Modelling autosomal dominant optic atrophy associated with OPA1 variants in iPSC-derived retinal ganglion cells

Autosomal dominant optic atrophy (DOA) is the most common inherited optic neuropathy, characterised by the preferential loss of retinal ganglion cells (RGCs), resulting in optic nerve degeneration and progressive bilateral central vision loss. Over 60% of genetically confirmed DOA patients carry variants in the nuclear OPA1 gene, which encodes for a ubiquitously expressed, mitochondrial GTPase protein. OPA1 has diverse functions within the mitochondrial network, facilitating inner membrane fusion and cristae modelling, regulating mitochondrial DNA maintenance and coordinating mitochondrial bioenergetics. There are currently no licensed disease-modifying therapies for DOA and the disease mechanisms driving RGC degeneration are poorly understood. Here, we describe the generation of isogenic, heterozygous OPA1 null iPSC (OPA1+/-) through CRISPR/Cas9 gene editing of a control cell line, in conjunction with the generation of DOA patient-derived iPSC carrying OPA1 variants, namely, the c.2708_2711delTTAG variant (DOA iPSC), and previously reported missense variant iPSC line (c.1334G>A, DOA+ iPSC) and CRISPR/Cas9 corrected controls. A two-dimensional (2D) differentiation protocol was used to study the effect of OPA1 variants on iPSC-RGC differentiation and mitochondrial function. OPA1+/-, DOA and DOA+ iPSC showed no differentiation deficit compared to control iPSC lines, exhibiting comparable expression of all relevant markers at each stage of differentiation. OPA1+/- and OPA1 variant iPSC-RGCs exhibited impaired mitochondrial homeostasis, with reduced bioenergetic output and compromised mitochondrial DNA maintenance. These data highlight mitochondrial deficits associated with OPA1 dysfunction in human iPSC-RGCs, and establish a platform to study disease mechanisms that contribute to RGC loss in DOA, as well as potential therapeutic interventions

Beam Dynamics and First Operation of the Sub-Harmonic Bunching System in the CTF3 Injector

The CLIC Test Facility 3 (CTF3), built at CERN by an international collaboration, aims at demonstrating the feasibility of the CLIC scheme by 2010. The CTF3 drive beam generation scheme relies on the use of a fast phase switch of a sub-harmonic bunching system in order to phase-code the bunches. The amount of charge in unwanted satellite bunches is an important quantity, which must be minimized. Beam dynamic simulations have been used to study the problem, showing the limitation of the present CTF3 design and the gain of potential upgrades. In this paper the results are discussed and compared with beam measurements taken during the first operation of the system

The Future of Our Seas: Marine scientists and creative professionals collaborate for science communication

To increase awareness of the current challenges facing the marine environment, the Future of Our Seas (FOOS) project brought together the expertise of scientists, public engagement experts and creatives to train and support a group of marine scientists in effective science communication and innovative public engagement. This case study aims to inspire scientists and artists to use the FOOS approach in training, activity design and development support (hereafter called the ‘FOOS programme’) to collaboratively deliver novel and creative engagement activities. The authors reflect on the experiences of the marine scientists: (1) attending the FOOS communication and engagement training; (2) creating and delivering public engagement activities; (3) understanding our audience; and (4) collaborating with artists. The authors also share what the artists and audiences learned from participating in the FOOS public engagement activities. These different perspectives provide new insights for the field with respect to designing collaborative training which maximizes the impact of the training on participants, creative collaborators and the public. Long-term benefits of taking part in the FOOS programme, such as initiating future collaborative engagement activities and positively impacting the scientists’ research processes, are also highlighted

Postoperative peri-axillary seroma following axillary artery cannulation for surgical treatment of acute type A aortic dissection

The arterial cannulation site for optimal tissue perfusion and cerebral protection during cardiopulmonary bypass (CPB) for surgical treatment of acute type A aortic dissection remains controversial. Right axillary artery cannulation confers significant advantages, because it provides antegrade arterial perfusion during cardiopulmonary bypass, and allows continuous antegrade cerebral perfusion during hypothermic circulatory arrest, thereby minimizing global cerebral ischemia. However, right axillary artery cannulation has been associated with serious complications, including problems with systemic perfusion during cardiopulmonary bypass, problems with postoperative patency of the artery due to stenosis, thrombosis or dissection, and brachial plexus injury. We herein present the case of a 36-year-old Caucasian man with known Marfan syndrome and acute type A aortic dissection, who had direct right axillary artery cannulation for surgery of the ascending aorta. Postoperatively, the patient developed an axillary perigraft seroma. As this complication has, not, to our knowledge, been reported before in cardiothoracic surgery, we describe this unusual complication and discuss conservative and surgical treatment options

Dynamic liquefaction of shear zones in intact loess during simulated earthquake loading

The 2010-2011 Canterbury earthquake sequence in New Zealand exposed loess-mantled slopes in the area to very high levels of seismic excitation (locally measured as >2 g). Few loess slopes showed permanent local downslope deformation, and most of these showed only limited accumulated displacement. A series of innovative dynamic back pressured shear-box tests were undertaken on intact and remoulded loess samples collected from one of the recently active slopes replicating field conditions under different simplified horizontal seismic excitations. During each test, the strength reduction and excess pore water pressures generated were measured as the sample failed. Test results suggest that although dynamic liquefaction could have occurred, a key factor was likely to have been that the loess was largely unsaturated at the times of the large earthquake events. The failure of intact loess samples in the tests was complex and variable due to the highly variable geotechnical characteristics of the material. Some loess samples failed rapidly as a result of dynamic liquefaction as seismic excitation generated an increase in pore-water pressure, triggering rapid loss of strength and thus of shear resistance. Following initial failure, pore pressure dissipated with continued seismic excitation and the sample consolidated, resulting in partial shear-strength recovery. Once excess pore-water pressures had dissipated, deformation continued in a critical effective stress state with no further change in volume. Remoulded and weaker samples, however, did not liquefy, and instead immediately reduced in volume with an accompanying slower and more sustained increase in pore pressure as the sample consolidated. Thereafter excess pressures dissipated and deformation continued at a critical state. The complex behaviour explained why, despite exceptionally strong ground shaking, there was only limited displacement and lack of run-out: dynamic liquefaction was unlikely to occur in the freely draining slopes. Dynamic liquefaction however remained a plausible mechanism to explain loess failure in some of the low-angle toe slopes, where a permanent water table was present in the loess

Persistent elastic behavior above a megathrust rupture patch: Nias island, West Sumatra

We quantify fore-arc deformation using fossil reefs to test the assumption commonly made in seismic cycle models that anelastic deformation of the fore arc is negligible. Elevated coral microatolls, paleoreef flats, and chenier plains show that the Sumatran outer arc island of Nias has experienced a complex pattern of relatively slow long-term uplift and subsidence during the Holocene epoch. This same island rose up to 2.9 m during the Mw 8.7 Sunda megathrust rupture in 2005. The mismatch between the 2005 and Holocene uplift patterns, along with the overall low rates of Holocene deformation, reflects the dominance of elastic strain accumulation and release along this section of the Sunda outer arc high and the relatively subordinate role of upper plate deformation in accommodating long-term plate convergence. The fraction of 2005 uplift that will be retained permanently is generally <4% for sites that experienced more than 0.25 m of coseismic uplift. Average uplift rates since the mid-Holocene range from 1.5 to −0.2 mm/a and are highest on the eastern coast of Nias, where coseismic uplift was nearly zero in 2005. The pattern of long-term uplift and subsidence is consistent with slow deformation of Nias along closely spaced folds in the north and trenchward dipping back thrusts in the southeast. Low Holocene tectonic uplift rates provide for excellent geomorphic and stratigraphic preservation of the mid-Holocene relative sea level high, which was under way by ∼7.3 ka and persisted until ∼2 ka

A High-Gradient Test of a 30 GHz Molybdenum-Iris Structure

The CLIC study is actively investigating a number of different materials in an effort to find ways to increase achievable accelerating gradient. So far a series of rf tests have been made with a set of identical-geometry structures: a W-iris 30 GHz structure, a Mo-iris 30 GHz structure (with pulses as long as 16 ns) and a scaled Mo-iris X-band structure. A second Mo-iris 30 GHz structure of the same geometry has now been tested in CTF3 with pulse lengths up to 350 ns. The structure was conditioned to a gradient of 140 MV/m with a 70 ns pulse length and a breakdown rate slope of 13 MV/m per decade has been measure

Complex rupture during the 12 January 2010 Haiti earthquake

Initially, the devastating M_w 7.0, 12 January 2010 Haiti earthquake seemed to involve straightforward accommodation of oblique relative motion between the Caribbean and North American plates along the Enriquillo–Plantain Garden fault zone. Here, we combine seismological observations, geologic field data and space geodetic measurements to show that, instead, the rupture process involved slip on multiple faults. Primary surface deformation was driven by rupture on blind thrust faults with only minor, deep, lateral slip along or near the main Enriquillo–Plantain Garden fault zone; thus the event only partially relieved centuries of accumulated left-lateral strain on a small part of the plate-boundary system. Together with the predominance of shallow off-fault thrusting, the lack of surface deformation implies that remaining shallowshear strain will be released in future surface-rupturing earthquakes on the Enriquillo–Plantain Garden fault zone, as occurred in inferred Holocene and probable historic events. We suggest that the geological signature of this earthquake—broad warping and coastal deformation rather than surface rupture along the main fault zone—will not be easily recognized by standard palaeoseismic studies. We conclude that similarly complex earthquakes in tectonic environments that accommodate both translation and convergence—such as the San Andreas fault through the Transverse Ranges of California—may be missing from the prehistoric earthquake record

CTF3 Design Report: Preliminary Phase

The design of CLIC is based on a two-beam scheme, where the short pulses of high power 30 GHz RF are extracted from a drive beam running parallel to the main beam. The 3rd generation CLIC Test Facility (CTF3) will demonstrate the generation of the drive beam with the appropriate time structure, the extraction of 30 GHz RF power from this beam, as well as acceleration of a probe beam with 30 GHz RF cavities. The project makes maximum use of existing equipment and infrastructure of the LPI complex, which became available after the closure of LEP. In the first stage of the project, the "Preliminary Phase", the existing LIL linac and the EPA ring, both modified to suit the new requirements, are used to investigate the technique of frequency multiplication by means of interleaving bunches from subsequent trains. This report describes the design of this phase