ALBERT

Description: Human gene mutations have revealed that a significant number of ADAMTS (a disintegrin-like and metalloproteinase (reprolysin type) with thrombospondin type 1 motifs) proteins are necessary for normal ocular development and eye function. Mutations in human ADAMTSL4 , encoding an ADAMTS-like protein which has been implicated in fibrillin microfibril biogenesis, cause ectopia lentis (EL) and EL et pupillae. Here, we report the first ADAMTSL4 mouse model, tvrm267 , bearing a nonsense mutation in Adamtsl4 . Homozygous Adamtsl4 tvrm267 mice recapitulate the EL phenotype observed in humans, and our analysis strongly suggests that ADAMTSL4 is required for stable anchorage of zonule fibers to the lens capsule. Unexpectedly, homozygous Adamtsl4 tvrm267 mice exhibit focal retinal pigment epithelium (RPE) defects primarily in the inferior eye. RPE dedifferentiation was indicated by reduced pigmentation, altered cellular morphology and a reduction in RPE-specific transcripts. Finally, as with a subset of patients with ADAMTSL4 mutations, increased axial length, relative to age-matched controls, was observed and was associated with the severity of the RPE phenotype. In summary, the Adamtsl4 tvrm267 model provides a valuable tool to further elucidate the molecular basis of zonule formation, the pathophysiology of EL and ADAMTSL4 function in the maintenance of the RPE.

Description: We have studied the impact of dust feedback on the survival and structure of vortices in protoplanetary discs using 2D shearing box simulations with Lagrangian dust particles. We consider dust with a variety of sizes (stopping time t s  = 10 –2 –1 –10 2 –1 ), from fully coupled with the gas to the decoupling limit. We find that a vortex is destroyed by dust feedback when the total dust-to-gas mass ratio within the vortex is larger than 30–50 per cent, independent of the dust size. The dust distribution can still be asymmetric in some cases after the vortex has been destroyed. With smaller amounts of dust, a vortex can survive for at least 100 orbits, and the maximum dust surface density within the vortex can be more than 100 times larger than the gas surface density, potentially facilitating planetesimal formation. On the other hand, in these stable vortices, small ( t s  〈  –1 ) and large ( t s –1 ) dust grains concentrate differently and affect the gas dynamics in different ways. The distribution of large dust is more elongated than that of small dust. Large dust ( t s –1 ) concentrates in the centre of the vortex and feedback leads to turn-over in vorticity towards the centre, forming a quiescent region within an anticyclonic vortex. Such a turn-over is absent if the vortex is loaded with small grains. We demonstrate that, in protoplanetary discs where both large and small dust grains are present and under the right condition, the concentration of large dust towards the vortex centre can lead to a quiescent centre, repelling the small dust and forming a small dust ring around the vortex centre. Such anticorrelations between small and large dust within vortices may explain the discrepancy between Atacama Large Millimeter Array and near-IR scattered light observations in the asymmetric region of transitional discs.

Description: We study the circularization of tidally disrupted stars on bound orbits around spinning supermassive black holes by performing 3D smoothed particle hydrodynamic simulations with post-Newtonian corrections. Our simulations reveal that debris circularization depends sensitively on the efficiency of radiative cooling. There are two stages in debris circularization if radiative cooling is inefficient: first, the stellar debris streams self-intersect due to relativistic apsidal precession; shocks at the intersection points thermalize orbital energy and the debris forms a geometrically thick, ring-like structure around the black hole. The ring rapidly spreads via viscous diffusion, leading to the formation of a geometrically thick accretion disc. In contrast, if radiative cooling is efficient, the stellar debris circularizes due to self-intersection shocks and forms a geometrically thin ring-like structure. In this case, the dissipated energy can be emitted during debris circularization as a precursor to the subsequent tidal disruption flare. The circularization time-scale is remarkably long in the radiatively efficient cooling case, and is also sensitive to black hole spin. Specifically, Lense–Thirring torques cause dynamically important nodal precession, which significantly delays debris circularization. On the other hand, nodal precession is too slow to produce observable signatures in the radiatively inefficient case. Since the stellar debris is optically thick and its photon diffusion time is likely longer than the time-scale of shock heating, our inefficient cooling scenario is more generally applicable in eccentric tidal disruption events (TDEs). However, in parabolic TDEs for M BH 2 x 10 6 M , the spin-sensitive behaviour associated with efficient cooling may be realized.

Description: Mutations in the ABCA4 gene are a common cause of autosomal recessive retinal degeneration. All mouse models to date are based on knockouts of Abca4 , even though the disease is often caused by missense mutations such as the complex allele L541P;A1038V (PV). We now show that the PV mutation causes severe human disease whereas the V mutation alone causes mild disease. Mutant ABCA4 proteins expressed heterologously in mammalian cells retained normal cellular localization. However, basal and all- trans -retinal-stimulated ATPase activities were reduced substantially for P and PV but only mildly for V. Electron microscopy revealed marked structural changes and misfolding for the P and PV mutants but few changes for the V mutant, consistent with the disease severity difference in patients. We generated Abca4 PV/PV knock-in mice homozygous for the complex PV allele to investigate the effects of this misfolding mutation in vivo . Mutant ABCA4 RNA levels approximated WT ABCA4 RNA levels but, surprisingly, only trace amounts of mutant ABCA4 protein were noted in the retina. RNA sequencing of WT, Abca4 –/– and Abca4 PV/PV mice revealed mild gene expression alterations in the retina and RPE. Similar to Abca4 –/– mice, Abca4 PV/PV mice showed substantial A2E and lipofuscin accumulation in their RPE cells but no retinal degeneration up to 12 months of age. Thus, rapid degradation of this large misfolded mutant protein in mouse retina caused little detectable photoreceptor degeneration. These findings suggest likely differences in the unfolded protein response between murine and human photoreceptors and support development of therapies directed at increasing this capability in patients.

Description: Arginase deficiency is caused by deficiency of arginase 1 (ARG1), a urea cycle enzyme that converts arginine to ornithine. Clinical features of arginase deficiency include elevated plasma arginine levels, spastic diplegia, intellectual disability, seizures and growth deficiency. Unlike other urea cycle disorders, recurrent hyperammonemia is typically less severe in this disorder. Normalization of plasma arginine levels is the consensus treatment goal, because elevations of arginine and its metabolites are suspected to contribute to the neurologic features. Using data from patients enrolled in a natural history study conducted by the Urea Cycle Disorders Consortium, we found that 97% of plasma arginine levels in subjects with arginase deficiency were above the normal range despite conventional treatment. Recently, arginine-degrading enzymes have been used to deplete arginine as a therapeutic strategy in cancer. We tested whether one of these enzymes, a pegylated human recombinant arginase 1 (AEB1102), reduces plasma arginine in murine models of arginase deficiency. In neonatal and adult mice with arginase deficiency, AEB1102 reduced the plasma arginine after single and repeated doses. However, survival did not improve likely, because this pegylated enzyme does not enter hepatocytes and does not improve hyperammonemia that accounts for lethality. Although murine models required dosing every 48 h, studies in cynomolgus monkeys indicate that less frequent dosing may be possible in patients. Given that elevated plasma arginine rather than hyperammonemia is the major treatment challenge, we propose that AEB1102 may have therapeutic potential as an arginine-reducing agent in patients with arginase deficiency.

Description: When a star is tidally disrupted by a supermassive black hole (SMBH), roughly half of its mass falls back to the SMBH at super-Eddington rates. As this gas is tenuously gravitationally bound and unable to cool radiatively, only a small fraction f in  〈〈 1 may accrete, with the majority instead becoming unbound in an outflow of velocity ~10 4 km s –1 . The outflow spreads laterally as it expands to large radii, encasing the SMBH and blocking the inner disc's EUV/X-ray radiation, which becomes trapped in a radiation-dominated nebula. Ionizing nebular radiation heats the inner edge of the ejecta, converting the emission to optical/near-UV wavelengths where photons more readily escape due to the lower opacity. This can explain the unexpectedly low and temporally constant effective temperatures of optically discovered tidal disruption event (TDE) flares. For high-mass SMBHs, M • 10 7 M , the ejecta can become fully ionized at an earlier stage, or for a wider range of viewing angles, producing a TDE flare accompanied by thermal X-ray emission. The peak optical luminosity is suppressed as the result of adiabatic losses in the inner disc wind when M •  〈〈 10 7 M , possibly contributing to the unexpected dearth of optical TDEs in galaxies with low-mass SMBHs. In the classical picture, where f in 1, TDEs de-spin supermassive SMBHs and cap their maximum spins well below theoretical accretion physics limits. This cap is relaxed in our model, and existing Fe Kα spin measurements provide preliminary evidence that f in  〈 1.

Description: The non-linear evolution of the Kelvin–Helmholtz instability is a popular test for code verification. To date, most Kelvin–Helmholtz problems discussed in the literature are ill-posed: they do not converge to any single solution with increasing resolution. This precludes comparisons among different codes and severely limits the utility of the Kelvin–Helmholtz instability as a test problem. The lack of a reference solution has led various authors to assert the accuracy of their simulations based on ad hoc proxies, e.g. the existence of small-scale structures. This paper proposes well-posed two-dimensional Kelvin–Helmholtz problems with smooth initial conditions and explicit diffusion. We show that in many cases numerical errors/noise can seed spurious small-scale structure in Kelvin–Helmholtz problems. We demonstrate convergence to a reference solution using both athena , a Godunov code, and dedalus , a pseudo-spectral code. Problems with constant initial density throughout the domain are relatively straightforward for both codes. However, problems with an initial density jump (which are the norm in astrophysical systems) exhibit rich behaviour and are more computationally challenging. In the latter case, athena simulations are prone to an instability of the inner rolled-up vortex; this instability is seeded by grid-scale errors introduced by the algorithm, and disappears as resolution increases. Both athena and dedalus exhibit late-time chaos. Inviscid simulations are riddled with extremely vigorous secondary instabilities which induce more mixing than simulations with explicit diffusion. Our results highlight the importance of running well-posed test problems with demonstrated convergence to a reference solution. To facilitate future comparisons, we include as supplementary material the resolved, converged solutions to the Kelvin–Helmholtz problems in this paper in machine-readable form.

Description: We consider the origins of enigmatic stellar populations in four Local Group galactic nuclei, specifically the Milky Way, M31, M32 and M33. These are centrally concentrated blue stars, found in three out of the four nuclear star clusters (NSCs) considered here. Their origins are unknown, but could include blue straggler (BS) stars, extended horizontal branch stars and young recently formed stars. Here, we calculate order-of-magnitude estimates for various collision rates, as a function of the host NSC environment and distance from the cluster centre. These rates are sufficiently high that BSs, formed via collisions between main-sequence (MS) stars, could contribute non-negligibly (~1–10 per cent in mass) to every surface brightness profile, with the exception of the Milky Way. Stellar evolution models show that the envelopes of red giant branch (RGB) stars must be nearly completely stripped to significantly affect their photometric appearance, which requires multiple collisions. Hence, the collision rates for individual RGB stars are only sufficiently high in the inner 0.1 pc of M31 and M32 for RGB destruction to occur. Collisions between white dwarfs and MS stars, which should ablate the stars, could offer a steady and significant supply of gas in every NSC in our sample. The gas could either fragment to form new stars, or accrete on to old MS stars already present. Thus, collisional processes could contribute significantly to the observed blue excesses in M31 and M33; future studies should be aimed at better constraining theoretical predictions to compliment existing and future observational data.

Description: Telomerase is an enzyme that adds repetitive DNA sequences to the ends of chromosomes and consists of two main subunits: the telomerase reverse transcriptase (TERT) protein and an associated telomerase RNA (TER). The telomerase essential N-terminal (TEN) domain is a conserved region of TERT proposed to mediate DNA substrate interactions. Here, we have employed single molecule telomerase binding assays to investigate the function of the TEN domain. Our results reveal telomeric DNA substrates bound to telomerase exhibit a dynamic equilibrium between two states: a docked conformation and an alternative conformation. The relative stabilities of the docked and alternative states correlate with the number of basepairs that can be formed between the DNA substrate and the RNA template, with more basepairing favoring the docked state. The docked state is further buttressed by the TEN domain and mutations within the TEN domain substantially alter the DNA substrate structural equilibrium. We propose a model in which the TEN domain stabilizes short RNA–DNA duplexes in the active site of the enzyme, promoting the docked state to augment telomerase processivity.