Genome-wide association identifies ATOH7 as a major gene determining human optic disc size

Optic nerve assessment is important for many blinding diseases, with cup-to-disc ratio (CDR) assessments commonly used in both diagnosis and progression monitoring of glaucoma patients. Optic disc, cup, rim area and CDR measurements all show substantial variation between human populations and high heritability estimates within populations. To identify loci underlying these quantitative traits, we performed a genome-wide association study in two Australian twin cohorts and identified rs3858145, P = 6.2 × 10−10, near the ATOH7 gene as associated with the mean disc area. ATOH7 is known from studies in model organisms to play a key role in retinal ganglion cell formation. The association with rs3858145 was replicated in a cohort of UK twins, with a meta-analysis of the combined data yielding P = 3.4 × 10−10. Imputation further increased the evidence for association for several SNPs in and around ATOH7 (P = 1.3 × 10−10 to 4.3 × 10−11, top SNP rs1900004). The meta-analysis also provided suggestive evidence for association for the cup area at rs690037, P = 1.5 × 10−7, in the gene RFTN1. Direct sequencing of ATOH7 in 12 patients with optic nerve hypoplasia, one of the leading causes of blindness in children, revealed two novel non-synonymous mutations (Arg65Gly, Ala47Thr) which were not found in 90 unrelated controls (combined Fisher's exact P = 0.0136). Furthermore, the Arg65Gly variant was found to have very low frequency (0.00066) in an additional set of 672 controls

N348I in the Connection Domain of HIV-1 Reverse Transcriptase Confers Zidovudine and Nevirapine Resistance

Analyzing HIV sequences from a Canadian cohort, Gilda Tachedjian and colleagues identify a common mutation in a little-studied domain of reverse transcriptase that confers resistance to two drug classes

Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors.

Loss-of-function mutations of cyclic-AMP response element binding protein, binding protein (CREBBP) are prevalent in lymphoid malignancies. However, the tumour suppressor functions of CREBBP remain unclear. We demonstrate that loss of Crebbp in murine haematopoietic stem and progenitor cells (HSPCs) leads to increased development of B-cell lymphomas. This is preceded by accumulation of hyperproliferative lymphoid progenitors with a defective DNA damage response (DDR) due to a failure to acetylate p53. We identify a premalignant lymphoma stem cell population with decreased H3K27ac, which undergoes transcriptional and genetic evolution due to the altered DDR, resulting in lymphomagenesis. Importantly, when Crebbp is lost later in lymphopoiesis, cellular abnormalities are lost and tumour generation is attenuated. We also document that CREBBP mutations may occur in HSPCs from patients with CREBBP-mutated lymphoma. These data suggest that earlier loss of Crebbp is advantageous for lymphoid transformation and inform the cellular origins and subsequent evolution of lymphoid malignancies

A computational and experimental investigation of the dissection of arterial tissue

The overall objective of this thesis is to provide a new understanding of the mechanisms underlying arterial fracture, and to extend this understanding to the initiation and propagation of aortic dissection using a combination of experimental testing and computational modelling. Aortic dissection is a lethal disease that involves the separation of the arterial layers and carries mortality rates as high as 1-2% per hour untreated. However, to date the exact pathophysiological processes and related biomechanisms underlying aortic dissection have not been uncovered. We present the development and implementation of a novel experimental technique to generate and characterise mode II crack initiation and propagation in arterial tissue. We begin with a demonstration that lap-shear testing of arterial tissue results in mixed mode fracture, rather than mode II. A detailed computational design of a novel experimental method (shear fracture ring test (SFRT)) to robustly and repeatably generate mode II crack initiation and propagation in arteries is presented. This method is based on generating a localised region of high shear adjacent to a cylindrical loading bar. Placement of a radial notch in this region of high shear stress is predicted to result in a kinking of the crack during a mode II initiation and propagation of the crack over a long distance in the circumferential (c)-direction along the circumferential-axial (c-a) plane. Fabrication and experimental implementation of the SFRT on excised ovine aorta specimens confirms that the novel test method results in pure mode II initiation and propagation. We demonstrate that the mode II fracture strength along the c-a plane is eight times higher than the corresponding mode I strength determined from a standard peel test. We also calibrate the mode II fracture energy based on our measurement of crack propagation rates. The mechanisms of fracture uncovered, along with the quantification of mode II fracture properties have significant implications for current understanding of the biomechanical conditions underlying aortic dissection. We observe that a standard exponential-CZM (E-CZM) is unable to capture the key trends associated with a collagenous interface undergoing fibrillation, namely, the non-linear crack growth observed during SFRT experiments. We propose an elastic fibrillation CZM (EF-CZM) and explore its conformability to the experimental data. An incremental improvement is obtained relative to the E-CZM; however, crack growth slows prematurely. It is found that the final regime of crack growth is insensitive to the model parameters. The EF-CZM fails to capture the key mechanisms underlying the fibrillation fracture process. It is hypothesised that the dissipative process of fibre pull-out may be an important consideration in phenomenologically capturing the experimental trends. Furthermore, we theorize that crack growth velocity and fibrillation may be related, and thus, a rate dependence may be necessary to phenomenologically capture the physics of the fibrillation process. Therefore, a viscoplastic CZM is developed, where the rate of strain hardening is dependent on the applied strain rate. We present a full exploration of the viscoplastic CZM and demonstrate a thermodynamic consideration of the CZM which demonstrates positive iii instantaneous incremental dissipation of the elastic and plastic components of the CZM throughout all loading scenarios considered in the present study. Finally we explore the conformability of viscoplastic CZM to the fracture experiments of FitzGibbon and McGarry (2020) and demonstrate that the introduction of a rate-dependent plasticity captures the key trends observed experimentally, namely, the slow crack growth regime proceeded by fast crack growth and again by slow crack growth. A realistic subject-specific aorta finite element model derived from a dual-venc MRI scan is developed. We investigate if spontaneous dissection will occur under extreme hypertensive lumen blood pressure loading, or if significant reduction in interface strength must occur in order for dissection to initiate. Importantly, it is also demonstrated that dissection initiation is a pure mode II fracture process, rather than a mixed mode or mode I process. We construct a parameterised idealised aorta model in order to assess the relative contribution for several anatomical and physiological factors to dissection risk. Such parametric analyses provide fundamental insight into the mechanics of stress localisation and delamination in the aorta. Overall, the detailed series of simulations suggest that variations in anatomical features and hypertensive loading will not result in a sufficient elevation of the stress state in the aorta wall to initiate dissection. Our results suggest that initiation of aortic dissection requires a significant reduction in the mode II fracture strength of the aortic wall, suggesting that dissection is preceded by structural and biomechanical remodelling. Finally, we examine the risk of dissection in an artery with a range of pre-existing injuries. The risk of dissection is examined in an artery with an intimal tear (radial notch). Finite element cohesive zone analyses suggest propagation of an intimal tear is not predicted for pressures less than P=275 mmHg in a healthy aorta. The risk of dissection is then examined in an artery with a pre-existing intraluminal septum and a patent false lumen. Computational fluid dynamics (CFD) analyses are performed, and pressure data is extracted and applied to a solid fracture model. The results of the combined fluid dynamics and finite element cohesive zone analyses suggest extensive propagation of a false lumen is not predicted at a slightly hypertensive systolic pressure of 140 mmHg in a healthy aorta. Even in extreme hypertensive loading conditions AD propagation is arrested due to blunting of the crack tip and an increase in the mode angle towards mode II. The results of this study suggest an intimal tear will not develop into a false lumen in a healthy normotensive aorta

Calculation of cycle lengths in higher order error feedback modulators with constant inputs

Higher order error feedback modulators are analyzed mathematically to investigate their periodic behavior. We derive nonlinear equations governing the systems and evaluate the quantizer error equations to determine optimum initial conditions from which maximum cycle lengths can be achieved. © 2006 IEEE

Calculation of cycle lengths in higher-order MASH DDSMs with constant inputs

A mathematical analysis is performed to investigate the periodic behavior of Multi stAge noise SHaping (MASH) Digital Delta-Sigma Modulators (DDSMs). The analysis is performed on fourth- and fifth-order MASH DDSMs with an odd initial condition on the first stage and all other states initially zeroed. We prove that the maximum cycle length for the fourth- and fifth-order MASH DDSM is 2N+2 where N is the wordlength of the modulator. In the case of fourth-order modulators, the maximum cycle length can be achieved when odd digital inputs are applied. In the case of fifth-order modulators, the cycle length is 2N+2 for all digital inputs. ©2010 IEEE

Calculation of the cycle length in a HK-MASH DDSM with multilevel quantizers

The HK-Multi stAge noise SHaping (MASH) Digital Delta-Sigma Modulator (DDSM) uses output feedback to make the quantization step appear prime, thereby maximising the cycle lengths for constant inputs. This structure uses a cascade of modified first-order error feedback modulator (EFM1) blocks with one-bit quantizers. Multibit quantizers are often used in DDSMs as the increased number of levels allows the quantizer to behave more linearly, thereby improving the stability of the modulator. In this paper, we analyse a HK-MASH DDSM with multi-level quantizers and show that the cycle length is always NL, regardless of initial conditions and the input value, where N is the cycle length of each stage and L is the number of stages in the DDSM. ©2010 IEEE