S. M. Jones

PTC124 targets genetic disorders caused by nonsense mutations

Nonsense mutations promote premature translational termination and cause anywhere from 5–70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124—a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2–8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.

Neogene overflow of Northern Component Water at the Greenland‐Scotland Ridge

In the North Atlantic Ocean, flow of North Atlantic Deep Water (NADW), and of its ancient counterpart Northern Component Water (NCW), across the Greenland-Scotland Ridge (GSR) is thought to have played an important role in ocean circulation. Over the last 60 Ma, the Iceland Plume has dynamically supported an area which encompasses the GSR. Consequently, bathymetry of the GSR has varied with time due to a combination of lithospheric plate cooling and fluctuations in the temperature and buoyancy within the underlying convecting mantle. Here, we reassess the importance of plate cooling and convective control on this northern gateway for NCW flow during the Neogene period, following Wright and Miller (1996). To tackle the problem, benthic foraminiferal isotope data sets have been assembled to examine δ13C gradients between the three major deep water masses (i.e., Northern Component Water, Southern Ocean Water, and Pacific Ocean Water). Composite records are reported on an astronomical timescale, and a nonparametric curve-fitting technique is used to produce regional estimates of δ13C for each water mass. Confidence bands were calculated, and error propagation techniques used to estimate %NCW and its uncertainty. Despite obvious reservations about using long-term variations of δ13C from disparate analyses and settings, and despite considerable uncertainties in our understanding of ancient oceanic transport pathways, the variation of NCW through time is consistent with independent estimates of the temporal variation of dynamical support associated with the Iceland Plume. Prior to 12 Ma, δ13C patterns overlap and %NCW cannot be isolated. Significant long-period variations are evident, which are consistent with previously published work. From 12 Ma, when lithospheric cooling probably caused the GSR to submerge completely, long-period δ13C patterns diverge significantly and allow reasonable %NCW estimates to be made. Our most robust result is a dramatic increase in NCW overflow between 6 and 2 Ma when dynamical support generated by the Iceland Plume was weakest. Between 6 and 12 Ma a series of variations in NCW overflow have been resolved.

V‐shaped ridges around Iceland: Implications for spatial and temporal patterns of mantle convection

[1] V-shaped lineations in the bathymetry and in the free-air gravity field surrounding Iceland result from crustal thickness variations caused by temporal variations in melt production rate at the Mid-Atlantic Ridge. We have studied the record of V-shaped ridges in the basins surrounding Iceland by plotting the shortwavelength component of the gravity field in terms of age versus distance from Iceland. The V-shaped ridge gravity signal is obscured by crustal segmentation and by sediment more than 1–2 km thick. The best V-shaped ridge record is found in the unsegmented part of the Irminger Basin, where Oligocene-Recent Vshaped ridges occur with a primary periodicity of 5–6 Myr and a secondary periodicity of 2–3 Myr. Vshaped ridge records from the Iceland Basin and from east of the Kolbeinsey Ridge to the north of Iceland correlate with the record from the Irminger Basin but are less complete. A record of uplift of the GreenlandIceland-Faroes Ridge based on paleoceanographic data is correlated with the gravity record of V-shaped ridges. There is less decisive evidence for V-shaped ridges in crust of Eocene age. The observation that Vshaped ridges propagate up to 1000 km from Iceland is compatible with a model in which the Iceland Plume head spreads out from the plume stalk below a depth of � 100 km, as suggested by geochemical arguments and studies of mantle rheology. Time-dependent flow in the plume head probably results from time-dependent flow up the plume stalk from deep below Iceland. These pulses may have triggered jumps in location of the spreading axis observed in the Icelandic geological record.

Present and past influence of the Iceland Plume on sedimentation

Abstract The Cenozoic development of the North Atlantic province has been dramatically influenced by the behaviour of the Iceland Plume, whose striking dominance is manifest by long-wavelength free-air gravity anomalies and by oceanic bathymetric anomalies. Here, we use these anomalies to estimate the amplitude and wavelength of present-day dynamic uplift associated with this plume. Maximum dynamic support in the North Atlantic is 1.5–2 km at Iceland itself. Most of Greenland is currently experiencing dynamic support of 0.5–1 km, whereas the NW European shelf is generally supported by <0.5 km. The proto-Iceland Plume had an equally dramatic effect on the Early Cenozoic palaeogeography of the North Atlantic margins, as we illustrate with a study of plume-related uplift, denudation and sedimentation on the continental shelf encompassing Britain and Ireland. We infer that during Paleocene time a hot subvertical sheet of asthenosphere welled up beneath an axis running from the Faroes through the Irish Sea towards Lundy, generating a welt of magmatic underplating of the crust which is known to exist beneath this axis. Transient and permanent uplift associated with this magmatic injection caused regional denudation, and consequently large amounts of clastic sediment have been shed into surrounding basins during Cenozoic time. Mass balance calculations indicate agreement between the volume of denuded material and the volume of Cenozoic sediments deposited offshore in the northern North Sea Basin and the Rockall Trough. The volume of material denuded from Britain and Ireland is probably insufficient to account for the sediment in the Faroe-Shetland Basin and an excess of sediment has been supplied to the Porcupine Basin. We emphasize the value of combining observations from both oceanic and continental realms to elucidate the evolution of the Iceland Plume through space and time.

Melting during late-stage rifting in Afar is hot and deep

Investigations of a variety of continental rifts and margins worldwide have revealed that a considerable volume of melt can intrude into the crust during continental breakup, modifying its composition and thermal structure. However, it is unclear whether the cause of voluminous melt production at volcanic rifts is primarily increased mantle temperature or plate thinning. Also disputed is the extent to which plate stretching or thinning is uniform or varies with depth with the entire continental lithospheric mantle potentially being removed before plate rupture. Here we show that the extensive magmatism during rifting along the southern Red Sea rift in Afar, a unique region of sub-aerial transition from continental to oceanic rifting, is driven by deep melting of hotter-than-normal asthenosphere. Petrogenetic modelling shows that melts are predominantly generated at depths greater than 80 kilometres, implying the existence of a thick upper thermo-mechanical boundary layer in a rift system approaching the point of plate rupture. Numerical modelling of rift development shows that when breakup occurs at the slow extension rates observed in Afar, the survival of a thick plate is an inevitable consequence of conductive cooling of the lithosphere, even when the underlying asthenosphere is hot. Sustained magmatic activity during rifting in Afar thus requires persistently high mantle temperatures, which would allow melting at high pressure beneath the thick plate. If extensive plate thinning does occur during breakup it must do so abruptly at a late stage, immediately before the formation of the new ocean basin.

Control of the symmetry of plume‐ridge interaction by spreading ridge geometry

The Iceland, Gal´apagos and Azores plumes have previously been identified as interacting asymmetrically with adjacent spreading centres. We present evidence that the flow fields in these plume heads are radially symmetric, but the geometry of the mid-ocean ridge systems imparts an asymmetric compositional structure on outflowing plume material. First, we quantify the degree of symmetry in geophysical and geochemical observables as a function of plume centre location. For each plume, we find that bathymetry and crustal thickness observations can be explained using a single centre of symmetry, with these calculated centres coinciding with independently inferred plume centre locations. The existence of these centres of symmetry suggests that the flow fields and temperature structure of the three plume heads are radially symmetric. However, no centres of symmetry can be found for the incompatible trace element and isotopic observations. To explain this, we develop a simple kinematic model to predict the effect of midocean ridge geometry on the chemical composition of outflowing plume material. The model assumes radially symmetric outflow from a compositionally heterogeneous plume source, consisting of a depleted mantle component and enriched blebs. These blebs progressively melt out during flow through the melting regions under spreading centres. Asymmetry in trace element and isotopic profiles develops when ridges either side of the plume centre receive material that has been variably depleted according to the length of flow path under the ridge. This model can successfully explain compositional asymmetry around Iceland and Gal´apagos in terms of an axisymmetric plume interacting with an asymmetric ridge system.

Cenozoic and Cretaceous transient uplift in the Porcupine Basin and its relationship to a mantle plume

Abstract The Mesozoic and Cenozoic history of the Porcupine Basin may be broadly summarized as a Jurassic synrift phase, followed by Cretaceous and Cenozoic post-rift subsidence. Two periods, Early Cretaceous and Early Eocene times, do not fit the simple pattern of post-rift subsidence and are characterized by increased sedimentation. We recognize distinctive sedimentological responses to the basin flanks being either exposed or submerged, and infer that transient regional uplift caused the Early Eocene event. Modelling subsidence histories of wells and of the Porcupine Bank allows quantification of the magnitude and timing of anomalous uplift and subsidence. Transient uplift of 300–600 m occurred at the Paleocene-Eocene boundary, followed by subsidence of 500–800 m after Early Eocene time, over a period with a minimum length of 25 Ma and a maximum of 55 Ma. Renewed rifting is unlikely to be responsible for the Paleogene subsidence because it cannot account for the preceding uplift, and significant normal faults of Paleogene age are absent. A Paleogene uplift-subsidence cycle has also been noted in the basins surrounding Scotland and along Hatton continental margin. One way to explain regional subsidence between Eocene time and the present is that the European plate moved off the topographic swell above the Iceland plume following continental separation between Greenland and Europe in Early Eocene time. Another possibility is that an anomalously hot layer c. 50 km thick was emplaced beneath the entire region just before the onset of sea-floor spreading in Early Eocene time and was then dissipated by convection following continental separation. A Cretaceous transient uplift-subsidence cycle that shares many similarities with the Paleogene cycle is also recognized. Immediately following Late Jurassic rifting, 200–700 m transient uplift occurred in Early Cretaceous time, followed by 0–500 m subsidence coeval with the onset of sea-floor spreading at the Goban Spur margin. The Cretaceous uplift-subsidence cycle might also be caused by anomalously hot mantle.

Palaeocene uplift and subsidence events in the Scotland–Shetland and North Sea region and their relationship to the Iceland Plume

This paper documents stratigraphic evidence for Palaeocene uplift and subsidence events in the Scotland–Shetland and North Sea region, and considers whether these were generated by the initiating Iceland Plume. The Palaeocene succession in the North Sea contains two types of stratigraphic surface. The high-gamma mudstone represents a maximum flooding event associated with marine transgression. The unconformity surface is overlain by sandstone, reworked chalk or tuff, and represents submarine or subaerial erosion and missing section. Biostratigraphic dating allows these surfaces to be correlated throughout the basin, where they occur within a suite of shelf, slope and basinal sedimentary rocks. At least 14 short duration (0.1–0.3 Ma), unconformity–maximum flooding couplets are recognized within the Danian to lowest Ypresian interval, which lasted from 65 to 54 Ma. These uplift–subsidence cycles may have been caused by episodic plume-related magmatic injection near the Moho and associated fluctuations in dynamic support. Alternatively, the short-term cycles may reflect a eustatic control. Regional mapping of the 14 events is required to confirm the relative importance of plume-related and eustatic events.

Shape and size of the starting Iceland plume swell

Abstract Emplacement of a large igneous province is usually accompanied by kilometre-scale uplift over an area of ∼10 6 km 2 . We have developed a method for mapping the dynamically supported swell associated with the North Atlantic Igneous Province by inverting palaeo-topographic information from continental margins. In the forward model, latest Palaeocene palaeo-topography around Britain and Ireland is calculated by correcting present-day topography for global sea-level change, denudation and dynamic support. We initially assume a Gaussian, axially symmetric dynamic support profile. Modelled coastlines are compared with palaeo-coastlines mapped on 2D and 3D reflection seismic data. In the inverse model, the amplitude, width and centre of the dynamically supported swell are determined by minimising misfit between modelled and observed coastlines. Uncertainties associated with global sea-level variation and denudation have little effect on this calculation. The best-fit dynamic support profile from inverting palaeo-coastline positions is in good agreement with dynamic support estimates from subsidence anomalies measured in extensional sedimentary basins fringing Britain and Ireland. However, a circular planform of dynamic support cannot simultaneously account for palaeo-coastlines, subsidence anomalies and the spatial extent of the North Atlantic Igneous Province. In combination, these data suggest that the swell was more irregular in planform. This inference can be tested in future by modelling stratigraphic data from offshore Norway, Greenland and Canada. The large areal extent and short time interval for inflation of the dynamically supported swell are best explained by rapid convective emplacement of an abnormally hot mantle layer horizontally beneath the lithosphere, during the starting phase of the Icelandic convective system. We emphasise the need to interpret the igneous record jointly with the dynamic support history when discussing models of large igneous province formation and mantle convection.

Comparison of modern and geological observations of dynamic support from mantle convection

The topographies of Africa and Antarctica form patterns of interlocking swells. The relationship between topography and gravity indicates that these swells are dynamically supported by mantle convection, with swell diameters of 1850 ± 450 km and full heights between 800 and 1800 m. The implication is that mantle convection not only supports swells surrounding hotspots but also influences topography across the entire surface areas of Africa and Antarctica. We investigate whether dynamically supported swells are also observed throughout the geological record, focusing on intensively studied Mesozoic–Cenozoic sedimentary rocks around Britain and Ireland. Vertical motions of Britain and Ireland, a typical piece of continental lithosphere far from a destructive plate boundary, have been demonstrably affected by dynamic support for over half of the past 200 Ma period. The diameters and maximum heights of the Mesozoic British swells and the modern African and Antarctic swells are similar. The ancient British swells grew in 5–10 Ma and decayed over 20–30 Ma, suggesting vertical motion rates comparable with those estimated from geomorphological studies of Africa. Igneous production rate and swell height are not correlated in the modern and the geological records. Mantle convection should be considered as a common control on regional sea level.