Enhancer Promoter Interactome and Mendelian Randomization Identify Network of Druggable Vascular Genes in Coronary Artery Disease

Coronary artery disease (CAD) is a multifactorial disorder, which is partly heritable. Herein, we implemented a mapping of CAD-associated candidate genes by using genome-wide enhancer-promoter conformation (H3K27ac-HiChIP) and expression quantitative trait loci (eQTL). Enhancer-promoter anchor loops from human coronary artery smooth muscle cells (HCASMC) explained 22% of the heritability for CAD. 3D enhancer-promoter genome mapping of CAD-genes in HCASMC was enriched in vascular eQTL genes. By using colocalization and Mendelian randomization analyses, we identified 58 causal candidate vascular genes including some druggable targets (MAP3K11, CAMK1D, PDGFD, IPO9 and CETP). A network analysis of causal candidate genes was enriched in TGF beta and MAPK pathways. The pharmacologic inhibition of causal candidate gene MAP3K11 in vascular SMC reduced the expression of athero-relevant genes and lowered cell migration, a cardinal process in CAD. Genes connected to enhancers are enriched in vascular eQTL and druggable genes causally associated with CAD.

Centrifuge Experiments of the Initiation of Self-Sustaining Subduction

<p>The post-Triassic age of all oceanic lithospheres indicates the efficiency and the sustainability of lithospheric subduction, which consumes the basaltic seafloor and recirculates it in the upper mantle. Since at present the initiation of subduction is very rare, comprehension of this cardinal process should be carried through modeling – numeric or analog. While deciphering processes through numeric modeling is commonly comprehensive, the analog models can determine major factor that constrain a tectonic procedure. Analog centrifuge experiments were applied to initiate self-sustained modelled subduction, trying to determine the critical factors that trigger its early stages.</p><p>Analytically we presumed that where densities of two lithospheric plates, juxtaposed across a weakness zone, exceed a critical value, then the denser lithosphere eventually will drive underneath the lighter one, provided the friction across the interface is not too high. Consequently, analog experiments were carried out in a centrifuge at acceleration of ca. 1000 g., deforming miniaturized models of three layers representing the asthenosphere, the ductile and the brittle lithosphere. The lithospheres were modeled to include lighter and denser components, juxtaposed along a slightly lubricated contact plane, where the density difference between these components was ca. 200 kg/m<sup>3</sup>. No mechanism of lateral force was applied in the experiment (even though such a vector exists in nature due to the seafloor spreading at the oceanic ridges), to test the possibility of subduction in domains where such a force is minor or non-existent.</p><p>The analog experiments showed that the penetration of the denser modeled lithosphere under the lighter one led to extension and subsequent break-up of the over-riding plate. That break-up generated seawards trench rollback, normal faulting, rifting, and formed proto-back-arc basins. Lateral differential reduction of the friction between the juxtaposed plates led to the development of arcuate subduction zones. The experimental miniaturization, and subsequent numerical and analytical modeling, suggest that the observed deformation in the analog models could be meaningful to the planet as well.</p><p>Constraints of the analog experimentation setting did not enable the modeling of the subduction beyond the initial stages, but there is ground to presume that at depths of 40-50 km, metamorphic processes of the generation of eclogites would change the initial mineralogy on the subducting plate. Reactions with water would convert basalts into metamorphic serpentinites and schists. Higher temperatures and pressures would melt parts of the subducted slab to generate felsic magmas, which would ascend towards the surface diapirically due to their lighter density. Alternately, low availability of H<sub>2</sub>O would gradually alter the oceanic basalt and gabbro into eclogite, which would sink into the mantle due to its increased density.</p>

Palaeobiology of Silurian Leptaeninae (Brachiopoda) from Gotland, Sweden

Leptaenine brachiopods are common and widespread on Gotland. Lepidoleptaena poulseni and Leptaena rhomboidalis retained a functional apical pedicle throughout ontogeny, and both had strong adductor muscles and robust ornamentation, allowing them to occupy shallow water and high energy environments. A pedicle-shortening muscle is present within the pedicle tube of Leptaena rhomboidalis. Leptaena sperion, L. depressa visbyensis, and L. depressa lata inhabited low energy environments, retaining very slender pedicles. L. depressa depressa and L. parvorugata atrophied the pedicle early and then lived ambitopically in deeper water. The presence or absence of the apical pedicle strongly influenced the cardinal process morphology. Leptaenine shells had a small gape. The lophophore was simple, similar to productids and Leptaenoidea. In closed valves, the inner epithelium of leptaenine trails remained exposed to the sea. This was probably important in gas exchange. The life position of pedically attached species was with the disc vertical. Some ambitopic specimens may have retained a similar attitude. Shells of L. depressa depressa and Lepidoleptaena poulseni commonly are encrusted by epibionts, apparently without problems for larger shells. Small shells are shown to have been killed by bryozoan epizoans. Repaired shell damage is rare on the disc but is common along the commisure.

Evolution of the Late Ordovician plaesiomyid brachiopod lineage in Laurentia

Multivariate analysis of 197 well-preserved specimens among 11 species of late Late Ordovician (Katian and Hirnantian) plaesiomyid brachiopods from North America revealed two trends of morphological changes: (1) increasing globosity and dorsal convexity from the early to late Katian, and (2) coarser, but fewer ribs in species from the paleoequatorial intracratonic seas compared with species from the mid- to high-tropical pericratonic shelves and platforms. Another notable change, albeit not quantified, was the enlargement of cardinal process in plaesiomyids from early to late Katian, characterized by a predominantly trilobed cardinal process in the intracratonic species versus a bilobed cardinal process in pericratonic species. Increases in dorsal convexity and shell globosity are interpreted to have allowed for development of a larger lophophore, improving the capacity and efficiency of filter feeding and gas exchange. Smaller but more frequently bifurcating ribs would have led to more numerous setae near the margin of the shell, resulting in increased sensitivity to environmental stimuli. Increased size and number of lobes of the cardinal process would have allowed for larger diductor muscles to open a larger, heavier shell. In this study, two new species, Plaesiomys periosa sp. nov. and Plaesiomys lenzi sp. nov., are proposed, and two existing species are transferred from Dinorthis to Plaesiomys.

Chathamirhynchia kahuitara, a new genus and species of Late Cretaceous rhynchonellide brachiopod from the Chatham Islands, New Zealand: shell structure, palaeoecology and biogeography

ABSTRACTA new rhynchonellide brachiopod has been collected from the Kahuitara Tuff (Campanian–Maastrichtian) of Pitt Island, Chatham Islands, New Zealand. Brachiopods are extremely rare in Cretaceous rocks from New Zealand, and this new genus and species is unlike any other rhynchonellide known from Australasia or elsewhere. Chathamirhynchia kahuitara is distinguished by its small size, strong ribbing, and well-developed sulciplicate folding, and internally by a large, robust cardinal process and raduliform crura. The shell structure of C. kahuitara is shown to be of typical fine fibrous ‘rhynchonellidine’ type. This brachiopod was probably strongly attached to volcanic rock or shells in a shallow-water, high-energy environment. Implications for the biogeography of brachiopods during the Late Cretaceous are briefly discussed.

Loop ultrastructure and development in Recent Megathiridoidea, with description of a new genus, Joania (type species Terebratula cordata Risso, 1826)

ABSTRACTThe loop configuration, structure and growth are studied in a series of megathiridoid dorsal valves ranging in length from 0·7 to 6 mm. The structure of the posterior and anterior sectors of the descending lamellae and their relationships with the socket ridges, dorsal septa and dorsal valve floor, are studied, illustrated and described. Detailed studies show that internal structures display great variability. In the megathiridoids the lamellae of more typical terebratulide loops are replaced by partially developed loops in early developmental stages, resulting in a mix of free sections of loop together with sections where the lophophore rests directly on the epithelium of the valve floor. Comments on the ecology of the megathiridoid species are included and relate their unusually wide gapes, which position their lophophores fully accessible to the open sea, with their strong lophophore attachments and loss of typical free loops. The new genus Joania (type species Terebratula cordata Risso, 1826) is erected for those Argyrotheca which, although having a typical megathiridoid brachidium, differ in their adult crural development, their narrow hinge line, their prominent cardinal process, their characteristic dorsal median septum and their tuberculate radial ridges terminating anteriorly in tubercles.

Evaluating internal versus external characters: Phylogenetic analyses of the Echinoconchidae, Buxtoniinae, and Juresaniinae (phylum Brachiopoda)

Evolutionary relationships between the Echinoconchidae, Productidae, Buxtoniinae, and Juresaniinae (Phylum Brachiopoda, Order Productida) have been the subject of debate for the better part of a century. The original (Muir-Wood and Williams, 1965) and revised (Brunton et al., 2000) Brachiopoda volumes of the Treatise on Invertebrate Paleontology use markedly different classifications and emphasize different characters. The 1965 Treatise classification for these taxa primarily was based on internal features, especially the cardinal process; the revised Treatise (2000) relied on external ornament and shell shape. Multiple phylogenetic analyses (global parsimony, stratocladistics, nearest-neighbor) of 14 genera, representing all of the relevant subfamilies and outgroups, are in strong agreement that 1) the subfamily Buxtoniinae belongs in the family Echinoconchidae, not to the Productidae; 2) the subfamily Juresaniinae is more closely related to the Echinoconchinae than to the Buxtoniinae; and 3) that internal characters, such as a shafted cardinal process and anterio-medial position of the brachial valve adductor field, provide the best phylogenetic signal, and are synapomorphic for the Echinoconchidae. Jackknifing and Bremer Support corroborate these results.

Hinge modifications and musculature of strophomenoid brachiopods: examples across the Ordovician-Silurian boundary, Anticosti Island, Quebec

Six modifications to the hinge occur in strophomenoid brachiopods from Anticosti Island: (1) overhanging socket ridges; (2) posterolateral socket ridges along the interarea articulate with grooves on the posterior of teeth; (3) anteromedian dental notches articulate with the crests of socket ridges; (4) dental crenulations on the surfaces of teeth mesh with socket ridges; (5) denticles extend laterally to the cardinal extremities; and (6) the margin of the ventral interarea fits into a long socket along the dorsal interarea forming a lateral tooth. Denticulate hinges and dental notches that typify Silurian and Devonian strophomenids begin in the fauna of the Ellis Bay Formation. Thus the most important interval of strophomenid faunal turnover was at the base of the Gamachian (the base of the Hirnantian) and not at the Ordovician–Silurian boundary. Muscle attachment pads in the delthyrial cavity do not correspond to the positions of either the adductor or diductor muscle scars. Pedicle adjustor muscles in modern brachiopods occupy this position. The round gap between the median fold of the pseudodeltidium and groove on chilidium is proposed as the point of emergence of the pedicle muscle. The tiny foramen, commonly sealed early in growth, is suggested to be part of a neanic water-intake system, active before the growth of the cardinal process in ephebic shells. Once the cardinal process appeared, the foramen was blocked. Recurring types of strophomenid ornamentation, such as posteriorly steepened rugae and checkerboard ornamentation, may have served as a plow to redistribute sediment as the shell was pulled backwards along the pedicle.