Experimental Model System Research Articles

Platelet Function Assay Using Dielectric Blood Coagulometry.

The hemostatic function of platelets is complementary to blood coagulation. However, traditional platelet function tests have primarily focused on measuring platelet aggregation, reducing their clinical effectiveness for antiplatelet drug monitoring. To address this limitation, we propose a new test principle that evaluates platelet function and the effects of antiplatelet drugs through blood coagulation reactions. This principle was validated in model experimental systems using blood samples from healthy volunteers (n = 11), where antiplatelet drugs such as aspirin, prostaglandin E1, or ticagrelor were added to the blood samples. Ticagrelor was tested at four concentration levels, covering the expected therapeutic range. We found that the complementary function of platelets can be assessed by monitoring the 1 MHz dielectric permittivity during the blood coagulation process, particularly the peak value. When reagents such as agonists (arachidonic acid, collagen, or adenosine diphosphate ADP) and calcium were mixed into the citrated blood with turbulence by pipetting, platelets became activated and aggregated before thrombin generation, resulting in a "consumed" state of platelets. Consequently, the contribution to the permittivity peak was minimal. By contrast, when blood spiked with antiplatelet drugs was tested, agonist-induced platelet aggregation was inhibited during the initial stage of the measurement. However, after thrombin generation, platelets were activated through the thrombin receptor. These activated platelets interacted with fibrin, thereby affecting the permittivity peak. The results of this validation process with Student's t-tests confirm the fundamental operating principle of the proposed platelet function assay, thereby contributing to antiplatelet therapy monitoring.

Impact of the crosstalk between the PTEN and PAFR as well as PAFR and EGFR pathways in cancer

The integration between the tumor-suppressive and oncogenic signaling pathways controls various cellular activities of cancer cells, including cell growth and apoptosis. While the activation of oncogenes fuels cancer progression and escape mechanisms, tumor suppressors regulate and counterbalance the negative effects of oncogenic signaling. Notably, phosphatase and tensin homolog (PTEN) constitute one of the important family members of tumor suppressor genes, which play critical roles in regulating the activities of tumor cells. Thus, an impaired, mutated, or loss of PTEN is associated with low survival or high tumor recurrence rates in cancer patients. Importantly, high tumor expression of a G-protein coupled platelet-activating factor-receptor (PAFR) is associated with increased tumor progression as well as decreased overall survival and poor prognosis in malignancies such as non-small cell lung cancer (NSCLC). Along similar lines, overactivation or mutations in epidermal growth factor receptor (EGFR) signaling are detected in various human malignancies and associated with poor prognosis. The goal of the current minireview was to highlight the significance of the mechanistic insights between the PTEN and PAFR as well as the PAFR and EGFR pathways in impacting cancer growth and/or efficacy of therapeutic agents in experimental model systems.

Intrathecal Immunoglobulin A Synthesis in Multiple Sclerosis: From Biological Aspects to Clinical Relevance.

Intrathecal immunoglobulin A (IgA) synthesis in multiple sclerosis (MS) has long earned little attention, despite a potential significance in disease pathogenesis and prognosis. The presence of IgA-positive plasma cells in MS lesions and along damaged axons suggests a role in disease pathogenesis. Available clinical evidence about a potential positive or negative prognostic role is scarce and inconclusive. Recent observations, however, highlight the migration of immune regulatory IgA-producing plasma cells from the gut to the central nervous system (CNS) in experimental autoimmune encephalitis models. A connection between intrathecal IgA synthesis and the gut-brain axis in MS was further corroborated by the discovery of gut microbiota-specific IgA+ B cells in human CNS during relapse. In this review, we summarize current evidence on the occurrence and immunopathology of intrathecal IgA synthesis in MS, explore its biological implications, and address methodological challenges regarding the detection of IgA as a major limitation and possible source of inconsistencies in clinical studies. By synthesizing these diverse lines of evidence, we highlight the importance of further research and the need for standardized detection methods to clarify the role of IgA in MS pathogenesis, disease progression, and as potential biomarker.

Emerging models to study competitive interactions within bacterial communities.

Within both abiotic and host environments, bacteria typically exist as diverse, multispecies communities and have crucial roles in human health, agriculture, and industry. In these communities, bacteria compete for resources, and these competitive interactions can shape the overall population structure and community function. Studying bacterial community dynamics requires experimental model systems that capture the different interaction networks between bacteria and their surroundings. We examine the recent literature advancing such systems, including (i) in silico models establishing the theoretical basis for how cell-to-cell interactions can influence population level dynamics, (ii) in vitro models characterizing specific interbacterial interactions, (iii) organ-on-a-chip models revealing the physiologically relevant parameters, such as spatial structure and mechanical forces, that bacteria encounter within a host, and (iv) in vivo plant and animal models connecting the host responses to interbacterial interactions. Each of these systems has greatly contributed to our understanding of bacterial community dynamics and can be used synergistically to understand how bacterial competition influences population architecture.

Aged Garlic Extract (AGE) and Its Constituent S-Allyl-Cysteine (SAC) Inhibit the Expression of Pro-Inflammatory Genes Induced in Bronchial Epithelial IB3-1 Cells by Exposure to the SARS-CoV-2 Spike Protein and the BNT162b2 Vaccine.

Garlic (Allium sativum L.) is a species of the onion family (Alliaceae) widely used as a food and a folk medicine. The objective of this study was to determine the effects of AGE (aged garlic extract) on pro-inflammatory genes relevant to COVID-19. To this aim, we treated bronchial epithelial IB3-1 cells with SARS-CoV-2 spike protein (S-protein) or with the COVID-19 BNT162b2 vaccine in the absence or in the presence of AGE. The results obtained demonstrated that AGE is a potent inhibitor of the S-protein-induced expression of the IL-1β, IL-6 and IL-8 genes. Bio-Plex analysis demonstrated that AGE reduced release of IL-6 and IL-8, which were highly induced by S-protein. No inhibition of cells' growth, toxicity and pro-apoptotic effects were found in AGE-treated cells. The effects of one of the major AGE constituents (S-allyl cysteine, SAC) were studied on the same experimental model systems. SAC was able to inhibit the S-protein-induced expression of IL-1β, IL-6 and IL-8 genes and extracellular release of IL-6 and IL-8, confirming that S-allyl-cysteine is one of the constituents of AGE that is responsible for inhibiting S-protein-induced pro-inflammatory genes. Docking experiments suggest that a possible mechanism of action of SAC is an interference with the activity of Toll-like receptors (TLRs), particularly TLR4, thereby inhibiting NF-κB- and NF-κB-regulated genes, such as IL-1β, IL-6 and IL-8 genes. These results suggest that both AGE and SAC deserve further experimental efforts to verify their effects on pro-inflammatory genes in SARS-CoV-2-infected cells.

Optimizing Numerical Weather Prediction Utility of the Maryland Mesonet with Observing System Simulation Experiments

Abstract The Maryland Mesonet project will construct a network of 75 surface observing stations with aims that include mitigating the statewide impact of severe convective storms and improving analyses of records. The spatial configuration of mesonet stations is expected to affect the utility newly provided observations will have via data assimilation, making it desirable to study the effects of mesonet configuration. Furthermore, the impact associated with any observing system configuration is constrained by errors inherent to the prediction systems used to generate forecasts, which may change with future advances in data assimilation methodology, physical parameterization schemes, and resource availability. To address such possibilities, we perform sets of observing system simulation experiments using a high-resolution regional modeling system to assess the expected impact of four candidate mesonet configurations. Experiments cover seven 18-h case study events featuring moist convective regimes associated with severe weather over the state of Maryland and are performed using two versions of our experimental modeling system: a “standard-uncertainty” configuration tuned to be representative of existing convective-allowing prediction systems and a “constrained-uncertainty” configuration with reduced boundary condition and model error that reflects a possible trajectory for future prediction systems. We find that the assimilation of mesonet data produces definitive improvements to analysis fields below 1000 m that are mediated by modeling system uncertainty. Conversely, mesonet impact on forecast verification is inconclusive and strongly variable across verification metrics. The impact of mesonet configuration appears limited by a saturation effect that caps local analysis improvements past a minimal density of observing stations. Significance Statement The Maryland Mesonet project will construct 75 surface observing stations to improve the analysis of records for Maryland’s surface weather conditions as well as predictions for severe weather events. The spatial placement of sensors is expected to influence the utility of a mesonet, making it desirable to optimize mesonet layouts. The utility provided by a mesonet may also be impacted by errors in prediction systems used to generate analyses and forecasts, which are themselves subject to change given future advances in prediction methods and resources. This study uses observing system simulation experiments (OSSEs)—which comprehensively simulate numerical weather prediction for a known “truth state” —to characterize improvement we may expect from mesonet observations and evaluate four potential mesonet configurations.

(Invited) Faradaic Electron Transfer in Inner Helmholtz Plane

Since the electrical double layer (EDL) is where heterogeneous electron transfer occurs, understanding the effects of the electrode-electrolyte interface structure on electrocatalysis is important. The strong electric field in the EDL offers unique environment for electrochemical reactions by altering the solvation structure and mass transport of redox species. Yet, it is challenging to evaluate the physicochemical properties of the matter within EDL, especially for the inner Helmholtz plane (IHP), where most electrochemical reactions occur. This is largely because of the lack of an appropriate model system for experiments. In this talk, the microscopic environment in the IHP of ionic liquids (ILs) is investigated through the reorganization energy reflecting the solvation structure. Exceptionally fast mass transport of Br2 in N-methyl-N-ethyl-pyrrolidinium polybromide allows to obtain bromine reduction voltammograms in which the current plateau is governed by electron-transfer kinetic and to evaluate the reorganization energy based on the Marcus-Hush-Chidsey model. This enables investigation of the microscopic environment in the IHP of the IL affecting electrocatalytic reactions through reorganization energy. As a demonstration, titanium oxide-modified Pt was employed to show pH-dependent reorganization energy, which suggests the switch of major ions at the IHP as a function of surface charges of electrodes. On the other hand, regulating the potential of zero charge (PZC) of electrodes by surface modification and preparation of alloys with various elemental compositions, the surface charge sensitive-ionic structure in ILs is introduced. References Kim, M.; Park, S.; Chung, T. D., Heterogeneous electron transfer reorganization energy at the inner Helmholtz plane in a polybromide redox-active ionic liquid. Chem. Sci. 2022, 13(30), 8821-8828. Kim, M.; Tetteh, E. B.; Savan, A.; Xiao, B.; Ludwig, A.; Schuhmann, W.; Chung, T. D., Reorganization energy in a polybromide ionic liquid measured by scanning electrochemical cell microscopy. J. Chem. Phys. 2023, 158(13), 134707. Kim, M.; Tetteh, E. B.; Krysiak, O. A.; Savan, A.; Xiao, B.; Piotrowiak, T. H.; Andronescu, C.; Ludwig, A.; Chung, T. D.; Schuhmann, W., Acidic Hydrogen Evolution Electrocatalysis at High-Entropy Alloys Correlates with its Composition-Dependent Potential of Zero Charge. Angew. Chem. Int. Ed. 2023, 62(39), e2023100.

Experimental models of antibiotic exposure and atopic disease.

In addition to numerous clinical studies, research using experimental models have contributed extensive evidence to the link between antibiotic exposure and atopic disease. A number of mouse models of allergy have been developed and used to uncover the specific effects of various microbiota members and perturbations on allergy development. Studies in mice that lack microbes entirely have also demonstrated the various components of the immune system that require microbial exposure. The importance of the early-life period and the mechanisms by which atopy "protective" species identified in human cohorts promote immune development have been elucidated in mice. Finally, non-animal models involving human-derived cells shed light on specific effects of bacteria on human epithelial and immune responses. When considered alongside clinical cohort studies, experimental model systems have provided crucial evidence for the link between the neonatal gut microbiota and allergic disease, immensely supporting the stewardship of antibiotic administration in infants. The following review aims to describe the range of experimental models used for studying factors that affect the relationship between the gut microbiota and allergic disease and summarize key findings that have come from research in animal and in vitro models.

TRESK channel activation ameliorates migraine-like pain via modulation of CGRP release from the trigeminovascular system and meningeal mast cells in experimental migraine models

AimsAccumulating evidence indicates the involvement of TRESK potassium channels in migraine, however, effects of TRESK activation on migraine-related mechanisms remain unclear. We explored effects of TRESK channel modulation on migraine-related behavioral and molecular markers in in-vivo and ex-vivo rat models of migraine. Main methodsThe selective TRESK activator cloxyquin at different doses, the TRESK inhibitor A2764, and the migraine drug sumatriptan were tested alone or in different combinations in nitroglycerin (NTG)-induced in-vivo model, and in ex-vivo meningeal, trigeminal ganglion and brainstem preparations in which CGRP release was induced by capsaicin. Mechanical allodynia, CGRP and c-fos levels in trigeminovascular structures and meningeal mast cells were evaluated. Key findingsCloxyquin attenuated NTG-induced mechanical allodynia, brainstem c-fos and CGRP levels, trigeminal ganglion CGRP levels and meningeal mast cell degranulation and number, in-vivo. It also diminished capsaicin-induced CGRP release from ex-vivo meningeal, trigeminal ganglion and brainstem preparations. Specific TRESK inhibitor A2764 abolished all effects of cloxyquin in in-vivo and ex-vivo. Combining cloxyquin and sumatriptan exerted a synergistic effect ex-vivo, but not in-vivo. SignificanceOur findings provide the experimental evidence for the anti-migraine effect of TRESK activation in migraine-like conditions. The modulation of TRESK channels may therefore be an attractive alternative strategy to relieve migraine pain.

Decorin, an exercise-induced secretory protein, is associated with improved prognosis in breast cancer patients but does not mediate anti-tumorigenic tissue crosstalk in mice

BackgroundRegular exercise can reduce incidence and progression of breast cancer, but the mechanisms for such effects are not fully understood. MethodsWe used a variety of rodent and human experimental model systems to determine whether exercise training can reduce tumor burden in breast cancer and to identify mechanism associated with any exercise training effects on tumor burden. ResultsWe show that voluntary wheel running slows tumor development in the mammary specific polyomavirus middle T antigen overexpression (MMTV-PyMT) mouse model of breast cancer but only when mice are not housed alone. We identify the proteoglycan decorin as a contraction-induced secretory factor that systemically increases in patients with breast cancer immediately following exercise. Moreover, high expression of decorin in tumors is associated with improved prognosis in patients, while treatment of breast cancer cells in vitro with decorin reduces cell proliferation. Notwithstanding, when we overexpressed decorin in murine muscle or injected recombinant decorin systemically into mouse models of breast cancer, elevated plasma decorin concentrations did not result in higher tumor decorin levels and tumor burden was not improved. ConclusionExercise training is anti-tumorigenic in a mouse model of luminal breast cancer, but the effect is abrogated by social isolation. The proteoglycan decorin is an exercise-induced secretory protein, and tumor decorin levels are positively associated with improved prognosis in patients. The hypothesis that elevated plasma decorin is a mechanism by which exercise training improves breast cancer progression in humans is not, however, supported by our pre-clinical data since elevated circulating decorin did not increase tumor decorin levels in these models.

Biogenic Sulfide-Mediated Iron Reduction at Low pH

Acid mine drainage (AMD) pollutes natural waters, but some impacted systems show natural attenuation. We sought to identify the biogeochemical mechanisms responsible for the natural attenuation of AMD. We hypothesized that biogenic sulfide-mediated iron reduction is one mechanism and tested this in an experimental model system. We found sulfate reduction occurred under acidic conditions and identified a suite of sulfate-reducing bacteria (SRB) belonging to the groups Desulfotomaculum, Desulfobacter, Desulfovibrio, and Desulfobulbus. Iron reduction was not detected in microcosms when iron-reducing bacteria or SRB were selectively inhibited. SRB also did not reduce iron enzymatically. Rather, the biogenic sulfide produced by SRB was found to be responsible for the reduction of iron at low pH. Addition of organic substrates and nutrients stimulated iron reduction and increased the pH. X-ray diffraction and an electron microprobe analysis revealed that the polycrystalline, black precipitate from SRB bioactive samples exhibited a greater diversity of iron chalcogenide minerals with reduced iron oxidation states, and minerals incorporating multiple metals compared to abiotic controls. The implication of this study is that iron reduction mediated by biogenic sulfide may be more significant than previously thought in acidic environments. This study not only describes an additional mechanism by which SRB attenuate AMD, which has practical implications for AMD-impacted sites, but also provides a link between the biogeochemical cycling of iron and sulfur.

Numerical integration of mechanical forces in center-based models for biological cell populations

Center-based models are used to simulate the mechanical behavior of biological cells during embryonic development or cancer growth. To allow for the simulation of biological populations potentially growing from a few individual cells to many thousands or more, these models have to be numerically efficient, while being reasonably accurate on the level of individual cell trajectories. In this work, we increase the robustness, accuracy, and efficiency of the simulation of center-based models by choosing the time steps adaptively in the numerical method and comparing five different integration methods. We investigate the gain in using single rate time stepping based on local estimates of the numerical errors for the forward and backward Euler methods of first order accuracy and a Runge-Kutta method and the trapezoidal method of second order accuracy. Properties of the analytical solution such as convergence to steady state and conservation of the center of gravity are inherited by the numerical solutions. Furthermore, we propose a multirate time stepping scheme that simulates regions with high local force gradients (e.g. as they happen after cell division) with multiple smaller time steps within a larger single time step for regions with smoother forces. These methods are compared for a model system in numerical experiments. We conclude, for example, that the multirate forward Euler method performs better than the Runge-Kutta method for low accuracy requirements but for higher accuracy the latter method is preferred. Only with frequent cell divisions the method with a fixed time step is the best choice.

Study on the Rules of Ground Settlement and Pipeline Deformation Considering the Combined Effects of Pipeline Damage Leakage and Shield Tunneling Construction

A pipeline with long-term “hidden leakage” will greatly reduce the stability of the ground between the pipeline and tunnel in the process of tunneling through existing pipelines in unsaturated soil. Excessive settlement of the surrounding strata and pipelines can occur when the shield excavation face approaches below a pipeline, which can lead to engineering accidents. This study is based on a self-developed model experimental system for tunneling through an existing pipeline with a double-line tunnel shield. The ground settlement and pipeline deformation caused by shield construction with small-scale and no leakages are investigated. An experimental study is conducted and the accuracy of the results is verified through a comparison with theoretical solutions. The results demonstrate that there is a significant increase in ground settlement and pipeline deformation under the influence of leakage water. It is also determined that the displacement field generated by the excavation of a double-line tunnel is not simply a superposition of the displacement field generated by the excavation of a single-line tunnel. The repeated disturbances caused by the excavation of a double-line tunnel significantly influences the redistribution of the displacement field. Additionally, a three-dimensional (3D) model of shield construction considering the influence of pipeline leakage is established. This study discusses the ground settlement and pipeline deformation patterns caused by changes in the vertical and horizontal leakage diffusion ranges. The computational results indicate that the diffusion depth of a leakage is the primary factor controlling the extent of settlement.

Constrained motion of self-propelling eccentric disks linked by a spring.

It has been supposed that the interplay of elasticity and activity plays a key role in triggering the non-equilibrium behaviors in biological systems. However, the experimental model system is missing to investigate the spatiotemporally dynamical phenomena. Here, a model system of an active chain, where active eccentric-disks are linked by a spring, is designed to study the interplay of activity, elasticity, and friction. Individual active chain exhibits longitudinal and transverse motions; however, it starts to self-rotate when pinning one end and self-beat when clamping one end. In addition, our eccentric-disk model can qualitatively reproduce such behaviors and explain the unusual self-rotation of the first disk around its geometric center. Furthermore, the structure and dynamics of long chains were studied via simulations without steric interactions. It was found that a hairpin conformation emerges in free motion, while in the constrained motions, the rotational and beating frequencies scale with the flexure number (the ratio of self-propelling force to bending rigidity), χ, as ∼(χ)4/3. Scaling analysis suggests that it results from the balance between activity and energy dissipation. Our findings show that topological constraints play a vital role in non-equilibrium synergy behaviors.

Functional loss of ERBB receptor feedback inhibitor 1 (MIG6) promotes glioblastoma tumorigenesis by aberrantactivation of epidermal growth factor receptor (EGFR).

Dysregulation of epidermal growth factor receptor (EGFR) is one of the most common mechanisms associated with the pathogenesis of various cancers. Mitogen-inducible gene 6 [MIG6; also known as ERBB receptor feedback inhibitor 1 (ERRFI1)], identified as a feedback inhibitor of EGFR, negatively regulates EGFR by directly inhibiting its kinase activity and facilitating its internalization, subsequently leading to degradation. Despite its proposed role as an EGFR-dependent tumor suppressor, the functional consequences and clinical relevance in cancer etiology remain incompletely understood. Here, we identify that the stoichiometric balance between MIG6 and EGFR is crucial in promoting EGFR-dependent oncogenic growth in various experimental model systems. In addition, a subset of ERRFI1 (the official gene symbol of MIG6) mutations exhibit impaired ability to suppress the enzymatic activation of EGFR at multiple levels. In summary, our data suggest that decreased or loss of MIG6 activity can lead to abnormal activation of EGFR, potentially contributing to cellular transformation. We propose that the mutation status of ERRFI1 and the expression levels of MIG6 can serve as additional biomarkers for guiding EGFR-targeted cancer therapies, including glioblastoma.

Abstract Mo071: Engineered Platform to Uncover Cellular Cross-Talk and Arrhythmogenesis in Idiopathic Ventricular Fibrillation (IVF)

Background: Idiopathic VF (IVF) represents an unmet clinical need with ~50% of patients having no known monogenic cause. This has resulted in the lack of an appropriate experimental model system, limiting effective treatment through an evidence-based approach. Within IVF, several subphenotypes have emerged through Deep Phenotyping. We recruited patients with Purkinje cell premature ventricular contraction-driven IVF (PVC-IVF) to generate induced pluripotent stem cells (iPSCs). Aim: To characterize PVC-IVF patient-specific iPSCs using a physiologically relevant engineered in vitro model. We hypothesize this model will allow for mechanistic characterization of PVC-IVF. Methods: Patient-specific iPSC-cardiomyocytes (CMs) and iPSC-cardiac fibroblasts (CFs) were plated on 10 kPa polydimethylsiloxane (PDMS) culture platform with Matrigel in either monolayers or interconnected 40 µm lanes ( Fig. 1A ). Optical mapping was used to characterize Ca 2+ handling and action potentials. Control cells were from non-diseased persons. Results: CM-CF coculture results in a monolayer yet maintains the underlying organization ( Fig. 1B-C ). Patterned constructs have increased conduction velocities and anisotropy. Custom stimulation protocols were developed to probe arrhythmia susceptibility and restitution kinetics ( Fig. 1D-E ). A genetic algorithm was used to optimize a biophysically detailed CM model which enabled identification of differential model parameters between IVF and control data ( Fig. 2A-B ). These data will be used to develop a Ca 2+ handling–conduction–contractility paradigm specific to PVC-IVF as well as a mechanistic-based understanding of the disorder. Conclusions: Topography informs CM structure, while CFs remodel the matrix to form a monolayer, enabling full field electrophysiological definition at the cell and tissue scale. The in vitro model provides a unique microenvironment to determine the arrhythmogenic mechanism of PVC-IVF.

Stable isotope-resolved metabolomics analyses of metabolic phenotypes reveal variable glutamine metabolism in different patient-derived models of non-small cell lung cancer from a single patient.

Stable isotope tracers have been increasingly used in preclinical cancer model systems, including cell culture and mouse xenografts, to probe the altered metabolism of a variety of cancers, such as accelerated glycolysis and glutaminolysis and generation of oncometabolites. Comparatively little has been reported on the fidelity of the different preclinical model systems in recapitulating the aberrant metabolism of tumors. We have been developing several different experimental model systems for systems biochemistry analyses of non-small cell lung cancer (NSCLC1) using patient-derived tissues to evaluate appropriate models for metabolic and phenotypic analyses. To address the issue of fidelity, we have carried out a detailed Stable Isotope-Resolved Metabolomics study of freshly resected tissue slices, mouse patient derived xenografts (PDXs), and cells derived from a single patient using both 13C6-glucose and 13C5,15N2-glutamine tracers. Although we found similar glucose metabolism in the three models, glutamine utilization was markedly higher in the isolated cell culture and in cell culture-derived xenografts compared with the primary cancer tissue or direct tissue xenografts (PDX). This suggests that caution is needed in interpreting cancer biochemistry using patient-derived cancer cells in vitro or in xenografts, even at very early passage, and that direct analysis of patient derived tissue slices provides the optimal model for ex vivo metabolomics. Further research is needed to determine the generality of these observations.

Neuropathy and pain in Fabry disease

Fabry disease (FD) is a multiorgan lysosomal storage disorder caused by mutations in the alfa-galactosidase A (GLA ) gene. Pathogenic GLA mutations lead to impaired or even lost enzyme activity, which causes the accumulation of sphingolipids, e.g., globotriaosylceramide, in cells and tissues. The majority of FD patients experience triggerable pain, mainly acral and burning, which often begins in early childhood. While small fiber pathology is assumed to be the basis of FD pain, the underlying molecular mechanisms are not well understood. This review summarizes the clinical characteristics of neuropathy and neuropathic pain in FD, presents current treatment options, and gives an overview of the latest findings from experimental and human model systems on the pathomechanisms contributing to small fiber pathology and FD-associated pain.

Rapid body colouration changes in Oryzias celebensis as a social signal influenced by environmental background.

Rapid body colouration changes in some animals, such as chameleons and octopuses, serve dual functions: camouflage and intraspecific communication. It has been hypothesized that these colouration changes originally evolved to provide camouflage and subsequently were co-opted as social signals; however, experimental model systems that are suitable for studying such evolutionary processes are limited. Here, we investigated the relationship between rapid colouration changes of the blackened markings and aggressive behaviours in male Oryzias celebensis, an Indonesian medaka fish, under triadic relationships (two males and one female) or three males conditions with two different environmental backgrounds. In an algae-covered tank, mimicking the common laboratory rearing conditions, males with blackened markings exhibited more frequent attacks towards different conspecific individuals compared with non-blackened males and females. The blackened males were seldom attacked by non-blackened males and females. By contrast, neither aggressive behaviours nor black colouration changes were observed in the transparent background condition with a brighter environment. These indicated that the blackened markings in O. celebensis serve as a social signal depending on the environmental backgrounds. Considering that such colouration changes for camouflage are widely conserved among teleost fishes, the traits are likely to be co-opted for displaying social signals in O. celebensis.

Controlled creation of point defects in three-dimensional colloidal crystals.

Crystal defects crucially influence the properties of crystalline materials and have been extensively studied. Even for the simplest type of defect-the point defect-however, basic properties such as their diffusive behavior, and their interactions, remain elusive on the atomic scale. Here, we demonstrate in situ control over the creation of isolated point defects in a three-dimensional (3D) colloidal crystal allowing insight on a single-particle level. Our system consists of thermoresponsive microgel particles embedded in a crystal of nonresponsive colloids. Heating this mixed-particle system triggers the shrinking of the embedded microgels, which then vacate their lattice positions, creating vacancy-interstitial pairs. We use temperature-controlled confocal laser scanning microscopy to verify and visualize the formation of the point defects. In addition, by reswelling the microgels we quantify the local lattice distortion around an interstitial defect. Our experimental model system provides a unique opportunity to shed light on the interplay between point defects, on the mechanisms of their diffusion, on their interactions, and on collective dynamics.