reviewed the case study before class while the CBL− group was presented with the case study during class. Analysis of open response tasks added to the pre- and post-surveys suggested that the case study supported both groups in applying the central dogma to the case, but the earlier presentation of the case to the CBL+ group promoted deeper thinking about the mechanistic causation of the transfer of the disease.

Reconsidering Context in Psychedelic Research: Rituals as Ancient Libraries of Knowledge

The outcomes of recent psychedelic research have been attracting more public attention in the media along with more private funding. This research is primarily being conducted in a clinically administered setting while attention to context has largely been ignored. Entheogens have been used by indigenous peoples in ritual settings as far as recorded history can be found. Modern clinical use has only been occurring within the last century. This leaves much to explore in terms of the context in which such a potent treatment has effect. This manuscript conceptualizes entheogenic spiritual rituals as ancient libraries of healing knowledge. It examines the therapeutic use of psychedelics from both the biomedical perspective of the diagnosis and treatment model contrasted with the ritual context. It discusses a number of explicit and implicit ritual attributes that may play a role in the healing process. Additionally, the manuscript identifies cultural assumptions of healing embedded in psychedelic study in favor of mechanistic causation that could be affecting a dismissal of the value of the ritual context. The paper proposes considerations for alternative research design philosophy along with the notion that spiritual rituals viewed as ancient libraries of healing knowledge may introduce hypotheses that current scientific bias is preventing researchers from realizing.

A systematic, complexity-reduction approach to dissect the kombucha tea microbiome.

One defining goal of microbiome research is to uncover mechanistic causation that dictates the emergence of structural and functional traits of microbiomes. However, the extraordinary degree of ecosystem complexity has hampered the realization of the goal. Here, we developed a systematic, complexity-reducing strategy to mechanistically elucidate the compositional and metabolic characteristics of microbiome by using the kombucha tea microbiome as an example. The strategy centered around a two-species core that was abstracted from but recapitulated the native counterpart. The core was convergent in its composition, coordinated on temporal metabolic patterns, and capable for pellicle formation. Controlled fermentations uncovered the drivers of these characteristics, which were also demonstrated translatable to provide insights into the properties of communities with increased complexity and altered conditions. This work unravels the pattern and process underlying the kombucha tea microbiome, providing a potential conceptual framework for mechanistic investigation of microbiome behaviors.

Approaching biology through the retrocausal apex in physics

Quantum stochasticity carries two incompatible implications. One is for the statistical divergence upon the prior absence of complete controllability over boundary conditions applied to mechanistic causation. One more alternative is for the statistical convergence upon the posterior decidability of measurement despite the absence of the prior decidability. Decidable measurement lacking the prior decidability is retrocausal. The quantum physical likelihood for the life world may derive from the statistical convergence proceeding in a durable manner. This observation suggests that there must have been some type of observers even internal to the lifeless world, otherwise no likelihood of identifying the objects of interest could be available there. Measurement activity intrinsic to the internal observers is indexical, while the similar activity specific to the external observer like us can be symbolic. The difference is in the phenomenological qualification since both are the observers of different types. A most conspicuous case demonstrating the phenomenological difference is revealed in the different nature of time to be employed and experienced there. Time serves as a principal attribute qualifying the phenomenon to be experienced as such. Qualification of time is observer dependent.

The Active Mechanism of Nucleosome Depletion by Poly(dA:dT) Tracts In Vivo.

Poly(dA:dT) tracts cause nucleosome depletion in many species, e.g., at promoters and replication origins. Their intrinsic biophysical sequence properties make them stiff and unfavorable for nucleosome assembly, as probed by in vitro nucleosome reconstitution. The mere correlation between nucleosome depletion over poly(dA:dT) tracts in in vitro reconstituted and in in vivo chromatin inspired an intrinsic nucleosome exclusion mechanism in vivo that is based only on DNA and histone properties. However, we compile here published and new evidence that this correlation does not reflect mechanistic causation. (1) Nucleosome depletion over poly(dA:dT) in vivo is not universal, e.g., very weak in S. pombe. (2) The energy penalty for incorporating poly(dA:dT) tracts into nucleosomes is modest (<10%) relative to ATP hydrolysis energy abundantly invested by chromatin remodelers. (3) Nucleosome depletion over poly(dA:dT) is much stronger in vivo than in vitro if monitored without MNase and (4) actively maintained in vivo. (5) S. cerevisiae promoters evolved a strand-biased poly(dA) versus poly(dT) distribution. (6) Nucleosome depletion over poly(dA) is directional in vivo. (7) The ATP dependent chromatin remodeler RSC preferentially and directionally displaces nucleosomes towards 5′ of poly(dA). Especially distribution strand bias and displacement directionality would not be expected for an intrinsic mechanism. Together, this argues for an in vivo mechanism where active and species-specific read out of intrinsic sequence properties, e.g., by remodelers, shapes nucleosome organization.

Corrigendum to: Mechanistic Causation and Constraints: Perspectival Parts and Powers, Non-perspectival Modal Patterns

Corrigendum to: Mechanistic Causation and Constraints: Perspectival Parts and Powers, Non-perspectival Modal Patterns

Sugammadex and Hypersensitivity-Related Reactions: a Review

The purpose of this review is to identify and understand the incidence and implications of sugammadex-induced hypersensitivity and anaphylaxis. This review also focuses on the mechanistic causation of anaphylaxis with regard to sugammadex administration and the management of anaphylaxis. The overall incidence of sugammadex-induced anaphylaxis is low, approximately 1:3500, and is comparable with other medications commonly used during the intraoperative period. Several studies and case reports have demonstrated that the mechanism of anaphylaxis is likely IgE- or basophil-mediated and that a diagnosis of anaphylaxis to confirm the etiology of urticaria, hypotension, bronchospasm, and other symptoms is based on positive skin prick testing, elevated tryptase levels, and dose-dependent activation of basophils during in vitro analysis. Bradycardia is a poorly understood adverse effect of sugammadex; however, the risk of bradycardia does not appear to be increased when compared with neostigmine. Sugammadex-induced anaphylaxis is a relatively rare complication but carries a risk of morbidity and mortality if inadequately identified and treated. Existing severity scales allow anesthesiologists to stratify the severity of an anaphylactic response and provide appropriate intraoperative treatment.

Role of Diet in the Development and Management of Crohn's Disease.

This article provides an updated review on the role of diet in the risk of developing Crohn's disease (CD) and CD management, areas of ongoing study. Higher intake of dietary fiber (fruit fiber) has been associated with a reduced risk for CD. The exclusive enteral nutrition (EEN) diet remains the most validated nutritional recommendation for inducing remission in CD. The specific carbohydrate diet (SCD) has demonstrated reductions in CD severity scores in conjunction with medical therapies, and larger trials on its efficacy are ongoing. Several new exclusion diets modeled after EEN and SCD have shown potential efficacy in smaller studies that warrant replication. There is a paucity of clear dietary recommendations for the reduction in risk of CD clinical relapse. There are various components of diet that likely impact risk for CD development and contribute to its disease course; however, studies are often limited in their size or ability to demonstrate mechanistic causation. Further studies including diets that aim to expand on the restrictive nature of EEN may lead to stronger evidence for a diet-based approach to CD management.

The Internal Clock: A Manifestation of a Misguided Mechanistic View of Causation?

Across various subfields within psychology, mechanistic causation is invoked regularly. When the temporal contiguity of the typical cause-effect relation is violated, mechanistic causation often assigns causal roles to mediating hypothetical constructs to account for observed effects. Two primary consequences of mechanistic causation are that 1) the proposed hypothetical constructs add what many behavior analysts consider an unnecessary step in the causal chain, and 2) these constructs then become the focus of study thereafter diverting attention from more accessible "causes." Constructs do not contribute directly to determining the control of behavior; thus, their reification as "causes" often distracts from variables that do fulfill a causal role. In this review, these consequences are discussed in relation to theories of interval timing proposing an internal clock. Not only has this clock been said to be a cause of behavior in experiments on temporally regulated behavior, but also the clock itself has been a frequent subject of study within the timing literature. Despite descriptive accounts of this sort initially serving a heuristic function for model development, the promotion from descriptive aid to causal factor has the potential to limit much of the heuristic value that mechanistic models of causation can provide to the analysis of behavior. Problems related to construct reification are less likely to be at issue when functional relations and the processes of establishing such behavior are emphasized as alternatives to mechanistic causation alone.

Mechanistic Causation and Constraints: Perspectival Parts and Powers, Non-perspectival Modal Patterns

Abstract Any successful account of the metaphysics of mechanistic causation must satisfy at least five key desiderata. In this article, I lay out these five desiderata and explain why existing accounts of the metaphysics of mechanistic causation fail to satisfy them. I then present an alternative account that does satisfy the five desiderata. According to this alternative account, we must resort to a type of ontological entity that is new to metaphysics, but not to science: constraints. In this article, I explain how a constraints-based metaphysics fits best with the emerging consensus on the nature of mechanistic explanation. 1Introduction2Renormalizability2.1The first two desiderata: Intrinsicness and productivity2.2The third desideratum: Scientific validity or non-mysteriousness2.3The fourth desideratum: Directionality2.4The fifth desideratum: Perspectival nature of mechanisms3Constraints and Causation3.1Multi-perspectival realism and causal structure3.2Causal structure as laws3.3Causal structures in analytical mechanics: Constraints3.4A metaphysics inspired by analytical mechanics: Constraints as ontologically primitive modal structures4Constraints and Mechanistic Causal Powers 4.1Inter- versus intra-perspectival categories4.2Mechanistic causal powers are grounded by constraints4.3Intrinsicness and constraints4.4Constraints and productiveness4.5Constraints and directionality5Conclusion

Rethinking Causality in Biological and Neural Mechanisms: Constraints and Control

Existing accounts of mechanistic causation are not suited for understanding causation in biological and neural mechanisms because they do not have the resources to capture the unique causal structure of control heterarchies. In this paper, we provide a new account on which the causal powers of mechanisms are grounded by time-dependent, variable constraints. Constraints can also serve as a key bridge concept between the mechanistic approach to explanation and underappreciated work in theoretical biology that sheds light on how biological systems channel energy to actively respond to the environment in adaptive ways, perform work, and fulfill the requirements to maintain themselves far from equilibrium. We show how the framework applies to several concrete examples of control in simple organisms as well as the nervous system of complex organisms.

Genetic Variants of Microtubule Actin Cross-linking Factor 1 (MACF1) Confer Risk for Parkinson's Disease.

The cytoskeleton not only provides structure, it is an active component of cell function, and in several neurodegenerative disorders, there is evidence of cytoskeletal collapse. Cytoskeletal proteins have been specifically implicated in the pathogenesis of Parkinson's disease (PD), where degeneration of dopaminergic (DA) neurons is the hallmark, but in which many factors may determine the resilience of DA neurons during aging and stress. Here we report that the human Microtubule Actin Cross-linking Factor 1 gene (MACF1), a downstream target of PD biochemical pathways, was significantly associated with PD in 713 nuclear families. A significant allelic association between PD and rs12118033, with P = 0.0098, was observed, and a P < 0.03 was observed in the association analysis by both a trend test and an allelic test. We further observed that it is the MACF1b isoform, not the MACF1a isoform, which is expressed in DA neurons from six human postmortem brains. In a Caenorhabditis elegans system, used to explore the effect of altered MACF1b on neurons, knockdown or knockout of the MACF1b orthologue vab-10 resulted in the selective loss of DA neurons, which validated MACF1's risk candidacy in PD. These findings strongly suggest that MACF1b may contribute to the genetic etiology and mechanistic causation of PD.

Natural Variation of Plant Metabolism: Genetic Mechanisms, Interpretive Caveats, and Evolutionary and Mechanistic Insights.

Combining quantitative genetics studies with metabolomics/metabolic profiling platforms, genomics, and transcriptomics is creating significant progress in identifying the causal genes controlling natural variation in metabolite accumulations and profiles. In this review, we discuss key mechanistic and evolutionary insights that are arising from these studies. This includes the potential role of transport and other processes in leading to a separation of the site of mechanistic causation and metabolic consequence. A reilluminated observation is the potential for genomic variation in the organelle to alter phenotypic variation alone and in epistatic interaction with the nuclear genetic variation. These studies are also highlighting new aspects of metabolic pleiotropy both in terms of the breadth of loci altering metabolic variation as well as the potential for broader effects on plant defense regulation of the metabolic variation than has previously been predicted. We also illustrate caveats that can be overlooked when translating quantitative genetics descriptors such as heritability and per-locus r(2) to mechanistic or evolutionary interpretations.

Plato on Necessity and Disorder

In the Timaeus, Plato makes a distinction between reason and necessity. This distinction is often accounted for as a distinction between two types of causation: purpose oriented causation and mechanistic causation. While reason is associated with the soul and taken to bring about its effects with the good and the beautiful as the end, necessity is understood in terms of a set of natural laws pertaining to material things. In this paper I shall suggest that there are reasons to reconsider the latter part of this account and argue for a non-mechanistic understanding of necessity. I will first outline how the notion of necessity is introduced in the dialogue. Next I will show how a mechanistic account of necessity fails to capture Plato’s purpose of treating it as a causal factor; and, finally, I will argue that this purpose is better understood as an attempt, on Plato’s part, to account for the causal origin of disorder and irrationality, an origin articulated in terms of a pre-cosmic situation and the notoriously difficult notion of the third kind.

Understanding mechanisms in the health sciences.

This article focuses on the assessment of mechanistic relations with specific attention to medicine, where mechanistic models are widely employed. I first survey recent contributions in the philosophical literature on mechanistic causation, and then take issue with Federica Russo and Jon Williamson's thesis that two types of evidence, probabilistic and mechanistic, are at stake in the health sciences. I argue instead that a distinction should be drawn between previously acquired knowledge of mechanisms and yet-to-be-discovered knowledge of mechanisms and that both probabilistic evidence and manipulation are essential with respect to newly discovered mechanisms.

Death of the user: Reconceptualizing subjects, objects, and their relations

The article explains why the concept of the user in Library and Information Science (LIS) user studies and information seeking behavior is theoretically inadequate and it proposes a reconceptualization of subjects, objects, and their relations according to a model of ‘double mediation.’ Formal causation (affordances) is suggested as a substitute for mechanistic causation. The notion of ‘affective causation’ is introduced. The works of several psychoanalysts and continental and Anglo-American philosophers are used as tools to develop the model.

Spinoza's Essentialist Model of Causation

Spinoza is most often seen as a stern advocate of mechanistic efficient causation, but examining his philosophy in relation to the Aristotelian tradition reveals this view to be misleading: some key passages of the Ethics resemble so much what Suárez writes about emanation that it is most natural to situate Spinoza's theory of causation not in the context of the mechanical sciences but in that of a late scholastic doctrine of the emanative causality of the formal cause; as taking a look at the seventeenth‐century philosophy of mathematics reveals, this is in consonance also with Spinoza's geometrical cast of mind. Against this background, I examine Spinoza's essentialist model of causation according to which each thing has a formal character determined by the thing's essence and what follows from that essence. In the case of real things this essential causal architecture results in efficacy, i.e. in bringing about real effects, the key idea being that without the essential, formally structured causal thrust there would be no efficacy in the first place. I also explain how this model accounts for efficient causation taking place between finite things.

Heritable Susceptibility Factors for the Development of Cancer

High frequencies of inherited DNA sequence variations (polymorphisms) are found in the human population. The involvement of polymorphic genes (especially for chemical metabolism and DNA repair) in the development of cancer is under intensive investigation. In our studies, we have irradiated blood lymphocytes from normal non-smokers with gamma-rays or UV-light to investigate genotypes and DNA repair functions. We found that XRCC1 399Gln and XRCC3 241Met were deficient in the repair of gamma-ray-but not UV-light-induced DNA damage that led to the expression of chromosome aberrations; therefore the variant genotypes are defective in base excision repair. The reverse was found with XPD 312Asn and XPD 751Gln; therefore they are defective in nucleotide excision repair. XRCC1 194Trp, OGG1 326Cys and APE1 148Glu had no DNA repair deficiency based on our experimental conditions. In another study, we investigated the role of some of these genes on the development of lung cancer. We found a significant increase of chromosome aberrations in patients and controls that had the XPD 751Gln and GSTM1 null genotypes, indicating a mechanistic causation of the disease. Therefore, inheritance of susceptibility genes can have significant impact on disease burden in the population. On the other hand, there are many questions that need to be addressed in order to evaluate the impact of susceptibility on cancer. These questions include the understanding of combinations of different polymorphic genes for susceptibility and of specific disease susceptibility for different ethnic populations.