Characterization of cutaneous and articular sensory neurons

Background: A wide range of stimuli can activate sensory neurons and neurons innervating specific tissues often have distinct properties. Here we used retrograde tracing to identify sensory neurons innervating the hind paw skin (cutaneous) and ankle/knee joints (articular), and combined immunohistochemistry and electrophysiology analysis to determine the neurochemical phenotype of cutaneous and articular neurons, as well as their electrical and chemical excitability. Results: Immunohistochemistry analysis using RetroBeads as a retrograde tracer confirmed previous data that cutaneous and articular neurons are a mixture of myelinated and unmyelinated neurons, and the majority of both populations are peptidergic. In whole-cell patch-clamp recordings from cultured dorsal root ganglion neurons, voltage-gated inward currents and action potential parameters were largely similar between articular and cutaneous neurons, although cutaneous neuron action potentials had a longer half-peak duration. An assessment of chemical sensitivity showed that all neurons responded to a pH 5.0 solution, but that acid-sensing ion channel (ASIC) currents, determined by inhibition with the non-selective ASIC antagonist benzamil, were of a greater magnitude in cutaneous compared to articular neurons. 40 – 50% of cutaneous and articular neurons responded to capsaicin, cinnamaldehyde and menthol, indicating similar expression levels of TRPV1, TRPA1 and TRPM8 respectively. By contrast, significantly more articular neurons responded to ATP than cutaneous neurons. Conclusion: This work makes a detailed characterization of cutaneous and articular sensory neurons, and highlights the importance of making recordings from identified neuronal populations: sensory neurons innervating different tissues have subtly different properties, possibly reflecting different functions.ISS was funded by an Erasmus for Graduate Students grant from the University of Coimbra. ZMAH and experiments were funded by an Arthritis Research Project Grant (Grant Reference 20930) to ESS. JDB was funded by a Corpus Christi College Study and Travel Grant. EStJS was funded by an Early Career Research Grant from the International Association for the Study of Pain. Thanks to Christoforos Tsantoulas for assistance with immunohistochemistry and members of the Smith lab for their technical assistance and help in preparing the manuscript.This is the final version of the article. It first appeared from SAGE via http://dx.doi.org/10.1177/174480691663638

Non-Redundant Spectral Dimensionality Reduction

Spectral dimensionality reduction algorithms are widely used in numerous domains, including for recognition, segmentation, tracking and visualization. However, despite their popularity, these algorithms suffer from a major limitation known as the "repeated Eigen-directions" phenomenon. That is, many of the embedding coordinates they produce typically capture the same direction along the data manifold. This leads to redundant and inefficient representations that do not reveal the true intrinsic dimensionality of the data. In this paper, we propose a general method for avoiding redundancy in spectral algorithms. Our approach relies on replacing the orthogonality constraints underlying those methods by unpredictability constraints. Specifically, we require that each embedding coordinate be unpredictable (in the statistical sense) from all previous ones. We prove that these constraints necessarily prevent redundancy, and provide a simple technique to incorporate them into existing methods. As we illustrate on challenging high-dimensional scenarios, our approach produces significantly more informative and compact representations, which improve visualization and classification tasks

Epigenetic reprogramming of fallopian tube fimbriae in BRCA mutation carriers defines early ovarian cancer evolution

The exact timing and contribution of epigenetic reprogramming to carcinogenesis are unclear. Women harbouring BRCA1/2 mutations demonstrate a 30–40-fold increased risk of high-grade serous extra-uterine Müllerian cancers (HGSEMC), otherwise referred to as ‘ovarian carcinomas’, which frequently develop from fimbrial cells but not from the proximal portion of the fallopian tube. Here we compare the DNA methylome of the fimbrial and proximal ends of the fallopian tube in BRCA1/2 mutation carriers and non-carriers. We show that the number of CpGs displaying significant differences in methylation levels between fimbrial and proximal fallopian tube segments are threefold higher in BRCA mutation carriers than in controls, correlating with overexpression of activation-induced deaminase in their fimbrial epithelium. The differentially methylated CpGs accurately discriminate HGSEMCs from non-serous subtypes. Epigenetic reprogramming is an early pre-malignant event integral to BRCA1/2 mutation-driven carcinogenesis. Our findings may provide a basis for cancer-preventative strategies

Characterization of cutaneous and articular sensory neurons.

BACKGROUND: A wide range of stimuli can activate sensory neurons and neurons innervating specific tissues often have distinct properties. Here, we used retrograde tracing to identify sensory neurons innervating the hind paw skin (cutaneous) and ankle/knee joints (articular), and combined immunohistochemistry and electrophysiology analysis to determine the neurochemical phenotype of cutaneous and articular neurons, as well as their electrical and chemical excitability. RESULTS: Immunohistochemistry analysis using RetroBeads as a retrograde tracer confirmed previous data that cutaneous and articular neurons are a mixture of myelinated and unmyelinated neurons, and the majority of both populations are peptidergic. In whole-cell patch-clamp recordings from cultured dorsal root ganglion neurons, voltage-gated inward currents and action potential parameters were largely similar between articular and cutaneous neurons, although cutaneous neuron action potentials had a longer half-peak duration (HPD). An assessment of chemical sensitivity showed that all neurons responded to a pH 5.0 solution, but that acid-sensing ion channel (ASIC) currents, determined by inhibition with the nonselective acid-sensing ion channel antagonist benzamil, were of a greater magnitude in cutaneous compared to articular neurons. Forty to fifty percent of cutaneous and articular neurons responded to capsaicin, cinnamaldehyde, and menthol, indicating similar expression levels of transient receptor potential vanilloid 1 (TRPV1), transient receptor potential ankyrin 1 (TRPA1), and transient receptor potential melastatin 8 (TRPM8), respectively. By contrast, significantly more articular neurons responded to ATP than cutaneous neurons. CONCLUSION: This work makes a detailed characterization of cutaneous and articular sensory neurons and highlights the importance of making recordings from identified neuronal populations: sensory neurons innervating different tissues have subtly different properties, possibly reflecting different functions.ISS was funded by an Erasmus for Graduate Students grant from the University of Coimbra. ZMAH and experiments were funded by an Arthritis Research Project Grant (Grant Reference 20930) to ESS. JDB was funded by a Corpus Christi College Study and Travel Grant. EStJS was funded by an Early Career Research Grant from the International Association for the Study of Pain. Thanks to Christoforos Tsantoulas for assistance with immunohistochemistry and members of the Smith lab for their technical assistance and help in preparing the manuscript.This is the final version of the article. It first appeared from SAGE via http://dx.doi.org/10.1177/174480691663638

Dominant ethnicity: from minority to majority

This article argues that the world is in the midst of a long-term transition from dominant minority to dominant majority ethnicity. Whereas minority domination was common in premodern societies, modernity (with its accent on democracy and popular sovereignty) has engendered a shift to dominant majority ethnicity. The article begins with conceptual clarifications. The second section provides a broad overview of the general patterns of ethnic dominance that derive from the logic of modern nationalism and democratisation. The third section discusses remnants of dominant minorities in the modern era and suggests that their survival hinges on peculiar historical and social circumstances coupled with resistance to democratisation. The fourth section shifts the focus to dominant majorities in the modern era and their relationship to national identities. The article ends with a discussion of the fortunes of dominant ethnicity in the West

Spatial and topological organization of DNA chains induced by gene co-localization

Transcriptional activity has been shown to relate to the organization of chromosomes in the eukaryotic nucleus and in the bacterial nucleoid. In particular, highly transcribed genes, RNA polymerases and transcription factors gather into discrete spatial foci called transcription factories. However, the mechanisms underlying the formation of these foci and the resulting topological order of the chromosome remain to be elucidated. Here we consider a thermodynamic framework based on a worm-like chain model of chromosomes where sparse designated sites along the DNA are able to interact whenever they are spatially close-by. This is motivated by recurrent evidence that there exists physical interactions between genes that operate together. Three important results come out of this simple framework. First, the resulting formation of transcription foci can be viewed as a micro-phase separation of the interacting sites from the rest of the DNA. In this respect, a thermodynamic analysis suggests transcription factors to be appropriate candidates for mediating the physical interactions between genes. Next, numerical simulations of the polymer reveal a rich variety of phases that are associated with different topological orderings, each providing a way to increase the local concentrations of the interacting sites. Finally, the numerical results show that both one-dimensional clustering and periodic location of the binding sites along the DNA, which have been observed in several organisms, make the spatial co-localization of multiple families of genes particularly efficient.Comment: Figures and Supplementary Material freely available on http://dx.doi.org/10.1371/journal.pcbi.100067

Female Burying Beetles Benefit from Male Desertion: Sexual Conflict and Counter-Adaptation over Parental Investment

Sexual conflict drives the coevolution of sexually antagonistic traits, such that an adaptation in one sex selects an opposing coevolutionary response from the other. Although many adaptations and counteradaptations have been identified in sexual conflict over mating interactions, few are known for sexual conflict over parental investment. Here we investigate a possible coevolutionary sequence triggered by mate desertion in the burying beetle Nicrophorus vespilloides, where males commonly leave before their offspring reach independence. Rather than suffer fitness costs as a consequence, our data suggest that females rely on the male's absence to recoup some of the costs of larval care, presumably because they are then free to feed themselves on the carcass employed for breeding. Consequently, forcing males to stay until the larvae disperse reduces components of female fitness to a greater extent than caring for young singlehandedly. Therefore we suggest that females may have co-evolved to anticipate desertion by their partners so that they now benefit from the male's absence

Susceptibility of hamsters to clostridium difficile isolates of differing toxinotype

Clostridium difficile is the most commonly associated cause of antibiotic associated disease (AAD), which caused ~21,000 cases of AAD in 2011 in the U.K. alone. The golden Syrian hamster model of CDI is an acute model displaying many of the clinical features of C. difficile disease. Using this model we characterised three clinical strains of C. difficile, all differing in toxinotype; CD1342 (PaLoc negative), M68 (toxinotype VIII) and BI-7 (toxinotype III). The naturally occurring non-toxic strain colonised all hamsters within 1-day post challenge (d.p.c.) with high-levels of spores being shed in the faeces of animals that appeared well throughout the entire experiment. However, some changes including increased neutrophil influx and unclotted red blood cells were observed at early time points despite the fact that the known C. difficile toxins (TcdA, TcdB and CDT) are absent from the genome. In contrast, hamsters challenged with strain M68 resulted in a 45% mortality rate, with those that survived challenge remaining highly colonised. It is currently unclear why some hamsters survive infection, as bacterial and toxin levels and histology scores were similar to those culled at a similar time-point. Hamsters challenged with strain BI-7 resulted in a rapid fatal infection in 100% of the hamsters approximately 26 hr post challenge. Severe caecal pathology, including transmural neutrophil infiltrates and extensive submucosal damage correlated with high levels of toxin measured in gut filtrates ex vivo. These data describes the infection kinetics and disease outcomes of 3 clinical C. difficile isolates differing in toxin carriage and provides additional insights to the role of each toxin in disease progression