Epistemic Closure in Folk Epistemology

We report the results of four empirical studies designed to investigate the extent to which an epistemic closure principle for knowledge is reflected in folk epistemology. Previous work by Turri (2015a) suggested that our shared epistemic practices may only include a source-relative closure principle—one that applies to perceptual beliefs but not to inferential beliefs. We argue that the results of our studies provide reason for thinking that individuals are making a performance error when their knowledge attributions and denials conflict with the closure principle. When we used research materials that overcome what we think are difficulties with Turri’s original materials, we found that participants did not reject closure. Furthermore, when we presented Turri’s original materials to non-philosophers with expertise in deductive reasoning (viz., professional mathematicians), they endorsed closure for both perceptual and inferential beliefs. Our results suggest that an unrestricted closure principle—one that applies to all beliefs, regardless of their source—provides a better model of folk patterns of knowledge attribution than a source-relative closure principle

SPH Simulations of Accretion Disks and Narrow Rings

We model a massless viscous disk using Smoothed Particle Hydrodynamics (SPH) and note that it evolves according to the Lynden-Bell \& Pringle theory (1974) until a non-axisymmetric instability develops at the inner edge of the disk. This instability may have the same origin as the instability of initially axisymmetric viscous disks discussed by Lyubarskij et al. (1994). To clarify the evolution we evolved single and double rings of particles. It is actually inconsistent with the SPH scheme to set up a single ring as an initial condition because SPH assumes a smoothed initial state. As would be expected from an SPH simulation, the ring rapidly breaks up into a band. We analyse the stability of the ring and show that the predictions are confirmed by the simulation.Comment: 11 pages, uuencoded compressed postscript with 2 figs, accepted PASA. Also available at http://www.maths.monash.edu.au/~maddison/me/papers.htm

Transcriptional Correlates of Proximal-Distal Identify and Regeneration Timing in Axolotl Limbs

Cells within salamander limbs retain memories that inform the correct replacement of amputated tissues at different positions along the length of the arm, with proximal and distal amputations completing regeneration at similar times. We investigated the possibility that positional memory is associated with variation in transcript abundances along the proximal-distal limb axis. Transcripts were deeply sampled from Ambystoma mexicanum limbs at the time they were administered fore arm vs upper arm amputations, and at 19 post-amputation time points. After amputation and prior to regenerative outgrowth, genes typically expressed by differentiated muscle cells declined more rapidly in upper arms while cell cycle transcripts were expressed more highly. These and other expression patterns suggest upper arms undergo more robust tissue remodeling and cell proliferation responses after amputation, and thus provide an explanation for why the overall time to complete regeneration is similar for proximal and distal amputations. Additionally, we identified candidate positional memory genes that were expressed differently between fore and upper arms that encode a surprising number of epithelial proteins and a variety of cell surface, cell adhesion, and extracellular matrix molecules. Also, genes were discovered that exhibited different, bivariate patterns of gene expression between fore and upper arms, implicating dynamic transcriptional regulation for the first time in limb regeneration. Finally, 43 genes expressed differently between fore and upper arm samples showed similar transcriptional patterns during retinoic acid-induced reprogramming of fore arm blastema cells into upper arm cells. Our study provides new insights about the basis of positional information in regenerating axolotl limbs

Characterization of in vitro Transcriptional Responses of Dorsal Root Ganglia Cultured in the Presence and Absence of Blastema Cells from Regenerating Salamander Limbs

During salamander limb regeneration, nerves provide signals that induce the formation of a mass of proliferative cells called the blastema. To better understand these signals, we developed a blastema-dorsal root ganglia (DRG) co-culture model system to test the hypothesis that nerves differentially express genes in response to cues provided by the blastema. DRG with proximal and distal nerve trunks were isolated from axolotls (Ambystoma mexicanum), cultured for five days, and subjected to microarray analysis. Relative to freshly isolated DRG, 1,541 Affymetrix probe sets were identified as differentially expressed and many of the predicted genes are known to function in injury and neurodevelopmental responses observed for mammalian DRG. We then cultured 5-day DRG explants for an additional five days with or without co-cultured blastema cells. On Day 10, we identified 27 genes whose expression in cultured DRG was significantly affected by the presence or absence of blastema cells. Overall, our study established a DRG-blastema in vitro culture system and identified candidate genes for future investigations of axon regrowth, nerve-blastema signaling, and neural regulation of limb regeneration

Spiny Mice (\u3cem\u3eAcomys\u3c/em\u3e) Exhibit Attenuated Hallmarks of Aging and Rapid Cell Turnover after UV Exposure in the Skin Epidermis

The study of long-lived and regenerative animal models has revealed diverse protective responses to stressors such as aging and tissue injury. Spiny mice (Acomys) are a unique mammalian model of skin wound regeneration, but their response to other types of physiological skin damage has not been investigated. In this study, we examine how spiny mouse skin responds to acute UVB damage or chronological aging compared to non-regenerative C57Bl/6 mice (M. musculus). We find that, compared to M. musculus, the skin epidermis in A. cahirinus experiences a similar UVB-induced increase in basal cell proliferation but exhibits increased epidermal turnover. Notably, A. cahirinus uniquely form a suprabasal layer co-expressing Keratin 14 and Keratin 10 after UVB exposure concomitant with reduced epidermal inflammatory signaling and reduced markers of DNA damage. In the context of aging, old M. musculus animals exhibit typical hallmarks including epidermal thinning, increased inflammatory signaling and senescence. However, these age-related changes are absent in old A. cahirinus skin. Overall, we find that A. cahirinus have evolved novel responses to skin damage that reveals new aspects of its regenerative phenotype

Tracking neural crest cell cycle progression in vivo

Analysis of cell cycle entry/exit and progression can provide fundamental insights into stem cell propagation, maintenance, and differentiation. The neural crest is a unique stem cell population in vertebrate embryos that undergoes long‐distance collective migration and differentiation into a wide variety of derivatives. Using traditional techniques such as immunohistochemistry to track cell cycle changes in such a dynamic population is challenging, as static time points provide an incomplete spatiotemporal picture. In contrast, the fluorescent, ubiquitination‐based cell cycle indicator (Fucci) system provides in vivo readouts of cell cycle progression and has been previously adapted for use in zebrafish. The most commonly used Fucci systems are ubiquitously expressed, making tracking of a specific cell population challenging. Therefore, we generated a transgenic zebrafish line, Tg(‐4.9sox10:mAG‐gmnn(1/100)‐2A‐mCherry‐cdt1(1/190)), in which the Fucci system is specifically expressed in delaminating and migrating neural crest cells. Here, we demonstrate validation of this new tool and its use in live high‐resolution tracking of cell cycle progression in the neural crest and derivative populations

Tracking neural crest cell cycle progression in vivo

Analysis of cell cycle entry/exit and progression can provide fundamental insights into stem cell propagation, maintenance, and differentiation. The neural crest is a unique stem cell population in vertebrate embryos that undergoes long‐distance collective migration and differentiation into a wide variety of derivatives. Using traditional techniques such as immunohistochemistry to track cell cycle changes in such a dynamic population is challenging, as static time points provide an incomplete spatiotemporal picture. In contrast, the fluorescent, ubiquitination‐based cell cycle indicator (Fucci) system provides in vivo readouts of cell cycle progression and has been previously adapted for use in zebrafish. The most commonly used Fucci systems are ubiquitously expressed, making tracking of a specific cell population challenging. Therefore, we generated a transgenic zebrafish line, Tg(‐4.9sox10:mAG‐gmnn(1/100)‐2A‐mCherry‐cdt1(1/190)), in which the Fucci system is specifically expressed in delaminating and migrating neural crest cells. Here, we demonstrate validation of this new tool and its use in live high‐resolution tracking of cell cycle progression in the neural crest and derivative populations

Gene Expression Patterns Specific to the Regenerating Limb of the Mexican Axolotl

Salamander limb regeneration is dependent upon tissue interactions that are local to the amputation site. Communication among limb epidermis, peripheral nerves, and mesenchyme coordinate cell migration, cell proliferation, and tissue patterning to generate a blastema, which will form missing limb structures. An outstanding question is how cross-talk between these tissues gives rise to the regeneration blastema. To identify genes associated with epidermis-nerve-mesenchymal interactions during limb regeneration, we examined histological and transcriptional changes during the first week following injury in the wound epidermis and subjacent cells between three injury types; 1) a flank wound on the side of the animal that will not regenerate a limb, 2) a denervated limb that will not regenerate a limb, and 3) an innervated limb that will regenerate a limb. Early, histological and transcriptional changes were similar between the injury types, presumably because a common wound-healing program is employed across anatomical locations. However, some transcripts were enriched in limbs compared to the flank and are associated with vertebrate limb development. Many of these genes were activated before blastema outgrowth and expressed in specific tissue types including the epidermis, peripheral nerve, and mesenchyme. We also identified a relatively small group of transcripts that were more highly expressed in innervated limbs versus denervated limbs. These transcripts encode for proteins involved in myelination of peripheral nerves, epidermal cell function, and proliferation of mesenchymal cells. Overall, our study identifies limb-specific and nerve-dependent genes that are upstream of regenerative growth, and thus promising candidates for the regulation of blastema formation

Local mechanical stimuli correlate with tissue growth in axolotl salamander joint morphogenesis

Movement-induced forces are critical to correct joint formation, but it is unclear how cells sense and respond to these mechanical cues. To study the role of mechanical stimuli in the shaping of the joint, we combined experiments on regenerating axolotl (Ambystoma mexicanum) forelimbs with a poroelastic model of bone rudiment growth. Animals either regrew forelimbs normally (control) or were injected with a transient receptor potential vanilloid 4 (TRPV4) agonist during joint morphogenesis. We quantified growth and shape in regrown humeri from whole-mount light sheet fluorescence images of the regenerated limbs. Results revealed significant differences in morphology and cell proliferation between groups, indicating that TRPV4 desensitization has an effect on joint shape. To link TRPV4 desensitization with impaired mechanosensitivity, we developed a finite element model of a regenerating humerus. Local tissue growth was the sum of a biological contribution proportional to chondrocyte density, which was constant, and a mechanical contribution proportional to fluid pressure. Computational predictions of growth agreed with experimental outcomes of joint shape, suggesting that interstitial pressure driven from cyclic mechanical stimuli promotes local tissue growth. Predictive computational models informed by experimental findings allow us to explore potential physical mechanisms involved in tissue growth to advance our understanding of the mechanobiology of joint morphogenesis.This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 841047 and the National Science Foundation under grant no. 1727518. J.J.M. has been also funded by the Spanish Ministry of Science and Innovation under grant no. DPI2016-74929-R, and by the local government Generalitat de Catalunya under grant no. 2017 SGR 1278. K.L. was supported by a Northeastern University Undergraduate Research and Fellowships PEAK Experiences Award.Peer ReviewedPostprint (published version

Simulations of spectral lines from an eccentric precessing accretion disc

Two dimensional SPH simulations of a precessing accretion disc in a q=0.1 binary system (such as XTE J1118+480) reveal complex and continuously varying shape, kinematics, and dissipation. The stream-disc impact region and disc spiral density waves are prominent sources of energy dissipation.The dissipated energy is modulated on the period P_{sh} = ({P_{orb}}^{-1}-{P_{prec}}^{-1}^{-1} with which the orientation of the disc relative to the mass donor repeats. This superhump modulation in dissipation energy has a variation in amplitude of ~10% relative to the total dissipation energy and evolves, repeating exactly only after a full disc precession cycle. A sharp component in the light curve is associated with centrifugally expelled material falling back and impacting the disc. Synthetic trailed spectrograms reveal two distinct "S-wave" features, produced respectively by the stream gas and the disc gas at the stream-disc impact shock. These S-waves are non-sinusoidal, and evolve with disc precession phase. We identify the spiral density wave emission in the trailed spectrogram. Instantaneous Doppler maps show how the stream impact moves in velocity space during an orbit. In our maximum entropy Doppler tomogram the stream impact region emission is distorted, and the spiral density wave emission is uppressed. A significant radial velocity modulation of the whole line profile occurs on the disc precession period. We compare our SPH simulation with a simple 3D model: the former is appropriate for comparison with emission lines while the latter is preferable for skewed absorption lines from precessing discs.Comment: See http://physics.open.ac.uk/FHMR/ for associated movie (avi) files. The full paper is in MNRAS press. Limited disk space limit of 650k, hence low resolution figure file