Two scientific perspectives on nerve signal propagation: how incompatible approaches jointly promote progress in explanatory understanding.

We present a case study of two scientific perspectives on the phenomenon of nerve signal propagation, a bio-electric and a thermodynamic perspective, and compare this case with two accounts of scientific perspectivism: those of Michela Massimi and Juha Saatsi, respectively. We demonstrate that the interaction between the bio-electric perspective and the thermodynamic perspective can be captured in Saatsi's terms of progress in explanatory understanding. Using insights from our case study, we argue that both the epistemic and pragmatic dimensions of scientific understanding are important for increasing explanatory understanding of phenomena.

Thinking about the action potential: the nerve signal as a window to the physical principles guiding neuronal excitability.

Ever since the work of Edgar Adrian, the neuronal action potential has been considered as an electric signal, modeled and interpreted using concepts and theories lent from electronic engineering. Accordingly, the electric action potential, as the prime manifestation of neuronal excitability, serving processing and reliable "long distance" communication of the information contained in the signal, was defined as a non-linear, self-propagating, regenerative, wave of electrical activity that travels along the surface of nerve cells. Thus, in the ground-breaking theory and mathematical model of Hodgkin and Huxley (HH), linking Nernst's treatment of the electrochemistry of semi-permeable membranes to the physical laws of electricity and Kelvin's cable theory, the electrical characteristics of the action potential are presented as the result of the depolarization-induced, voltage- and time-dependent opening and closure of ion channels in the membrane allowing the passive flow of charge, particularly in the form of Na and K -ions, into and out of the neuronal cytoplasm along the respective electrochemical ion gradient.

Absence of tissue transglutaminase reduces amyloid-beta pathology in APP23 mice.

Aims: Alzheimer's disease (AD) is characterised by amyloid-beta (Aβ) aggregates in the brain. Targeting Aβ aggregates is a major approach for AD therapies, although attempts have had little to no success so far. A novel treatment option is to focus on blocking the actual formation of Aβ multimers.

The thermodynamic theory of action potential propagation: a sound basis for unification of the physics of nerve impulses.

The thermodynamic theory of action potential propagation challenges the conventional understanding of the nerve signal as an exclusively electrical phenomenon. Often misunderstood as to its basic tenets and predictions, the thermodynamic theory is virtually ignored in mainstream neuroscience. Addressing a broad audience of neuroscientists, we here attempt to stimulate interest in the theory.

Tissue Transglutaminase Expression Associates With Progression of Multiple Sclerosis.

Objective: The clinical course of multiple sclerosis (MS) is variable and largely unpredictable pointing to an urgent need for markers to monitor disease activity and progression. Recent evidence revealed that tissue transglutaminase (TG2) is altered in patient-derived monocytes. We hypothesize that blood cell-derived TG2 messenger RNA (mRNA) can potentially be used as biomarker in patients with MS.

Solving the crisis in psychopharmacological research: Cellular-membrane(s) pharmacology to the rescue?

There is an urgent need for the introduction of novel and better (i.e., improved risk-benefit profile) compounds for the treatment of major psychiatric disorders, in particular mood and psychotic disorders.

Increased transcription of transglutaminase 1 mediates neuronal death in in vitro models of neuronal stress and Aβ1-42-mediated toxicity.

Alzheimer's disease (AD) is the most common cause of dementia. At the pre-symptomatic phase of the disease, the processing of the amyloid precursor protein (APP) produces toxic peptides, called amyloid-β 1-42 (Aβ 1-42). The downstream effects of Aβ 1-42 production are not completely uncovered.

Lower scores in pharmacokinetics than in pharmacodynamics assessment among students in a health and life sciences curriculum.

In pharmacology teaching, pharmacokinetics (PK) and pharmacodynamics (PD) may be defined as part of the 'general pharmacology' domain, whereas effects of drugs on the autonomic nervous system and clinical trial design might be defined as part of the 'medical' and 'clinical' pharmacology domain, respectively. We recently designed a pharmacology course covering these domains for second year Health and Life Sciences students at the Vrije Universiteit Amsterdam (VU). We used a combination of lectures, problem-based learning and practicals to transfer knowledge to students in order for them to acquire sufficient knowledge and insight to solve real-world pharmacological problems.

Tissue Transglutaminase contributes to myelin phagocytosis in interleukin-4-treated human monocyte-derived macrophages.

Macrophages exert either a detrimental or beneficial role in Multiple Sclerosis (MS) pathology, depending on their inflammatory environment. Tissue Transglutaminase (TG2), a calcium-dependent cross-linking enzyme, has been described as a novel marker for anti-inflammatory, interleukin-4 (IL-4) polarized macrophages (M(IL-4)), which represent a subpopulation of macrophages with phagocytic abilities. Since TG2 is expressed in macrophages in active human MS lesions, we questioned whether TG2 drives the differentiation of M(IL-4) into an anti-inflammatory phenotype and whether it plays a role in the phagocytosis of myelin by these cells.

Interaction between tissue transglutaminase and amyloid-beta: Protein-protein binding versus enzymatic crosslinking.

Self-interaction, chaperone binding and posttranslational modification of amyloid-beta (Aβ) is essential in the initiation and propagation of Aβ aggregation. Aggregation results in insoluble Aβ deposits characteristic of Alzheimer's disease (AD) brain lesions, i.e.

A Qualitative Study on Experiences and Perspectives of Members of a Dutch Medical Research Ethics Committee.

The aim of this research was to gain insight into the experiences and perspectives of individual members of a Medical Research Ethics Committee (MREC) regarding their individual roles and possible tensions within and between these roles. We conducted a qualitative interview study among members of a large MREC, supplemented by a focus group meeting. Respondents distinguish five roles: protector, facilitator, educator, advisor and assessor.

Tissue Transglutaminase Promotes Early Differentiation of Oligodendrocyte Progenitor Cells.

Demyelinated lesions of the central nervous system are characteristic for multiple sclerosis (MS). Remyelination is not very effective, particular at later stages of the disease, which results in a chronic neurodegenerative character with worsening of symptoms. Previously, we have shown that the enzyme Tissue Transglutaminase (TG2) is downregulated upon differentiation of oligodendrocyte progenitor cells (OPCs) into myelin-forming oligodendrocytes and that TG2 knock-out mice lag behind in remyelination after cuprizone-induced demyelination.

Thinking About the Nerve Impulse: The Prospects for the Development of a Comprehensive Account of Nerve Impulse Propagation.

Currently, a scientific debate is ongoing about modeling nerve impulse propagation. One of the models discussed is the celebrated Hodgkin-Huxley model of the action potential, which is central to the electricity-centered conception of the nerve impulse that dominates contemporary neuroscience. However, this model cannot represent the nerve impulse completely, since it does not take into account non-electrical manifestations of the nerve impulse for which there is ample experimental evidence.

Tissue Transglutaminase Appears in Monocytes and Macrophages but Not in Lymphocytes in White Matter Multiple Sclerosis Lesions.

Leukocyte infiltration is an important pathological hallmark of multiple sclerosis (MS) and is therefore targeted by current MS therapies. The enzyme tissue transglutaminase (TG2) contributes to monocyte/macrophage migration and is present in MS lesions and could be a potential therapeutic target. We examined the cellular identity of TG2-expressing cells by immunohistochemistry in white matter lesions of 13 MS patients; 9 active and chronic active lesions from 4 patients were analyzed in detail.

Correction: Characterization of Transglutaminase 2 activity inhibitors in monocytes in vitro and their effect in a mouse model for multiple sclerosis.

[This corrects the article DOI: 10.1371/journal.pone.

Differential Expression of Tissue Transglutaminase Splice Variants in Peripheral Blood Mononuclear Cells of Primary Progressive Multiple Sclerosis Patients.

Multiple Sclerosis (MS) is an inflammatory and neurodegenerative disorder of the central nervous system (CNS) characterized by inflammation and immune cell infiltration in the brain parenchyma. Tissue transglutaminase (TG2), a calcium-dependent cross-linking enzyme, has been shown to be present in infiltrating MHC-II positive cells in lesions of patients suffering from MS. Moreover, TG2 mRNA levels in peripheral blood mononuclear cells (PBMC)-derived from primary progressive (PP)-MS patients correlated with clinical parameters, thus highlighting the importance of TG2 in MS pathology.

Thinking about the nerve impulse: A critical analysis of the electricity-centered conception of nerve excitability.

Nerve impulse generation and propagation are often thought of as solely electrical events. The prevalence of this view is the result of long and intense study of nerve impulses in electrophysiology culminating in the introduction of the Hodgkin-Huxley model of the action potential in the 1950s. To this day, this model forms the physiological foundation for a broad area of neuroscientific research.

In vivo evaluation of two tissue transglutaminase PET tracers in an orthotopic tumour xenograft model.

Background: The protein cross-linking enzyme tissue transglutaminase (TG2; EC 2.3.2.

Tissue transglutaminase in astrocytes is enhanced by inflammatory mediators and is involved in the formation of fibronectin fibril-like structures.

Background: During multiple sclerosis (MS) lesion formation, inflammatory mediators are produced by microglial cells and invading leukocytes. Subsequently, hypertrophic astrocytes fill the lesion and produce extracellular matrix (ECM) proteins that together form the astroglial scar. This is beneficial because it seals off the site of central nervous system (CNS) damage.

Monocyte-derived tissue transglutaminase in multiple sclerosis patients: reflecting an anti-inflammatory status and function of the cells?

Background: Leukocyte infiltration into the central nervous system is an important feature of multiple sclerosis (MS) pathology. Among the infiltrating cells, monocytes comprise the largest population and are considered to play a dual role in the course of the disease. The enzyme tissue transglutaminase (TG2), produced by monocytes, plays a central role in monocyte adhesion/migration in animal models of MS.

Astrocyte-derived tissue Transglutaminase affects fibronectin deposition, but not aggregation, during cuprizone-induced demyelination.

Astrogliosis as seen in Multiple Sclerosis (MS) develops into astroglial scarring, which is beneficial because it seals off the site of central nervous system (CNS) damage. However, astroglial scarring also forms an obstacle that inhibits axon outgrowth and (re)myelination in brain lesions. This is possibly an important cause for incomplete remyelination in the CNS of early stage MS patients and for failure in remyelination when the disease progresses.

Development of fluorine-18 labeled peptidic PET tracers for imaging active tissue transglutaminase.

Introduction: The protein-protein crosslinking activity of the enzyme tissue transglutaminase (TG2; EC 2.3.2.

Monocyte behaviour and tissue transglutaminase expression during experimental autoimmune encephalomyelitis in transgenic CX3CR1 mice.

Leukocyte infiltration into the central nervous system (CNS) is a key pathological feature in multiple sclerosis (MS) and the MS animal model experimental autoimmune encephalomyelitis (EAE). Recently, preventing leukocyte influx into the CNS of MS patients is the main target of MS therapies and insight into cell behaviour in the circulation is needed for further elucidation of such therapies. In this study, we aimed at in vivo visualization of monocytes in a time-dependent manner during EAE.