The genetic basis of human height : the role of estrogen

Height is a complex physical trait that displays strong heritability. Adult height is related to length of the long bones, which is determined by growth at the epiphyseal growth plate. Longitudinal bone growth occurs via the process of endochondral ossification, where bone forms over the differentiating cartilage template at the growth plate. Estrogen plays a major role in regulating longitudinal bone growth and is responsible for inducing the pubertal growth spurt and fusion of the epiphyseal growth plate. However, the mechanism by which estrogen promotes epiphyseal fusion is poorly understood. It has been hypothesised that estrogen functions to regulate growth plate fusion by stimulating chondrocyte apoptosis, angiogenesis and bone cell invasion in the growth plate. Another theory has suggested that estrogen exposure exhausts the proliferative capacity of growth plate chondrocytes, which accelerates the process of chondrocyte senescence, leading to growth plate fusion. The overall objective of this study was to gain a greater understanding of the molecular mechanisms behind estrogen-mediated growth and height attainment by examining gene regulation in chondrocytes and the role of some of these genes in normal height inheritance. With the heritability of height so well established, the initial hypothesis was that genetic variation in candidate genes associated with longitudinal bone growth would be involved in normal adult height variation. The height-related genes FGFR3, CBFA1, ER and CBFA1 were screened for novel polymorphisms using denaturing HPLC and RFLP analysis. In total, 24 polymorphisms were identified. Two SNPs in ER (rs3757323 C>T and rs1801132 G>C) were strongly associated with adult male height and displayed an 8 cm and 9 cm height difference between homozygous genotypes, respectively. The TC haplotype of these SNPs was associated with a 6 cm decrease in height and remarkably, no homozygous carriers of the TC haplotype were identified in tall subjects. No significant associations with height were found for polymorphisms in the FGFR3, CBFA1 or VDR genes. In the epiphyseal growth plate, chondrocyte proliferation, matrix synthesis and chondrocyte hypertrophy are all major contributors to long bone growth. As estrogen plays such a significant role in both growth and final height attainment, another hypothesis of this study was that estrogen exerted its effects in the growth plate by influencing chondrocyte proliferation and mediating the expression of chondrocyte marker genes. The examination of genes regulated by estrogen in chondrocyte-like cells aimed to identify potential regulators of growth plate fusion, which may further elucidate mechanisms involved in the cessation of linear growth. While estrogen did not dramatically alter the proliferation of the SW1353 cell line, gene expression experiments identified several estrogen regulated genes. Sixteen chondrocyte marker genes were examined in response to estrogen concentrations ranging from 10-12 M to 10-8 M over varying time points. Of the genes analysed, IHH, FGFR3, collagen II and collagen X were not readily detectable and PTHrP, GHR, ER, BMP6, SOX9 and TGF1 mRNAs showed no significant response to estrogen treatments. However, the expression of MMP13, CBFA1, BCL-2 and BAX genes were significantly decreased. Interestingly, the majority of estrogen regulated genes in SW1353 cells are expressed in the hypertrophic zone of the growth plate. Estrogen is also known to regulate systemic GH secretion and local GH action. At the molecular level, estrogen functions to inhibit GH action by negatively regulating GH signalling. GH treated SW1353 cells displayed increases in MMP9 mRNA expression (4.4-fold) and MMP13 mRNA expression (64-fold) in SW1353 cells. Increases were also detected in their respective proteins. Treatment with AG490, an established JAK2 inhibitor, blocked the GH mediated stimulation of both MMP9 and MMP13 mRNA expression. The application of estrogen and GH to SW1353 cells attenuated GH-stimulated MMP13 levels, but did not affect MMP9 levels. Investigation of GH signalling revealed that SW1353 cells have high levels of activated JAK2 and exposure to GH, estrogen, AG490 and other signalling inhibitors did not affect JAK2 phosphorylation. Interestingly, AG490 treatment dramatically decreased ERK2 signalling, although GH did stimulate ERK2 phosphorylation above control levels. AG490 also decreased CBFA1 expression, a transcription factor known to activate MMP9 and MMP13. Finally, GH and estrogen treatment increased expression of SOCS3 mRNA, suggesting that SOCS3 may regulate JAK/STAT signalling in SW1353 cells. The modulation of GH-mediated MMP expression by estrogen in SW1353 cells represents a potentially novel mechanism by which estrogen may regulate longitudinal bone growth. However, further investigation is required in order to elucidate the precise mechanisms behind estrogen and GH regulation of MMP13 expression in SW1353 cells. This study has provided additional evidence that estrogen and the ER gene are major factors in the regulation of growth and the determination of adult height. Newly identified polymorphisms in the ER gene not only contribute to our understanding of the genetic basis of human height, but may also be useful in association studies examining other complex traits. This study also identified several estrogen regulated genes and indicated that estrogen modifies the expression of genes which are primarily expressed in the hypertrophic region of the epiphyseal growth plate. Furthermore, synergistic studies incorporating GH and estrogen have revealed the ability of estrogen to attenuate the effects of GH on MMP13 expression, revealing potential pathways by which estrogen may modulate growth plate fusion, longitudinal bone growth and even arthritis.

Human brain regions required for the dividing and switching of attention between two features of a single object

This combined PET and ERP study was designed to identify the brain regions activated in switching and divided attention between different features of a single object using matched sensory stimuli and motor response. The ERP data have previously been reported in this journal [64]. We now present the corresponding PET data. We identified partially overlapping neural networks with paradigms requiring the switching or dividing of attention between the elements of complex visual stimuli. Regions of activation were found in the prefrontal and temporal cortices and cerebellum. Each task resulted in different prefrontal cortical regions of activation lending support to the functional subspecialisation of the prefrontal and temporal cortices being based on the cognitive operations required rather than the stimuli themselves.

Discovery and characterization of IGFBP-mediated endocytosis in the human retinal pigment epithelial cell line ARPE-19

Insulin-like growth factor binding proteins (IGFBPs) are prime regulators of IGF-action in numerous cell types including the retinal pigment epithelium (RPE). The RPE performs several functions essential for vision, including growth factor secretion and waste removal via a phagocytic process mediated in part by vitronectin (Vn). In the course of studying the effects of IGFBPs on IGF-mediated VEGF secretion and Vn-mediated phagocytosis in the RPE cell line ARPE-19, we have discovered that these cells avidly ingest synthetic microspheres (2.0 μm diameter) coated with IGFBPs. Given the novelty of this finding and the established role for endocytosis in mediating IGFBP actions in other cell types, we have explored the potential role of candidate cell surface receptors. Moreover, we have examined the role of key IGFBP structural motifs, by comparing responses to three members of the IGFBP family (IGFBP-3, IGFBP-4 and IGFBP-5) which display overlapping variations in primary structure and glycosylation status. Coating of microspheres (FluoSpheres®, sulfate modified polystyrene filled with a fluorophore) was conducted at 37 °C for 1 h using 20 μg/mL of test protein, followed by extensive washing. Binding of proteins was confirmed using a microBCA assay. The negative control consisted of microspheres treated with 0.1% bovine serum albumin (BSA), and all test samples were post-treated with BSA in an effort to coat any remaining free protein binding sites, which might otherwise encourage non-specific interactions with the cell surface. Serum-starved cultures of ARPE-19 cells were incubated with microspheres for 24 h, using a ratio of approximately 100 microspheres per cell. Uptake of microspheres was quantified using a fluorometer and was confirmed visually by confocal fluorescence microscopy. The ARPE-19 cells displayed little affinity for BSA-treated microspheres, but avidly ingested large quantities of those pre-treated with Vn (ANOVA; p < 0.001). Strong responses were also observed towards recombinant formulations of non-glycosylated IGFBP-3, glycosylated IGFBP-3 and glycosylated IGFBP-5 (all p < 0.001), while glycosylated IGFBP-4 induced a relatively minor response (p < 0.05). The response to IGFBP-3 was unaffected in the presence of excess soluble IGFBP-3, IGF-I or Vn. Likewise, soluble IGFBP-3 did not induce uptake of BSA-treated microspheres. Antibodies to either the transferrin receptor or type 1 IGF-receptor displayed slight inhibitory effects on responses to IGFBPs and Vn. Heparin abolished responses to Vn, IGFBP-5 and non-glycosylated IGFBP-3, but only partially inhibited the response to glycosylated IGFBP-3. Our results demonstrate for the first time IGFBP-mediated endocytosis in ARPE-19 cells and suggest roles for the IGFBP-heparin-binding domain and glycosylation status. These findings have important implications for understanding the mechanisms of IGFBP actions on the RPE, and in particular suggest a role for IGFBP-endocytosis.

Concentrations of polybrominated diphenyl ethers (PBDEs) in matched samples of human milk, dust and indoor air

Polybrominated diphenyl ethers (PBDEs) are lipophilic, persistent pollutants found worldwide in environmental and human samples. Exposure pathways for PBDEs remain unclear but may include food, air and dust. The aim of this study was to conduct an integrated assessment of PBDE exposure and human body burden using 10 matched samples of human milk, indoor air and dust collected in 2007–2008 in Brisbane, Australia. In addition, temporal analysis was investigated comparing the results of the current study with PBDE concentrations in human milk collected in 2002–2003 from the same region. PBDEs were detected in all matrices and the median concentrations of BDEs -47 and -209 in human milk, air and dust were: 4.2 and 0.3 ng/g lipid; 25 and 7.8 pg/m3; and 56 and 291 ng/g dust, respectively. Significant correlations were observed between the concentrations of BDE-99 in air and human milk (r = 0.661, p = 0.038) and BDE-153 in dust and BDE-183 in human milk (r = 0.697, p = 0.025). These correlations do not suggest causal relationships — there is no hypothesis that can be offered to explain why BDE-153 in dust and BDE-183 in milk are correlated. The fact that so few correlations were found in the data could be a function of the small sample size, or because additional factors, such as sources of exposure not considered or measured in the study, might be important in explaining exposure to PBDEs. There was a slight decrease in PBDE concentrations from 2002–2003 to 2007–2008 but this may be due to sampling and analytical differences. Overall, average PBDE concentrations from these individual samples were similar to results from pooled human milk collected in Brisbane in 2002–2003 indicating that pooling may be an efficient, cost-effective strategy of assessing PBDE concentrations on a population basis. The results of this study were used to estimate an infant's daily PBDE intake via inhalation, dust ingestion and human milk consumption. Differences in PBDE intake of individual congeners from the different matrices were observed. Specifically, as the level of bromination increased, the contribution of PBDE intake decreased via human milk and increased via dust. As the impacts of the ban of the lower brominated (penta- and octa-BDE) products become evident, an increased use of the higher brominated deca-BDE product may result in dust making a greater contribution to infant exposure than it does currently. To better understand human body burden, further research is required into the sources and exposure pathways of PBDEs and metabolic differences influencing an individual's response to exposure. In addition, temporal trend analysis is necessary with continued monitoring of PBDEs in the human population as well as in the suggested exposure matrices of food, dust and air.

In-vehicle avatars to elicit social response and change driving behaviour

Social and psychological theories have provided a plethora of evidence showing that the physical difficulty to express appropriate social interactions between drivers expresses itself in aggression, selfish driving and anti-social behaviour. Therefore there is a need to improve interactions between drivers and allow clearer collective decision making between them. Personal characteristics and the driving situations play strong roles in driver’s aggression. Our approach is centered around the driving situation as opposed to focusing on personality characteristics. It examines aggression and manipulates contextual variables such as driver’s eye contact exchanges. This paper presents a new unobtrusive in-vehicle system that aims at communicating drivers’ intentions, elicit social responses and increasing mutual awareness. It uses eye gaze as a social cue to affect collective decision making with the view to contribute to safe driving. The authors used a driving simulator to design a case control experiment in which eye gaze movements are conveyed with an avatar. Participants were asked to drive through different types of intersections. An avatar representing the head of the other driver was displayed and driver behaviour was analysed. Significant eye gaze pattern difference where observed when an avatar was displayed. Drivers cautiously refer to the avatar when information is required on the intention of others (e.g. when they do not have the right of way). The majority of participants reported the perception of “being looked at”. The number of glances and time spent gazing at the avatar did not indicate an unsafe distraction by standards of in-vehicle device ergonomic design. Avatars were visually consulted primarily in less demanding driving situations, which underlines their non-distractive nature.

The mechanical response of the ovine lumbar anulus fibrosus to uniaxial, biaxial and shear loads

Analytical and computational models of the intervertebral disc (IVD) are commonly employed to enhance understanding of the biomechanics of the human spine and spinal motion segments. The accuracy of these models in predicting physiological behaviour of the spine is intrinsically reliant on the accuracy of the material constitutive representations employed to represent the spinal tissues. There is a paucity of detailed mechanical data describing the material response of the reinforced­ground matrix in the anulus fibrosus of the IVD. In the present study, the ‘reinforced­ground matrix’ was defined as the matrix with the collagen fibres embedded but not actively bearing axial load, thus incorporating the contribution of the fibre-fibre and fibre-matrix interactions. To determine mechanical parameters for the anulus ground matrix, mechanical tests were carried out on specimens of ovine anulus, under unconfined uniaxial compression, simple shear and biaxial compression. Test specimens of ovine anulus fibrosus were obtained with an adjacent layer of vertebral bone/cartilage on the superior and inferior specimen surface. Specimen geometry was such that there were no continuous collagen fibres coupling the two endplates. Samples were subdivided according to disc region - anterior, lateral and posterior - to determine the regional inhomogeneity in the anulus mechanical response. Specimens were loaded at a strain rate sufficient to avoid fluid outflow from the tissue and typical stress-strain responses under the initial load application and under repeated loading were determined for each of the three loading types. The response of the anulus tissue to the initial and repeated load cycles was significantly different for all load types, except biaxial compression in the anterior anulus. Since the maximum applied strain exceeded the damage strain for the tissue, experimental results for repeated loading reflected the mechanical ability of the tissue to carry load, subsequent to the initiation of damage. To our knowledge, this is the first study to provide experimental data describing the response of the ‘reinforced­ground matrix’ to biaxial compression. Additionally, it is novel in defining a study objective to determine the regionally inhomogeneous response of the ‘reinforced­ground matrix’ under an extensive range of loading conditions suitable for mechanical characterisation of the tissue. The results presented facilitate the development of more detailed and comprehensive constitutive descriptions for the large strain nonlinear elastic or hyperelastic response of the anulus ground matrix.

Low fat loss response after medium-term supervised exercise in obese is associated with exercise-induced increase in food reward

Objective: To examine exercise-induced changes in the reward value of food during medium-term supervised exercise in obese individuals. ---------- Subjects/Methods: The study was a 12-week supervised exercise intervention prescribed to expend 500 kcal/day, 5 d/week. 34 sedentary obese males and females were identified as responders (R) or non-responders (NR) to the intervention according to changes in body composition relative to measured energy expended during exercise. Food reward (ratings of liking and wanting, and relative preference by forced choice pairs) for an array of food images was assessed before and after an acute exercise bout. ---------- Results. 20 responders and 14 non-responders were identified. R lost 5.2 kg±2.4 of total fat mass and NR lost 1.7 kg±1.4. After acute exercise, liking for all foods increased in NR compared to no change in R. Furthermore, NR showed an increase in wanting and relative preference for high-fat sweet foods. These differences were independent of 12-weeks regular exercise and weight loss. ---------- Conclusion. Individuals who showed an immediate post-exercise increase in liking and increased wanting and preference for high-fat sweet foods displayed a smaller reduction in fat mass with exercise. For some individuals, exercise increases the reward value of food and diminishes the impact of exercise on fat loss.

Real-time performance modelling of a sustained attention to response task

Vigilance declines when exposed to highly predictable and uneventful tasks. Monotonous tasks provide little cognitive and motor stimulation and contribute to human errors. This paper aims to model and detect vigilance decline in real time through participant’s reaction times during a monotonous task. A lab-based experiment adapting the Sustained Attention to Response Task (SART) is conducted to quantify the effect of monotony on overall performance. Then relevant parameters are used to build a model detecting hypovigilance throughout the experiment. The accuracy of different mathematical models are compared to detect in real-time – minute by minute - the lapses in vigilance during the task. We show that monotonous tasks can lead to an average decline in performance of 45%. Furthermore, vigilance modelling enables to detect vigilance decline through reaction times with an accuracy of 72% and a 29% false alarm rate. Bayesian models are identified as a better model to detect lapses in vigilance as compared to Neural Networks and Generalised Linear Mixed Models. This modelling could be used as a framework to detect vigilance decline of any human performing monotonous tasks.

Comparison of human alveolar osteoblasts cultured on polymer-ceramic composite scaffolds and tissue culture plates

The effects of medical grade polycaprolactone–tricalcium phosphate (mPCL–TCP) (80:20) scaffolds on primary human alveolar osteoblasts (AOs) were compared with standard tissue-culture plates. Of the seeded AOs, 70% adhered to and proliferated on the scaffold surface and within open and interconnected pores; they formed multi-layered sheets and collagen fibers with uniform distribution within 28 days. Elevation of alkaline phosphatase activity occurred in scaffold–cell constructs independent of osteogenic induction. AO proliferation rate increased and significant decrease in calcium concentration of the medium for both scaffolds and plates under induction conditions were seen. mPCL–TCP scaffolds significantly influenced the AO expression pattern of osterix and osteocalcin (OCN). Osteogenic induction down-regulated OCN at both RNA and protein level on scaffolds (3D) by day 7, and up-regulated OCN in cell-culture plates (2D) by day 14, but OCN levels on scaffolds were higher than on cell-culture plates. Immunocytochemical signals for type I collagen, osteopontin and osteocalcin were detected at the outer parts of scaffold–cell constructs. More mineral nodules were found in induced than in non-induced constructs. Only induced 2D cultures showed nodule formation. mPCL–TCP scaffolds appear to stimulate osteogenesis in vitro by activating a cellular response in AO's to form mineralized tissue. There is a fundamental difference between culturing AOs on 2D and 3D environments that should be considered when studying osteogenesis in vitro.

Human optical axial length and defocus

Purpose: To investigate the short term influence of imposed monocular defocus upon human optical axial length (the distance from anterior cornea to retinal pigment epithelium) and ocular biometrics. Methods: Twenty-eight young adult subjects (14 myopes and 14 emmetropes) had eye biometrics measured before and then 30 and 60 minutes after exposure to monocular (right eye) defocus. Four different monocular defocus conditions were tested, each on a separate day: control (no defocus), myopic (+3 D defocus), hyperopic (-3 D defocus) and diffuse (0.2 density Bangerter filter) defocus. The fellow eye was optimally corrected (no defocus). Results: Imposed defocus caused small but significant changes in optical axial length (p<0.0001). A significant increase in optical axial length (mean change +8 ± 14 μm, p=0.03) occurred following hyperopic defocus, and a significant reduction in optical axial length (mean change -13 ± 14 μm, p=0.0001) was found following myopic defocus. A small increase in optical axial length was observed following diffuse defocus (mean change +6 ± 13 μm, p=0.053). Choroidal thickness also exhibited some significant changes with certain defocus conditions. No significant difference was found between myopes and emmetropes in the changes in optical axial length or choroidal thickness with defocus. Conclusions: Significant changes in optical axial length occur in human subjects following 60 minutes of monocular defocus. The bi-directional optical axial length changes observed in response to defocus implies the human visual system is capable of detecting the presence and sign of defocus and altering optical axial length to move the retina towards the image plane.

The urban littoral frontier : land reclamation in the history of human settlements

The urban waterfront may be regarded as the littoral frontier of human settlement. Typically, over the years, it advances, sometimes retreats, where terrestrial and aquatic processes interact and frequently contest this margin of occupation. Because most towns and cities are sited beside water bodies, many of these urban centers on or close to the sea, their physical expansion is constrained by the existence of aquatic areas in one or more directions from the core. It is usually much easier for new urban development to occur along or inland from the waterfront. Where other physical constraints, such as rugged hills or mountains, make expansion difficult or expensive, building at greater densities or construction on steep slopes is a common response. This kind of development, though technically feasible, is usually more expensive than construction on level or gently sloping land, however. Moreover, there are many reasons for developing along the shore or riverfront in preference to using sites further inland. The high cost of developing existing dry land that presents serious construction difficulties is one reason for creating new land from adjacent areas that are permanently or periodically under water. Another reason is the relatively high value of artificially created land close to the urban centre when compared with the value of existing developable space at a greater distance inland. The creation of space for development is not the only motivation for urban expansion into aquatic areas. Commonly, urban places on the margins of the sea, estuaries, rivers or great lakes are, or were once, ports where shipping played an important role in the economy. The demand for deep waterfronts to allow ships to berth and for adjacent space to accommodate various port facilities has encouraged the advance of the urban land area across marginal shallows in ports around the world. The space and locational demands of port related industry and commerce, too, have contributed to this process. Often closely related to these developments is the generation of waste, including domestic refuse, unwanted industrial by-products, site formation and demolition debris and harbor dredgings. From ancient times, the foreshore has been used as a disposal area for waste from nearby settlements, a practice that continues on a huge scale today. Land formed in this way has long been used for urban development, despite problems that can arise from the nature of the dumped material and the way in which it is deposited. Disposal of waste material is a major factor in the creation of new urban land. Pollution of the foreshore and other water margin wetlands in this way encouraged the idea that the reclamation of these areas may be desirable on public health grounds. With reference to examples from various parts of the world, the historical development of the urban littoral frontier and its effects on the morphology and character of towns and cities are illustrated and discussed. The threat of rising sea levels and the heritage value of many waterfront areas are other considerations that are addressed.

Impacts and adaptation response of infrastructure and communities to heatwaves : the southern Australian experience of 2009

From 27 January to 8 February during the summer of 2009, southern Australia experienced one of the nation‘s most severe heatwaves. Governments, councils, utilities, hospitals and emergency response organisations and the community were largely underprepared for an extreme event of this magnitude. This case study targets the experience and challenges faced by decision makers and policy makers and focuses on the major metropolitan areas affected by the heatwave — Melbourne and Adelaide. The study examines the 2009 heatwave‘s characteristics; its impacts (on human health, infrastructure and human services); the degree of adaptive capacity (vulnerability and resilience) of various sectors, communities and individuals; and the reactive responses of government and emergency and associated services and their effectiveness. Barriers and challenges to adaptation and increasing resilience are also identified and further areas for research are suggested. This study does not include details of the heatwave‘s effects beyond Victoria and South Australia, or its economic impacts, or of Victoria‘s 'Black Saturday‘ bushfires.

INTS3 controls the hSSB1-mediated DNA damage response

Human SSB1 (single-stranded binding protein 1 [hSSB1]) was recently identified as a part of the ataxia telangiectasia mutated (ATM) signaling pathway. To investigate hSSB1 function, we performed tandem affinity purifications of hSSB1 mutants mimicking the unphosphorylated and ATM-phosphorylated states. Both hSSB1 mutants copurified a subset of Integrator complex subunits and the uncharacterized protein LOC58493/c9orf80 (henceforth minute INTS3/hSSB-associated element [MISE]). The INTS3–MISE–hSSB1 complex plays a key role in ATM activation and RAD51 recruitment to DNA damage foci during the response to genotoxic stresses. These effects on the DNA damage response are caused by the control of hSSB1 transcription via INTS3, demonstrating a new network controlling hSSB1 function.

Wavefront aberrations and the depth of focus of the human eye

The depth of focus (DOF) can be defined as the variation in image distance of a lens or an optical system which can be tolerated without incurring an objectionable lack of sharpness of focus. The DOF of the human eye serves a mechanism of blur tolerance. As long as the target image remains within the depth of focus in the image space, the eye will still perceive the image as being clear. A large DOF is especially important for presbyopic patients with partial or complete loss of accommodation (presbyopia), since this helps them to obtain an acceptable retinal image when viewing a target moving through a range of near to intermediate distances. The aim of this research was to investigate the DOF of the human eye and its association with the natural wavefront aberrations, and how higher order aberrations (HOAs) can be used to expand the DOF, in particular by inducing spherical aberrations ( 0 4 Z and 0 6 Z ). The depth of focus of the human eye can be measured using a variety of subjective and objective methods. Subjective measurements based on a Badal optical system have been widely adopted, through which the retinal image size can be kept constant. In such measurements, the subject.s tested eye is normally cyclopleged. Objective methods without the need of cycloplegia are also used, where the eye.s accommodative response is continuously monitored. Generally, the DOF measured by subjective methods are slightly larger than those measured objectively. In recent years, methods have also been developed to estimate DOF from retinal image quality metrics (IQMs) derived from the ocular wavefront aberrations. In such methods, the DOF is defined as the range of defocus error that degrades the retinal image quality calculated from the IQMs to a certain level of the possible maximum value. In this study, the effect of different amounts of HOAs on the DOF was theoretically evaluated by modelling and comparing the DOF of subjects from four different clinical groups, including young emmetropes (20 subjects), young myopes (19 subjects), presbyopes (32 subjects) and keratoconics (35 subjects). A novel IQM-based through-focus algorithm was developed to theoretically predict the DOF of subjects with their natural HOAs. Additional primary spherical aberration ( 0 4 Z ) was also induced in the wavefronts of myopes and presbyopes to simulate the effect of myopic refractive correction (e.g. LASIK) and presbyopic correction (e.g. progressive power IOL) on the subject.s DOF. Larger amounts of HOAs were found to lead to greater values of predicted DOF. The introduction of primary spherical aberration was found to provide moderate increase of DOF while slightly deteriorating the image quality at the same time. The predicted DOF was also affected by the IQMs and the threshold level adopted. We then investigated the influence of the chosen threshold level of the IQMs on the predicted DOF, and how it relates to the subjectively measured DOF. The subjective DOF was measured in a group of 17 normal subjects, and we used through-focus visual Strehl ratio based on optical transfer function (VSOTF) derived from their wavefront aberrations as the IQM to estimate the DOF. The results allowed comparison of the subjective DOF with the estimated DOF and determination of a threshold level for DOF estimation. Significant correlation was found between the subject.s estimated threshold level for the estimated DOF and HOA RMS (Pearson.s r=0.88, p<0.001). The linear correlation can be used to estimate the threshold level for each individual subject, subsequently leading to a method for estimating individual.s DOF from a single measurement of their wavefront aberrations. A subsequent study was conducted to investigate the DOF of keratoconic subjects. Significant increases of the level of HOAs, including spherical aberration, coma and trefoil, can be observed in keratoconic eyes. This population of subjects provides an opportunity to study the influence of these HOAs on DOF. It was also expected that the asymmetric aberrations (coma and trefoil) in the keratoconic eye could interact with defocus to cause regional blur of the target. A dual-Badal-channel optical system with a star-pattern target was used to measure the subjective DOF in 10 keratoconic eyes and compared to those from a group of 10 normal subjects. The DOF measured in keratoconic eyes was significantly larger than that in normal eyes. However there was not a strong correlation between the large amount of HOA RMS and DOF in keratoconic eyes. Among all HOA terms, spherical aberration was found to be the only HOA that helped to significantly increase the DOF in the studied keratoconic subjects. Through the first three studies, a comprehensive understanding of DOF and its association to the HOAs in the human eye had been achieved. An adaptive optics system was then designed and constructed. The system was capable of measuring and altering the wavefront aberrations in the subject.s eye and measuring the resulting DOF under the influence of different combination of HOAs. Using the AO system, we investigated the concept of extending the DOF through optimized combinations of 0 4 Z and 0 6 Z . Systematic introduction of a targeted amount of both 0 4 Z and 0 6 Z was found to significantly improve the DOF of healthy subjects. The use of wavefront combinations of 0 4 Z and 0 6 Z with opposite signs can further expand the DOF, rather than using 0 4 Z or 0 6 Z alone. The optimal wavefront combinations to expand the DOF were estimated using the ratio of increase in DOF and loss of retinal image quality defined by VSOTF. In the experiment, the optimal combinations of 0 4 Z and 0 6 Z were found to provide a better balance of DOF expansion and relatively smaller decreases in VA. Therefore, the optimal combinations of 0 4 Z and 0 6 Z provides a more efficient method to expand the DOF rather than 0 4 Z or 0 6 Z alone. This PhD research has shown that there is a positive correlation between the DOF and the eye.s wavefront aberrations. More aberrated eyes generally have a larger DOF. The association of DOF and the natural HOAs in normal subjects can be quantified, which allows the estimation of DOF directly from the ocular wavefront aberration. Among the Zernike HOA terms, spherical aberrations ( 0 4 Z and 0 6 Z ) were found to improve the DOF. Certain combinations of 0 4 Z and 0 6 Z provide a more effective method to expand DOF than using 0 4 Z or 0 6 Z alone, and this could be useful in the optimal design of presbyopic optical corrections such as multifocal contact lenses, intraocular lenses and laser corneal surgeries.