Sequence Stratigraphy and Evolution of a Basin-Slope Succession: The Late Proterozoic Wonoka Formation, Flinders Ranges, South Australia

A shelf to basin‐slope transition is vertically and laterally exposed within the Late Proterozoic Wonoka Formation in the northern Flinders Ranges of South Australia. The shelf to basin‐slope transition can be divided into four units (C to F) which are defined on the basis of facies, sedimentary structures, contacts, stratal geometry, and the type and abundance of down‐slope mass movement. The lowest unit (C) is mudstone dominated and parallel laminated with rare synsedimentary slides. Unit D, a thin, resedimented siliciclastic‐carbonate unit deposited on a sequence boundary at the end of unit C progradation, displays a lateral facies change from well bedded ‘outer shelf deposits in the east to basin‐slope debris flows in the west. Unit E forms a shallowing and coarsening upward succession from ‘outer shelf siltstone to ‘inner shelf storm wave influenced sandstone deposits. The unit thickens westwards, in the interpreted down‐slope direction, where it becomes finer grained and thinner bedded and displays an increasing abundance of synsedimentary slides. Unit F, deposited on an inferred shelf to basin‐slope transition, coarsens and shallows upward, thickens to the west and contains the highest percentage of sandstone and synsedimentary slides. Unit G, deposited at shelf depths, also shallows and coarsens upward from a thin, basal carbonate‐siliciclastic member, with sandstone increasing upsection to a gradational contact with the Pound Subgroup. Three sequences can be defined within this transition on the basis of facies, stratal terminations, and facies discontinuities at inferred sequence boundaries. Each sequence is marked by a transgressive base, overlain by a shallowing‐upward succession. On the inferred shelf and near the shelfbreak, toward the top of the succession, facies discontinuities at sequence boundaries are more obvious, with distinct contrasts in lithology and inferred palaeoenvironments; farther down‐slope and stratigraphically lower in the succession, the boundaries are cryptic, and only lateral tracing of the contacts from the shelf to the slope or the observation of stratal terminations permits them to be recognized

Working Hypotheses for the Origin of the Wonoka Canyons (Neoproterozoic), South Australia

Recent attempts to apply concepts of sequence stratigraphy to the Neoproterozoic Wilpena Group of the Adelaide "geosyncline" in South Australia have provided an important new method for improving the resolution of intrabasinal correlation in sparsely fossiliferous and unfossiliferous strata. Eight regional unconformities are now recognized within or bounding the Wilpena Group. The most prominent of these, at or near the base of the Wonoka Formation, is expressed by a series of spectacular incised valleys or canyons, some more than 1 km deep and dated as approx 630 to 580 Ma. The canyons developed following an interval of continental rifting that took place between about 800 and 700 Ma and prior to a second phase of accelerated subsidence of uncertain origin in Early Cambrian time (after about 560 Ma). Subsidence during the intervening span of more than 140 my was in part of thermal origin and in part due to the withdrawal of buried salt at depth, but it may also have involved additional extension for which little direct structural evidence is preserved. The canyons are incised into a succession of shallow marine mainly terrigenous strata that accumulated in a broad north- and east-facing ramp. They are exposed in two distinct belts within and east of the Flinders Ranges, in an area that is about 275 km in a north-south direction and about 175 km east-west. The canyons are inferred to have been filled by shallow marine sediments primarily on the basis of sedimentary structures interpreted as combined flow and oscillation ripples and hummocky cross-stratification. If this is correct, development of the canyons was related to regional lowering of depositional base level by more than 1 km. Recent work also indicates a second phase of valley incision at an unconformity immediately above the main canyons and involving a relative sealevel fall of at least 200 m. Two working hypotheses are advanced to account for the origin of the Wonoka canyons: regional uplift and an evaporitic lowering of sealevel in an isolated basin, analogous to the Messinian event in the Mediterranean. Any regional uplift would likely have been of tectonic origin. Diapirism associated with buried salt cannot account for the wide distribution of erosion or for pronounced uplift in an extensional setting lacking evidence for basin inversion or compressional deformation coeval with sedimentation. One possible mechanism for tectonic uplift involves inhomogeneous extension of the lithosphere, with the amount of extension balanced at all levels on a regional scale possibly by means of detachment faults. Possible difficulties with this hypothesis are the requirement of relatively uniform uplift over distances of hundreds of kilometers and the fact that repeated large-scale lowering of base level implies oscillatory vertical motions that are not readily explained. An evaporitic drawdown accounts for the wide distribution and scale of the canyons and for repeated lowering of base level. Possible difficulties in this case are the presence within the canyon fill of facies that have been interpreted to be of tidal origin; the fact that unlike the Messinian crisis in the Mediterranean, the Wonoka canyons do not appear to have been drowned rapidly; and the lack of direct evidence for evaporities of appropriate age. Neither hypothesis accounts for the apparent absence of appreciable meteoric diagenesis in areas far removea from sites of canyon incision. Two additional conclusions are as follows. First, neither of the hypotheses precludes eustasy as an important control on sedimentation. Sequence stratigraphic comparisons with other basins of the same general age should focus primarily on the time of formation of sequence boundaries not on the geometry of the boundaries or the facies involved. Second, a drawdown in excess of 1 km implies that the adjacent basin was originally at least this deep and hence likely underlain at least locally by highly attenuated continental crust or oceanic crust. Either hypothesis therefore has important implications for the tectonic development of the Adelaide geosyncline

Late Proterozoic Patsy Springs Canyon, Adelaide Geosyncline: Submarine or Subaerial Origin?

A significant aspect of Late Proterozoic sedimentation in the Adelaide Geosyncline, South Australia, is the presence of kilometre-deep erosional incisions which have been termed canyons. These structures were formerly described to be of submarine origin, cut and filled in an inferred basin-slope setting by subaqueous processes. Subsequent detailed research, particularly on a specific incision known as Patsy Springs Canyon, indicates that sedimentary structures within some of the canyon-filling sediments are indicative of deposition above fair weather wave base. In addition, an unusual carbonate unit, which is observed to veneer upper portions of canyon shoulders and to contribute to carbonate breccias interbedded with canyon-fill, has a stable isotope signature which may imply a non-marine origin. The presence of the carbonate veneer, where it is in situ, suggests that at least upper portions of the canyons could have been emergent during the canyon-filling phase. Considering these observations, and combining them with regional stratigraphical relationships, an alternative model for canyon genesis is proposed involving subaerial erosion and subsequent filling by coastal onlap. Such a model requires base-level changes of the order of 1 km, in order to account for observed canyon cutting and filling. Vertical movements associated with halokinesis, or thermally-induced uplift of the order of 1 km, could have resulted in the observed erosional events. Alternatively, a Messinian-style evaporitic lowering of base-level is currently receiving serious attention. With present knowledge this mechanism most satisfactorily explains all observations

How the Cathedral Embraced the Bazaar, and the Bazaar Became a Cathedral

Peer reviewe

Renal Denervation Update From the International Sympathetic Nervous System Summit:JACC State-of-the-Art Review

Three recent renal denervation studies in both drug-naïve and drug-treated hypertensive patients demonstrated a significant reduction of ambulatory blood pressure compared with respective sham control groups. Improved trial design, selection of relevant patient cohorts, and optimized interventional procedures have likely contributed to these positive findings. However, substantial variability in the blood pressure response to renal denervation can still be observed and remains a challenging and important problem. The International Sympathetic Nervous System Summit was convened to bring together experts in both experimental and clinical medicine to discuss the current evidence base, novel developments in our understanding of neural interplay, procedural aspects, monitoring of technical success, and others. Identification of relevant trends in the field and initiation of tailored and combined experimental and clinical research efforts will help to address remaining questions and provide much-needed evidence to guide clinical use of renal denervation for hypertension treatment and other potential indications

Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains

This is the author accepted manuscript. The final version is available from American Chemical Society via the DOI in this recordBromodomains have been pursued intensively over the past several years as emerging targets for the devel-opment of anti-cancer and anti-inflammatory agents. It has recently been shown that some kinase inhibitors are able to potently inhibit the bromodomains of BRD4. The clinical activities of PLK inhibitor BI-2536 and JAK2-FLT3 inhibitor TG101348 have been attributed to this unexpected poly-pharmacology, indicating that dual-kinase/bromodomain activity may be advantageous in a therapeutic context. However, for target validation and biological investigation, a more selec-tive target profile is desired. Here we report that benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones, versatile ATP-site di-rected kinase pharmacophores utilized in the development of inhibitors of multiple kinases including a number of previ-ously reported kinase chemical probes, are also capable of exhibiting potent BRD4-dependent pharmacology. Using a dual kinase-bromodomain inhibitor of the kinase domains of ERK5 and LRRK2, and the bromodomain of BRD4 as a case study, we define the structure-activity relationships required to achieve dual kinase/BRD4 activity as well as how to di-rect selectivity towards inhibition of either ERK5 or BRD4. This effort resulted in identification of one of the first report-ed kinase-selective chemical probes for ERK5 (JWG-071), a BET selective inhibitor with 1 μM BRD4 IC50 (JWG-115), and additional inhibitors with rationally designed polypharmacology (JWG-047, JWG-069). Co-crystallography of seven representative inhibitors with the first bromodomain of BRD4 demonstrate that distinct atropisomeric conformers rec-ognize the kinase ATP-site and the BRD4 acetyl lysine binding site, conformational preferences supported by rigid dock-ing studies.This work was supported by NIH (Grant No. U54HL127365, to N.S.G. and J.W.; No. NIH P50 GM107618, to X.X. and S.C.B.; Nos. NIH U54 HD093540 and P01 CA066996, to J.Q.), the Medical Research Council (No. MC_UU_12016/2, to D.R.A.), the Spanish Ministerio de Economia y Competitividad (MINECO) (Grant No. SAF2015-60268R, to J.M.L.), and Fondo Europeo de Desarrollo Regional (FEDER) funds (to J.M.L.). D.L.B. was supported as a Merck Fellow of Damon Runyon Cancer Research Foundation (No. DRG-2196-14)

Sympatho-renal axis in chronic disease

Essential hypertension, insulin resistance, heart failure, congestion, diuretic resistance, and functional renal disease are all characterized by excessive central sympathetic drive. The contribution of the kidney’s somatic afferent nerves, as an underlying cause of elevated central sympathetic drive, and the consequences of excessive efferent sympathetic signals to the kidney itself, as well as other organs, identify the renal sympathetic nerves as a uniquely logical therapeutic target for diseases linked by excessive central sympathetic drive. Clinical studies of renal denervation in patients with resistant hypertension using an endovascular radiofrequency ablation methodology have exposed the sympathetic link between these conditions. Renal denervation could be expected to simultaneously affect blood pressure, insulin resistance, sleep disorders, congestion in heart failure, cardiorenal syndrome and diuretic resistance. The striking epidemiologic evidence for coexistence of these disorders suggests common causal pathways. Chronic activation of the sympathetic nervous system has been associated with components of the metabolic syndrome, such as blood pressure elevation, obesity, dyslipidemia, and impaired fasting glucose with hyperinsulinemia. Over 50% of patients with essential hypertension are hyperinsulinemic, regardless of whether they are untreated or in a stable program of treatment. Insulin resistance is related to sympathetic drive via a bidirectional mechanism. In this manuscript, we review the data that suggests that selective impairment of renal somatic afferent and sympathetic efferent nerves in patients with resistant hypertension both reduces markers of central sympathetic drive and favorably impacts diseases linked through central sympathetics—insulin resistance, heart failure, congestion, diuretic resistance, and cardiorenal disorders