Degree of Cajal-Retzius cell mislocalisation correlates with the severity of structural brain defects in mouse models of dystroglycanopathy

The secondary dystroglycanopathies are characterized by the hypoglycosylation of alpha dystroglycan, and are associated with mutations in at least 18 genes that act on the glycosylation of this cell surface receptor rather than the Dag1 gene itself. At the severe end of the disease spectrum, there are substantial structural brain defects, the most striking of which is often cobblestone lissencephaly. The aim of this study was to determine the gene‐specific aspects of the dystroglycanopathy brain phenotype through a detailed investigation of the structural brain defects present at birth in three mouse models of dystroglycanopathy—the FKRPKD, which has an 80% reduction in Fkrp transcript levels; the Pomgnt1null, which carries a deletion of exons 7–16 of the Pomgnt1 gene; and the Largemyd mouse, which carries a deletion of exons 5–7 of the Large gene. We show a rostrocaudal and mediolateral gradient in the severity of brain lesions in FKRPKD, and to a lesser extent Pomgnt1null mice. Furthermore, the mislocalization of Cajal–Retzius cells is correlated with the gradient of these lesions and the severity of the brain phenotype in these models. Overall these observations implicate gene‐specific differences in the pathogenesis of brain lesions in this group of disorders

Carbonate facies, sequences and associated diagenesis, upper cretaceous, tremp basin, Spanish pyrenees

This thesis details the results of an integrated study of carbonate platform sedimentology, geometry, evolution and diagenesis within a sequence stratigraphic framework. This study has been based on the Upper Cretaceous carbonates within the Tremp basin of the Spanish Pyrenees, which, through the effects of minor tectonic deformation during the later parts of the Pyrenean orogeny, are exceptionally well exposed and can be studied in the form of a platform to basin cross-section upon a scale that is comparable to that of a seismic section. This study concentrates on the mid-Turonian to Coniacian-aged Congest platform and its associated basinal succession, whose sedimentology and geometrical features, in particular cyclic progradational cycles, and evidence of repeated flooding and exposure of the platform-top are interpreted in terms of . fluctuations in relative sea-level and associated variations in available accommodation space. These interpretations, together with evidence of subaerial exposure in the form of karst features, intensive dissolution and the presence of speleo-cements, are used to propose a dynamic 'forced regression' model for the evolution of the Congost platform, which involves two phases of platform development, separated by a period of forced regression. The primary and secondary porosity afforded by the abundant bi-mineralic rudists within the platform-top sediments allows for a detailed and comprehensive diagenetic study of these carbonates, in the form of a case study for a number of interesting diagenetic features. In addition to standard petrography, cathodoluminescence and stable isotope studies have been employed and have allowed the identification of such features as botryoidal calcitic marine cements, neomorphism which occurred in lagoonal waters and speleo-cements. This study also provides a detailed investigation of the diagenesis associated with subaerial exposure and the development of sequence boundaries. Differences in the early diagenesis of these carbonates from different parts of the Congost platform suggest that two separate phases of platform development experienced: 1) differing pore-fluid regimes; 2) differing frequencies and duration of subaerial exposure events; and 3) different magnitudes of relative sea-level fall. These features are considered in terms of variations in accommodation space during platform development and are used to develop the dynamic 'forced regression' model for the evolution of the Congost platform. A succession of Cenomanian to Santonian-aged basinal and slope sediments which can be correlated with the contemporaneous Santa Fe, Congost and Sant Comeli platforms and contain a large amount of allochthonous debris, much of which is derived from underiying units, are described and interpreted in terms of local tectonic activity and relative sea-level change. The final part of this thesis presents a new sequence stratigraphic model for the mid-Turonian to Coniacian-aged Congost platform which is compatible with the observations and conclusions of this study. This new sequence stratigraphic model suggests that the Congost platform developed within two separate depositional sequences, albeit with one being on a much larger scale than the other. Sequence boundaries are characterised by subaerial exposure on the platform top which can be correlated with hardgrounds and/or glauconite accumulations within the more basinal locations, overlain by deeper-water facies. The presence of submarine onlap surfaces and down-slope slide deposits immediately above the sequence boundaries suggests that the major transgressive events which followed sequence boundary development were brought about by local extensional tectonic activity, while the stratigraphic cyclicity within the sequences and major falls in sea-level which produced the sequence boundaries are interpreted to have resulted largely from eustatic processes

The origin of the Narrow Line Region of Mrk 3: an overpressured jet cocoon

We have obtained HST FOC long-slit optical spectroscopy of the Narrow Line Region of the Seyfert 2 galaxy Mrk 3. In the region cospatial with the radio-jet the velocity field is highly perturbed and shows two velocity systems separated by as much as 1700 km/s. We interpret this to be the consequence of the rapid expansion of a cocoon of hot gas, shocked and heated by the radio-emitting outflow, which compresses and accelerates the ambient gas. The NLR itself is essentially a cylindrical shell expanding supersonically. From the size and velocity of the expanding region, we derive an upper limit to the radio-source age, ~ 2 E42 erg/s required to inflate the cocoon and estimate that the jet minimum advance speed is 3 E-3 pc per year. The total kinetic energy of the high velocity NLR gas can be estimated as ~6 E54 erg, comparable to the total energy carried by the jet over its lifetime and this quantitatively supports the idea that the NLR gas is accelerated by the jet. If the advance speed of Mrk 3 is representative of the Seyfert population then these sources must also be short lived and probably recurrent. The jet kinetic luminosity of Mrk 3 is between 2 and 3 orders of magnitude smaller than that derived for radio-loud AGNs with similar emission-line luminosity. On the other hand, the fraction of jet power dissipated in radio-emission is similar. We speculate that the main distinction between radio-quiet and radio-loud AGN is ascribed to a difference in jet power rather than to a different efficiency in synchrotron emission production.Comment: 13 pages, 8 figures, Astrophysical Journal in pres

Uncovering of intraspecies macular heterogeneity in cynomolgus monkeys using hybrid machine learning optical coherence tomography image segmentation

The fovea is a depression in the center of the macula and is the site of the highest visual acuity. Optical coherence tomography (OCT) has contributed considerably in elucidating the pathologic changes in the fovea and is now being considered as an accompanying imaging method in drug development, such as antivascular endothelial growth factor and its safety profiling. Because animal numbers are limited in preclinical studies and automatized image evaluation tools have not yet been routinely employed, essential reference data describing the morphologic variations in macular thickness in laboratory cynomolgus monkeys are sparse to nonexistent. A hybrid machine learning algorithm was applied for automated OCT image processing and measurements of central retina thickness and surface area values. Morphological variations and the effects of sex and geographical origin were determined. Based on our findings, the fovea parameters are specific to the geographic origin. Despite morphological similarities among cynomolgus monkeys, considerable variations in the foveolar contour, even within the same species but from different geographic origins, were found. The results of the reference database show that not only the entire retinal thickness, but also the macular subfields, should be considered when designing preclinical studies and in the interpretation of foveal data

Gridded and direct Epoch of Reionisation bispectrum estimates using the Murchison Widefield Array

We apply two methods to estimate the 21~cm bispectrum from data taken within the Epoch of Reionisation (EoR) project of the Murchison Widefield Array (MWA). Using data acquired with the Phase II compact array allows a direct bispectrum estimate to be undertaken on the multiple redundantly-spaced triangles of antenna tiles, as well as an estimate based on data gridded to the $uv$-plane. The direct and gridded bispectrum estimators are applied to 21 hours of high-band (167--197~MHz; $z$=6.2--7.5) data from the 2016 and 2017 observing seasons. Analytic predictions for the bispectrum bias and variance for point source foregrounds are derived. We compare the output of these approaches, the foreground contribution to the signal, and future prospects for measuring the bispectra with redundant and non-redundant arrays. We find that some triangle configurations yield bispectrum estimates that are consistent with the expected noise level after 10 hours, while equilateral configurations are strongly foreground-dominated. Careful choice of triangle configurations may be made to reduce foreground bias that hinders power spectrum estimators, and the 21~cm bispectrum may be accessible in less time than the 21~cm power spectrum for some wave modes, with detections in hundreds of hours.Comment: 19 pages, 10 figures, accepted for publication in PAS

Transgenic Rescue of the LARGEmyd Mouse: A LARGE Therapeutic Window?

LARGE is a glycosyltransferase involved in glycosylation of α-dystroglycan (α-DG). Absence of this protein in the LARGEmyd mouse results in α-DG hypoglycosylation, and is associated with central nervous system abnormalities and progressive muscular dystrophy. Up-regulation of LARGE has previously been proposed as a therapy for the secondary dystroglycanopathies: overexpression in cells compensates for defects in multiple dystroglycanopathy genes. Counterintuitively, LARGE overexpression in an FKRP-deficient mouse exacerbates pathology, suggesting that modulation of α-DG glycosylation requires further investigation. Here we demonstrate that transgenic expression of human LARGE (LARGE-LV5) in the LARGEmyd mouse restores α-DG glycosylation (with marked hyperglycosylation in muscle) and that this corrects both the muscle pathology and brain architecture. By quantitative analyses of LARGE transcripts we also here show that levels of transgenic and endogenous LARGE in the brains of transgenic animals are comparable, but that the transgene is markedly overexpressed in heart and particularly skeletal muscle (20–100 fold over endogenous). Our data suggest LARGE overexpression may only be deleterious under a forced regenerative context, such as that resulting from a reduction in FKRP: in the absence of such a defect we show that systemic expression of LARGE can indeed act therapeutically, and that even dramatic LARGE overexpression is well-tolerated in heart and skeletal muscle. Moreover, correction of LARGEmyd brain pathology with only moderate, near-physiological LARGE expression suggests a generous therapeutic window

The Murchison Widefield Array: the Square Kilometre Array Precursor at low radio frequencies

The Murchison Widefield Array (MWA) is one of three Square Kilometre Array Precursor telescopes and is located at the Murchison Radio-astronomy Observatory in the Murchison Shire of the mid-west of Western Australia, a location chosen for its extremely low levels of radio frequency interference. The MWA operates at low radio frequencies, 80-300 MHz, with a processed bandwidth of 30.72 MHz for both linear polarisations, and consists of 128 aperture arrays (known as tiles) distributed over a ~3 km diameter area. Novel hybrid hardware/software correlation and a real-time imaging and calibration systems comprise the MWA signal processing backend. In this paper the as-built MWA is described both at a system and sub-system level, the expected performance of the array is presented, and the science goals of the instrument are summarised.Comment: Submitted to PASA. 11 figures, 2 table