The connexin mimetic peptide Gap27 and Cx43-Knockdown reveal differential roles for Connexin43 in wound closure events in skin model systems

In the epidermis, remodelling of Connexin43 is a key event in wound closure. However, controversy between the role of connexin channel and non-channel functions exist. We compared the impact of SiRNA targeted to Connexin43 and the connexin mimetic peptide Gap27 on scrape wound closure rates and hemichannel signalling in adult keratinocytes (AK) and fibroblasts sourced from juvenile foreskin (JFF), human neonatal fibroblasts (HNDF) and adult dermal tissue (ADF). The impact of these agents, following 24 h exposure, on (encoding Connexin43), and gene expression, and Connexin43 and pSmad3 protein expression levels, were examined by qPCR and Western Blot respectively. In all cell types Gap27 (100-100 μM) attenuated hemichannel activity. In AK and JFF cells, Gap27 (100 nM-100 μM) enhanced scrape wound closure rates by ~50% but did not influence movement in HNDF or ADF cells. In both JF and AK cells, exposure to Gap27 for 24 h reduced the level of Cx43 protein expression but did not affect the level in ADF and HNDF cells. Connexin43-SiRNA enhanced scrape wound closure in all the cell types under investigation. In HDNF and ADF, Connexin43-SiRNA enhanced cell proliferation rates, with enhanced proliferation also observed following exposure of HDNF to Gap27. By contrast, in JFF and AK cells no changes in proliferation occurred. In JFF cells, Connexin43-SiRNA enhanced levels and in JFF and ADF cells both Connexin43-SiRNA and Gap27 enhanced pSmad3 protein expression levels. We conclude that Connexin43 signalling plays an important role in cell migration in keratinocytes and foreskin derived fibroblasts, however, different pathways are evoked and in dermal derived adult and neonatal fibroblasts, inhibition of Connexin43 signalling plays a more significant role in regulating cell proliferation than cell migration

Anatomy and growth of a Holocene clinothem in the Gulf of Papua

High-resolution seismic profiles and sedimentological data from grab samples and long cores provide an unprecedented picture of the structure, sedimentology, and late Quaternary development of two Gulf of Papua ( GoP) clinothems, one probably Stage 3 and 4 in age and one Holocene in age. The older was partially eroded during Stage 2 and partially covered by the younger clinothem during Stage 1. The younger clinothem consists of three stratigraphic units separated by two surfaces of erosion, bypass, or correlative surfaces of lap. The surfaces were formed by changes in accommodation and sediment supply. The underlying physiography of the older clinothem also appears to play an important role in governing the shape of the younger clinothem. In the northern gulf, oblique clinoforms of the younger clinothem suggest that the rate of sediment supply from the northern rivers outstripped the formation of new accommodation, whereas in the south, sigmoidal clinoforms indicate that accommodation increased faster than sediment supply. The origin of the new accommodation remains uncertain because of limited age constraints. On the basis of sediment thickness, stratal geometry, and acoustic character, off-shelf transport appears to be the dominant sediment transport direction, with preferential accumulation on the promontories and bypass in the valleys. Presently, observed and computed modern flows and complex gyres in shallow water coupled with wave- and current-supported gravity flows or river floods can explain the form, internal clinoform shapes, and mineralogy of the younger Gulf of Papua clinothem

Characterising encapsulated nuclear waste using cosmic-ray muon tomography

Tomographic imaging techniques using the Coulomb scattering of cosmic-ray muons have been shown previously to successfully identify and characterise low- and high-Z materials within an air matrix using a prototype scintillating-fibre tracker system. Those studies were performed as the first in a series to assess the feasibility of this technology and image reconstruction techniques in characterising the potential high-Z contents of legacy nuclear waste containers for the UK Nuclear Industry. The present work continues the feasibility study and presents the first images reconstructed from experimental data collected using this small-scale prototype system of low- and high-Z materials encapsulated within a concrete-filled stainless-steel container. Clear discrimination is observed between the thick steel casing, the concrete matrix and the sample materials assayed. These reconstructed objects are presented and discussed in detail alongside the implications for future industrial scenarios.Comment: 6 pages, 4 figure

An ALMA Search for Substructure, Fragmentation, and Hidden Protostars in Starless Cores in Chamaeleon I

We present an Atacama Large Millimeter/submillimeter Array (ALMA) 106 GHz (Band 3) continuum survey of the complete population of dense cores in the Chamaeleon I molecular cloud. We detect a total of 24 continuum sources in 19 different target fields. All previously known Class 0 and Class I protostars in Chamaeleon I are detected, whereas all of the 56 starless cores in our sample are undetected. We show that the Spitzer+Herschel census of protostars in Chamaeleon I is complete, with the rate at which protostellar cores have been misclassified as starless cores calculated as <1/56, or < 2%. We use synthetic observations to show that starless cores collapsing following the turbulent fragmentation scenario are detectable by our ALMA observations when their central densities exceed ~10^8 cm^-3, with the exact density dependent on the viewing geometry. Bonnor-Ebert spheres, on the other hand, remain undetected to central densities at least as high as 10^10 cm^-3. Our starless core non-detections are used to infer that either the star formation rate is declining in Chamaeleon I and most of the starless cores are not collapsing, matching the findings of previous studies, or that the evolution of starless cores are more accurately described by models that develop less substructure than predicted by the turbulent fragmentation scenario, such as Bonnor-Ebert spheres. We outline future work necessary to distinguish between these two possibilities.Comment: Accepted by Ap

Centimeter to decimeter hollow concretions and voids in Gale Crater sediments, Mars

Voids and hollow spheroids between ∼1 and 23 cm in diameter occur at several locations along the traverse of the Curiosity rover in Gale crater, Mars. These hollow spherical features are significantly different from anything observed in previous landed missions. The voids appear in dark-toned, rough-textured outcrops, most notably at Point Lake (sols 302-305) and Twin Cairns Island (sol 343). Point Lake displays both voids and cemented spheroids in close proximity; other locations show one or the other form. The spheroids have 1-4 mm thick walls and appear relatively dark-toned in all cases, some with a reddish hue. Only one hollow spheroid (Winnipesaukee, sol 653) was analyzed for composition, appearing mafic (Fe-rich), in contrast to the relatively felsic host rock. The interior surface of the spheroid appears to have a similar composition to the exterior with the possible exceptions of being more hydrated and slightly depleted in Fe and K. Origins of the spheroids as Martian tektites or volcanic bombs appear unlikely due to their hollow and relatively fragile nature and the absence of in-place clearly igneous rocks. A more likely explanation to both the voids and the hollow spheroids is reaction of reduced iron with oxidizing groundwater followed by some re-precipitation as cemented rind concretions at a chemical reaction front. Although some terrestrial concretion analogs are produced from a precursor siderite or pyrite, diagenetic minerals could also be direct precipitates for other terrestrial concretions. The Gale sediments differ from terrestrial sandstones in their high initial iron content, perhaps facilitating a higher occurrence of such diagenetic reactions

CCAT-prime: Science with an Ultra-widefield Submillimeter Observatory at Cerro Chajnantor

We present the detailed science case, and brief descriptions of the telescope design, site, and first light instrument plans for a new ultra-wide field submillimeter observatory, CCAT-prime, that we are constructing at a 5600 m elevation site on Cerro Chajnantor in northern Chile. Our science goals are to study star and galaxy formation from the epoch of reionization to the present, investigate the growth of structure in the Universe, improve the precision of B-mode CMB measurements, and investigate the interstellar medium and star formation in the Galaxy and nearby galaxies through spectroscopic, polarimetric, and broadband surveys at wavelengths from 200 um to 2 mm. These goals are realized with our two first light instruments, a large field-of-view (FoV) bolometer-based imager called Prime-Cam (that has both camera and an imaging spectrometer modules), and a multi-beam submillimeter heterodyne spectrometer, CHAI. CCAT-prime will have very high surface accuracy and very low system emissivity, so that combined with its wide FoV at the unsurpassed CCAT site our telescope/instrumentation combination is ideally suited to pursue this science. The CCAT-prime telescope is being designed and built by Vertex Antennentechnik GmbH. We expect to achieve first light in the spring of 2021.Comment: Presented at SPIE Millimeter, Submillimeter, and Far-Infrared Detectors and Instrumentation for Astronomy IX, June 14th, 201

Indestructibility of Vopenka's Principle

We show that Vopenka's Principle and Vopenka cardinals are indestructible under reverse Easton forcing iterations of increasingly directed-closed partial orders, without the need for any preparatory forcing. As a consequence, we are able to prove the relative consistency of these large cardinal axioms with a variety of statements known to be independent of ZFC, such as the generalised continuum hypothesis, the existence of a definable well-order of the universe, and the existence of morasses at many cardinals.Comment: 15 pages, submitted to Israel Journal of Mathematic

The human Discs large protein (Dlg1) interacts with and maintains Connexin 43 at the plasma membrane in keratinocytes

Gap junction channels, composed of connexins, allow direct cell-to-cell communication. Connexin 43 (Cx43) is widely expressed in tissues, including the epidermis. In a previous study of human papillomavirus-positive cervical epithelial tumour cells, we identified Cx43 as a binding partner of the human homologue of Drosophila Discs large (Dlg1). Dlg1 is a member of the membrane associated-guanylate kinase (MAGUK) scaffolding protein family that is known to control cell shape and polarity. Here we show that Cx43 also interacts with Dlg1 in uninfected keratinocytes in vitro and in keratinocytes, dermal cells and adipocytes in normal human epidermis in vivo. Depletion of Dlg1 in keratinocytes did not alter Cx43 transcription but was associated with a reduction in Cx43 protein levels. Reduced Dlg1 levels in keratinocytes resulted in a reduction in Cx43 at the plasma membrane with a concomitant reduction in gap junctional intercellular communication and relocation of Cx43 to the Golgi compartment. Our data suggest a key role for Dlg1 in maintaining Cx43 at the plasma membrane in keratinocytes

Consideration of pannexin 1 channels in covid-19 pathology and treatment

Copyright © 2020 the American Physiological Society Pannexin 1 (PANX1) is a ubiquitously expressed, channel-forming protein found in a number of tissues throughout the body (e.g., lung, vasculature, liver, central nervous system, immune system) that is important in many key physiological and immune responses (18, 55). PANX1 channels passively flux ATP (predominantly), multiple metabolites, and likely other small anions (37, 39). PANX1 channels regulate inflammation and host responses to several pathogens, including viruses (36, 42, 53). While there is currently no evidence suggesting novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and PANX1 directly interact, there is an urgent need for therapeutic strategies, especially those targeting the hyperinflammation and cytokine storm that occurs in severe cases of COVID-19 (27, 41). Here we argue that PANX1, and drugs known to target PANX1 (including the FDA-approved drug probenecid), should be the focus of further investigation in the context of SARS-CoV-2 infection and its associated pathology in COVID-19 patients