Identification of apolipoprotein A-I as a "STOP" signal for myopia

Good visual acuity requires that the axial length of the ocular globe is matched to the refractive power of the cornea and lens to focus the images of distant objects onto the retina. During the growth of the juvenile eye, this is achieved through the emmetropization process that adjusts the ocular axial length to compensate for the refractive changes that occur in the anterior segment. A failure of the emmetropization process can result in either excessive or insufficient axial growth, leading to myopia or hyperopia, respectively. Emmetropization is mainly regulated by the retina, which generates two opposite signals: "GO/GROW" signals to increase axial growth and "STOP" signals to block it. The presence of GO/GROW and STOP signals was investigated by a proteomics analysis of the retinas from chicken with experimental myopia and hyperopia. Of 18 differentially expressed proteins that were identified, five displayed an expression profile corresponding to GO/GROW signals, and two corresponded to STOP signals. Western blotting confirmed that apolipoprotein A-I (apoA-I) has the characteristics of a STOP signal both in the retina as well as in the fibrous sclera. In accordance with this, intraocular application of the peroxisome proliferator-activated receptor alpha agonist GW7647 resulted in up-regulation of apoA-I levels and in a significant reduction of experimental myopia. In conclusion, using a comprehensive functional proteomics analysis of chicken ocular growth models we identified targets for ocular growth control. The correlation of elevated apoA-I levels with reduced ocular axial growth points toward a functional relationship with the observed morphological changes of the eye.     

Coevolution of visual signals and eye morphology in Polistes paper wasps

To be effective, signals must propagate through the environment and be detected by receivers. As a result, signal form evolves in response to both the constraints imposed by the transmission environment and receiver perceptual abilities. Little work has examined the extent to which signals may act as selective forces on receiver sensory systems to improve the efficacy of communication. If receivers benefit from accurate signal assessment, selection could favour sensory organs that improve discrimination of established signals. Here, we provide evidence that visual resolution coevolves with visual signals in Polistes wasps. Multiple Polistes species have variable facial patterns that function as social signals, whereas other species lack visual signals. Analysis of 19 Polistes species shows that maximum eye facet size is positively associated with both eye size and presence of visual signals. Relatively larger facets within the eye''s acute zone improve resolution of small images, such as wasp facial signals. Therefore, sensory systems may evolve to optimize signal assessment. Sensory adaptations to facilitate signal detection may represent an overlooked area of the evolution of animal communication.     

Insulin receptor-mediated organ overgrowth in <Emphasis Type="Italic">Drosophila</Emphasis> is not restricted by body size

Recent studies have demonstrated that insulin receptor (Inr) signalling plays an important role in determining organ size and maintaining proportionality in normal animals. However, it is unclear whether the activity of this pathway in a developing organ is invariably a dominant determinant of its mass or whether size can be restricted by other non-autonomous growth regulatory mechanisms if a tissue starts to outgrow the rest of the body. To test this in Drosophila, we induced excess Inr-dependent growth by removal of the Inr signalling antagonist, DPTEN, in the eyes of flies with dramatically different body sizes. Although our data suggest a very limited level of growth competition between organs in animals with giant eyes, there do not appear to be mechanisms by which neighbouring structures substantially inhibit eye overgrowth, even when the resulting organ is many times enlarged relative to the rest of the animal. Overall, our results support a simple model in which organs are normally maintained in proportion to each other, primarily because they all respond similarly to levels of insulin-like factors and other growth regulators. Given the evolutionarily conserved role of insulin receptor signalling in growth control, our data may also help to explain why this pathway is so frequently hyperactivated in mammalian tumours.     

Analysis of Homeostatic Mechanisms in Biochemical Networks

Cell metabolism is an extremely complicated dynamical system that maintains important cellular functions despite large changes in inputs. This “homeostasis” does not mean that the dynamical system is rigid and fixed. Typically, large changes in external variables cause large changes in some internal variables so that, through various regulatory mechanisms, certain other internal variables (concentrations or velocities) remain approximately constant over a finite range of inputs. Outside that range, the mechanisms cease to function and concentrations change rapidly with changes in inputs. In this paper we analyze four different common biochemical homeostatic mechanisms: feedforward excitation, feedback inhibition, kinetic homeostasis, and parallel inhibition. We show that all four mechanisms can occur in a single biological network, using folate and methionine metabolism as an example. Golubitsky and Stewart have proposed a method to find homeostatic nodes in networks. We show that their method works for two of these mechanisms but not the other two. We discuss the many interesting mathematical and biological questions that emerge from this analysis, and we explain why understanding homeostatic control is crucial for precision medicine.     

Tumor necrosis factor-alpha mediates one component of competitive, experience-dependent plasticity in developing visual cortex

Rapid, experience-dependent plasticity in developing visual cortex is thought to be competitive. After monocular visual deprivation, the reduction in response of binocular neurons to one eye is matched by a corresponding increase to the other. Chronic optical imaging in mice deficient in TNFalpha reveals the normal initial loss of deprived-eye responses, but the subsequent increase in response to the open eye is absent. This mutation also blocks homeostatic synaptic scaling of mEPSCs in visual cortex in vitro, without affecting LTP. In monocular cortex, thought not to be subject to competition, responses in TNFalpha mutants are as reduced as in the binocular zone. Pharmacological inhibition of endogenous TNFalpha in wild-type mice phenocopies the knockout. These findings suggest that experience-dependent competition in developing visual cortex is the outcome of two distinct, noncompetitive processes, a loss of deprived-eye responses followed by an apparently homeostatic increase in responses dependent on TNFalpha signaling.     

The refractive development of the eye of the American kestrel (Falco sparverius): a new avian model

Summary Most measures of avian visual performance are carried out on commonly available domestic species such as the chicken, and most of the data on avian induced refractive error deals with chickens. Raptors are predatory birds in which good visual resolving ability is particularly important. Behavioral studies indicate that the eyes of raptors have two to three times the resolving ability of the human eye. The domestic chicken is precocial at hatching whereas most raptors are semi-altricial. This study was an effort to determine if the effect of early visual deprivation on the refractive development of the chicken eye can be reproduced in the American kestrel, a species which is not domesticated and in which the need for acute vision is particularly important.Visual deprivation was achieved by unilaterally applying translucent plastic goggles over the eyes of kestrels two days after hatching. Refractive error was measured using a retinoscope and trial lenses. Ocular growth was monitored by A-scan ultrasonography, and frozen ocular sections of sacrificed birds. The effect of the experimental manipulation on the contralateral control eye and body weight was evaluated each day over a 42-day period. The goggles did not significantly affect the normal changes in body weight or the normal pattern of ocular growth and refractive development in the untreated eyes. An analysis of the refractive state changes as a result of form deprivation was made each week for 6 weeks after hatching on both the treated and untreated eyes in a separate group of experimental birds. Visual form deprivation caused a significant myopic shift in refractive error and a significant increase in the vitreous chamber depth in the treated eyes at 3 and 6 weeks of age. However, the amount of myopia produced is much less than that induced in chicks, and in certain cases hyperopia is produced. The kestrels recover from myopia and hyperopia within 10 days of goggle removal, after 3 to 4 weeks of deprivation.This study is the first indication that chickens may not be a representative bird model for studying form deprivation myopia. First, myopia is not always produced in kestrels in response to form deprivation. Second, kestrels are severely myopic at hatching and therefore, the direction of emmetropization is opposite to that found in hatchling chicks.     

The mechanism of interaction between visual flow and eye velocity signals for heading perception

A translating eye receives a radial pattern of motion that is centered on the direction of heading. If the eye is rotating and translating, visual and extraretinal signals help to cancel the rotation and to perceive heading correctly. This involves (1) an interaction between visual and eye movement signals and (2) a motion template stage that analyzes the pattern of visual motion. Early interaction leads to motion templates that integrate head-centered motion signals in the visual field. Integration of retinal motion signals leads to late interaction. Here, we show that retinal flow limits precision of heading. This result argues against an early, vector subtraction type of interaction, but is consistent with a late, gain field type of interaction with eye velocity signals and neurophysiological findings in area MST of the monkey.     

Harmonic Oscillations in Homeostatic Controllers: Dynamics of the p53 Regulatory System

Homeostatic mechanisms are essential for the protection and adaptation of organisms in a changing and challenging environment. Previously, we have described molecular mechanisms that lead to robust homeostasis/adaptation under inflow or outflow perturbations. Here we report that harmonic oscillations occur in models of such homeostatic controllers and that a close relationship exists between the control of the p53/Mdm2 system and that of a homeostatic inflow controller. This homeostatic control model of the p53 system provides an explanation why large fluctuations in the amplitude of p53/Mdm2 oscillations may arise as part of the homeostatic regulation of p53 by Mdm2 under DNA-damaging conditions. In the presence of DNA damage p53 is upregulated, but is subject to a tight control by Mdm2 and other factors to avoid a premature apoptotic response of the cell at low DNA damage levels. One of the regulatory steps is the Mdm2-mediated degradation of p53 by the proteasome. Oscillations in the p53/Mdm2 system are considered to be part of a mechanism by which a cell decides between cell cycle arrest/DNA repair and apoptosis. In the homeostatic inflow control model, harmonic oscillations in p53/Mdm2 levels arise when the binding strength of p53 to degradation complexes increases. Due to the harmonic character of the oscillations rapid fluctuating noise can lead, as experimentally observed, to large variations in the amplitude of the oscillation but not in their period, a behavior which has been difficult to simulate by deterministic limit-cycle models. In conclusion, the oscillatory response of homeostatic controllers may provide new insights into the origin and role of oscillations observed in homeostatically controlled molecular networks.     

530nm单色光诱导豚鼠近视眼模型的建立

目的应用530 nm单色光光照建立一种新型近视眼动物模型。方法20只约2周龄健康雄性豚鼠,随机分成两组（n=10）,实验组和对照组分别在绿光（530 nm）和白光（色温5000 k）下进行饲养。设置照明参数：光量子数相同,为每秒3×10-4μmol/cm2;实测光强度绿光为0.150 mW/cm2,白光为0.247 mW/cm2。实验前每组进行眼球生物学测量（屈光度、角膜曲率、眼轴各部分长度）,光照后12周重复测量以上数据,每只豚鼠均取右侧眼参数进行统计分析。结果光照前两组生物学测量参数差异无显著性。光照12周后,绿光组屈光度发生-3.125±0.76 D的变化,白光组为-1.075±0.71D,绿光组同对照白光组相比平均形成约2.0 D的近视,差异有显著性;绿光组眼轴和玻璃体腔分别增长0.98±0.13 mm与0.33±0.14 mm,对照组分别为0.77±0.22 mm与0.13±0.14 mm,绿光组较对照组眼轴和玻璃体腔长度延长较快,差异有显著性;光照后两组角膜曲率半径、前房深度和晶状体厚度均发生不同程度增加,但两组间变化差异无显著性。结论530 nm单色光诱导豚鼠眼球眼轴和玻璃体腔长度延长较快,产生近视.     

The development of extraocular muscle calcium homeostasis parallels visuomotor system maturation

Extraocular muscle is modulated by unique genetic and epigenetic factors to produce an atypical phenotype. As a prelude to regulation studies, we characterized the development of cation homeostasis in the predominately fast-twitch extraocular muscles. By atomic absorption spectroscopy, total muscle calcium content declined from birth to postnatal day 27 and, thereafter, stabilized at a low level in limb but increased dramatically in extraocular muscle (to 40x limb values). By ELISA, the slow isoform of sarcoplasmic reticulum Ca2+-ATPase predominated in neonatal eye muscle, but subsequently was largely replaced by the fast isoform. This replacement in eye muscle was completed later than in limb. Residual, slow Ca2+-ATPase likely resides in an unusual slow tonic fiber type characteristic of eye muscle. Maturation of the definitive extraocular muscle Ca2+-ATPase pattern paralleled myofiber Ca2+ and sarcoplasmic reticulum content. These data show that, like myosin heavy chain expression patterns, the development of cation homeostatic mechanisms in extraocular muscle parallels landmarks in the maturation of vision and eye movement control systems. Findings suggest that cation homeostasis in extraocular muscle may be susceptible to perturbations of the developing visual sensory system, as we have previously shown for myosin.     

Nutritional Modulation of Somatotropic Axis-cytokine Relationships in Cattle: A Brief Review

The objective of this review is to summarize data on the interrelationships that exist between nutrition, the endocrine system and their modulation of plasma tumor necrosis factor-α responses to endotoxin in cattle. During stress, intake of nutrients often is compromised and a percentage of available nutrients are diverted away from growth processes to stabilize other physiological processes of a higher survival priority. Management practices that minimize the magnitude and duration of disease stress will aid in speeding the return to homeostatic equilibrium. However, the shift away from growth during stress is almost inevitable as a mechanism to survive. Some degree of control and management of the metabolic cost of disease stress involves understanding the integration of nutritional, endocrine and immune signals by cells and working with the natural homeostatic processes. Endocrine hormones and immune system cytokine signals participate in redirecting nutrient use during disease stress. In an intricate interplay, hormones and cytokines regulate, modify and modulate each other's production and tissue interactions to alter metabolic priorities. Levels of dietary protein and energy intake affect patterns of hormones and cytokines in the blood after endotoxin challenge and further modulate the biological actions of many of these regulatory effectors. In vivo, administration of growth hormone to young calves has significant effects to decrease the many specific physiological responses to endotoxemia. Many aspects of nutrition can attenuate or facilitate this effect.     

Cell density sensing and size determination

The social amoeba Dictyostelium discoideum is one of the leading model systems used to study how cells count themselves to determine the number and/or density of cells. In this review, we describe work on three different cell-density sensing systems used by Dictyostelium. The first involves a negative feedback loop in which two secreted signals inhibit cell proliferation during the growth phase. As the cell density increases, the concentrations of the secreted factors concomitantly increase, allowing the cells to sense their density. The two signals act as message authenticators for each other, and the existence of two different signals that require each other for activity may explain why previous efforts to identify autocrine proliferation-inhibiting signals in higher eukaryotes have generally failed. The second system involves a signal made by growing cells that is secreted only when they starve. This then allows cells to sense the density of just the starving cells, and is an example of a mechanism that allows cells in a tissue to sense the density of one specific cell type. The third cell density counting system involves cells in aggregation streams secreting a signal that limits the size of fruiting bodies. Computer simulations predicted, and experiments then showed, that the factor increases random cell motility and decreases cell-cell adhesion to cause streams to break up if there are too many cells in the stream. Together, studies on Dictyostelium cell density counting systems will help elucidate how higher eukaryotes regulate the size and composition of tissues.     

Regulation of human eye growth by the energy density of the radiation in the retina--a biophysical theory in ophthalmology

A number of theoretical and experimental models analyze regulation of eye growth in humans and animals. In this article we introduce a biophysical theory to explain human eye growth from an energetic point of view. We find different energy densities of the electromagnetic radiation in the retina for hyperopic, emmetropic and myopic eyes. We postulate a relation between the different energy densities of the radiation in the retina and growth regulation by the retina. Based on this relation between physics and biology we are modeling emmetropization, missing emmetropization in severe hyperopia and development and progression of myopia in correspondence with a number of clinical and experimental results.     

An investigation of the mechanisms of eye movement control

Summary Feedback mechanisms exist in all the periferal sense organs including the eye, which acts as a highly efficient position control servo system. Histological studies so far have not revealed the precise circuitry of the eye movement control system but some information about it can be obtained by a study of the sources of feedback. Existing theories have considered three types of feedback originating in the oculomotor tract, in the proprioceptive fibres of the extrinsic eye muscles and from retinal image displacement. In the present experiments an optical arrangement has been used to vary or eliminate the amount of information available from retinal image motion, and the response of the eye to simple harmonic displacement of a target has been recorded. The response curves of gain (eyeball movement divided by target motion) against frequency indicate that the system is lion linear when the image falls in the retinal region which is insensitive to position. Outside this area, retinal image position is used as negative feedback but the information from the oculomotor tract must be regenerative. There is also evidence for feedback proportional to the first derivative of eyeball position and this function is ascribed to the proprioceptive signals; this form of feedback appears to saturate for large amplitude movements, thus avoiding heavy damping of the flick movements.A schematic eye movement control system having the same characteristics as the eye is proposed. The transfer function of this system indicates that it should be unstable if the sign of the retinal image feedback loop is reversed. Experiments with this form of feedback show that steady fixation is impossible and the eye performs a pendular nystagmus.     

Aberrations of chick eyes during normal growth and lens induction of myopia

Understanding the control of eye growth may lead to the prevention of nearsightedness (myopia). Chicks develop refractive errors in response to defocusing lenses by changing the rate of eye elongation. Changes in optical image quality and the optical signal in lens compensation are not understood. Monochromatic ocular aberrations were measured in 16 chicks that unilaterally developed myopia in response to unilateral goggles with −15D lenses and in 6 chicks developing naturally. There is no significant difference in higher-order root mean square aberrations (RMSA) between control eyes of the goggled birds and eyes of naturally developing chicks. Higher-order RMSA for a constant pupil size exponentially decreases in the chick eye with age more slowly than defocus. In the presence of a defocusing lens, the exponential decrease begins after day 2. In goggled eyes, asymmetric aberrations initially increase significantly, followed by an exponential decrease. Higher-order RMSA is significantly higher in goggled eyes than in controls. Equivalent blur, a new measure of image quality that accounts for increasing pupil size with age, exponentially decreases with age. In goggled eyes, this decrease also occurs after day 2. The fine optical structure, reflected in higher-order aberrations, may be important in understanding normal development and the development of myopia.     

视觉功能训练联合托吡卡胺滴眼液治疗假性近视的临床疗效观察

摘要 目的：探讨视觉功能训练联合托吡卡胺滴眼液在治疗假性近视中的临床疗效。方法：选取中国人民解放军陆军特色医学中心眼科和重庆佑佑宝贝妇儿医院眼科2019年2月至2019年8月收治的400例假性近视患儿作为研究对象,将其随机分为对照组和观察组(n=200)。对照组给予滴眼液缓解眼疲劳治疗,观察组则采用视觉功能训练联合托吡卡胺滴眼液治疗。比较两组患儿治疗前及治疗2个月、6个月后裸眼视力、眼轴长度、屈光度、正相对调节量和视疲劳评分的变化。结果：治疗2个月和6个月后,观察组患儿裸眼视力分别为(0.75±0.05)和(0.81±0.04),较对照组显著上升(P<0.05);屈光度分别为(+0.05±0.50)和(+0.06±0.48),明显高于对照组(P<0.05);正相对调节量检测结果依次是(-1.98±0.07)和(-2.51±0.24),较对照组明显增加(P<0.05)。两组患儿视觉感知双眼视功能均有明显改善,其中观察组视觉功能恢复显著高于对照组(P<0.05)。视疲劳调查显示观察组患儿视疲劳评分分别为(6.90±0.89)分和(3.91±0.89)分,显著低于对照组(P<0.05)。结论：视觉功能训练联合托吡卡胺滴眼液治疗能有效提高患儿裸眼视力、改善屈光度、正相对调节量和视觉感知功能,从而减少视疲劳,预防近视。     

Homeostatic signals do not drive post-thymic T cell maturation

Recent thymic emigrants, the youngest T cells in the lymphoid periphery, undergo a 3 week-long period of functional and phenotypic maturation before being incorporated into the pool of mature, na?ve T cells. Previous studies indicate that this maturation requires T cell exit from the thymus and access to secondary lymphoid organs, but is MHC-independent. We now show that post-thymic T cell maturation is independent of homeostatic and costimulatory pathways, requiring neither signals delivered by IL-7 nor CD80/86. Furthermore, while CCR7/CCL19,21-regulated homing of recent thymic emigrants to the T cell zones within the secondary lymphoid organs is not required for post-thymic T cell maturation, an intact dendritic cell compartment modulates this process. It is thus clear that, unlike T cell development and homeostasis, post-thymic maturation is focused not on interrogating the T cell receptor or the cell's responsiveness to homeostatic or costimulatory signals, but on some as yet unrecognized property.     

Rapid,Accurate, and Non-Invasive Measurement of Zebrafish Axial Length and Other Eye Dimensions Using SD-OCT Allows Longitudinal Analysis of Myopia and Emmetropization

Refractive errors in vision can be caused by aberrant axial length of the eye, irregular corneal shape, or lens abnormalities. Causes of eye length overgrowth include multiple genetic loci, and visual parameters. We evaluate zebrafish as a potential animal model for studies of the genetic, cellular, and signaling basis of emmetropization and myopia. Axial length and other eye dimensions of zebrafish were measured using spectral domain-optical coherence tomography (SD-OCT). We used ocular lens and body metrics to normalize and compare eye size and relative refractive error (difference between observed retinal radial length and controls) in wild-type and lrp2 zebrafish. Zebrafish were dark-reared to assess effects of visual deprivation on eye size. Two relative measurements, ocular axial length to body length and axial length to lens diameter, were found to accurately normalize comparisons of eye sizes between different sized fish (R² = 0.9548, R² = 0.9921). Ray-traced focal lengths of wild-type zebrafish lenses were equal to their retinal radii, while lrp2 eyes had longer retinal radii than focal lengths. Both genetic mutation (lrp2) and environmental manipulation (dark-rearing) caused elongated eye axes. lrp2 mutants had relative refractive errors of −0.327 compared to wild-types, and dark-reared wild-type fish had relative refractive errors of −0.132 compared to light-reared siblings. Therefore, zebrafish eye anatomy (axial length, lens radius, retinal radius) can be rapidly and accurately measured by SD-OCT, facilitating longitudinal studies of regulated eye growth and emmetropization. Specifically, genes homologous to human myopia candidates may be modified, inactivated or overexpressed in zebrafish, and myopia-sensitizing conditions used to probe gene-environment interactions. Our studies provide foundation for such investigations into genetic contributions that control eye size and impact refractive errors.