Identification and functional characterization of two patterning genes, Zic4 and Ten_m3, in topographic map formation of the visual pathway

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, February 2010.Cataloged from PDF version of thesis.Includes bibliographical references (p. 114-123).A central feature of visual pathway development is its organization into retinotopic maps. The developmental process by which these maps form involves a transition from early patterning cues to arrays of axonal guidance factors allowing the relative order of retinotopic axons to be preserved. Mechanisms linking patterning molecules of early development to topographic wiring and subsequent functional responses are not well understood. In this thesis, I performed a microarray screen comparing gene expression in early visual and auditory regions of the thalamus in order to identify early patterning candidates with a potential role in visual pathway differentiation. Among the candidates enriched in the visual thalamus, the transcription factor, Zic4, was found to be expressed in gradients of the developing retina, lateral geniculate nucleus (LGN) and primary visual cortex (V 1). Mice lacking Zic4 exhibited a deficit in eye-specific patterning to the thalamus that was complementary to the phenotype seen in mice lacking Tenm3, a type II homophilic transmembrane receptor and transcriptional regulator. Using intrinsic signal optical imaging techniques, I characterized the functional properties of primary visual cortical retinotopic maps in Zic4 and Ten_m3 null mice and identified complementary changes in the ipsilateral representation of V1, as well as evidence for eye-specific mismatch in the cortical binocular zone. Additionally, complementary positional shifts in VI were found in these mutants identifying a bidirectional modulation of mapping mechanisms in the visual pathway.(cont.) In order to test whether Zic4 and Ten_m3 interact in serial or parallel pathways, I analyzed the retinogeniculate and cortical maps in the combination mutant. The Ten_m3/Zic4 double null mouse exhibited a partial rescue of retinogeniculate mapping and a complete reversal of the cortical changes found in either mutant alone, suggesting that the two genes interact to modulate common downstream effectors in opposite directions. In sum, this thesis presents a gene microarray screen used to identify Zic4 as a novel visual patterning gene, characterizes its loss-of-function phenotype on retinotopic mapping in the thalamus and cortex, and studies its antagonistic interaction with Ten_m3, another visual pathway patterning gene with a complementary loss-of-function phenotype.by Sam H. Horng.Ph.D

Performance Analysis of Position Tracking Control With PID Controller Using An Improved Optimization Technique

An Electro-Hydraulic Actuator (EHA) system is usually utilized in production industry such as automotive industry which requires precision, high force and long operating hours. When dealing with the production of engineering parts that require precision, high force and long operating hours, a controller is usually required. It is observed from the literature, an appropriate tuning technique is essential in order to obtain optimal controller’s performance. Therefore, a computational tuning technique, namely Priority-based Fitness Particle Swarm Optimization (PFPSO) is proposed to obtain the parameters of the Proportional-Integral-Derivative (PID) controller in this paper. The performance of the EHA system will be evaluated and compared based on the priority characters of the PFPSO tuning technique, which included settling time and overshoot percentage that affect the output results of the EHA system. As a result, it is observed that the priority based on settling time produced a better result, which enhances the steady-state performance of the EHA system that fulfills the requirement of the precision contro

Classical and metaheuristic optimizations performance in an electro-hydraulic control system

Electro-Hydraulic Actuator (EHA) system is a prevalent mechanism in industrial sectors. This system commonly involving works that required high force such as steel, automotive and aerospace industries. It is a challenging task to acquire precision when dealing with a system that can produce high force. Besides, since most of the mechanical actuator performance varies with time, it is even difficult to ensure its robustness characteristic towards time. Therefore, this paper proposed the industrial’s wellknown controller, which is the Proportional-Integral-Derivative (PID) controller that can improve the precision of the EHA system. Then, an enhanced PID controller, which is the fractional order PID (FOPID) controller will be applied. A classical and metaheuristic optimization methods, which are gradient descent (GD) and particle swarm optimization (PSO) algorithm are used to obtaining the optimal gains of both controllers. In addition, to examine the tracking performance of the designed controllers, the performance of the proposed optimization algorithms is analysed. As a result, in a practical point of view, it can be inferred that the PSO algorithm is capable to generate more practical sense of gains compared with GD, and the precision characteristic of the FOPID is greater than the PID controller

Comparison Of Fractional Order PID Controller And Sliding Mode Controller With Computational Tuning Algorithm

The industry processes involving punching, lifting, and digging usually require high precision, high force and long operating hours that increase the prestige in the usage of the electrohydraulic actuator (EHA) system. These processes with the companion of the EHA system usually possess high dynamic complexities that are hard to be controlled and require well-designed and powerful control system. Therefore, this paper will involve the examination of the designed controllers which is applied to the EHA system. Firstly, the conventional proportional-integral-derivative (PID) controller which is the famous controller in the industry is designed. Then, the improved PID controller, which is known as the fractional order PID (FO-PID) controller is designed. After that, the design of the gradually famous robust controller in the education field, which is the sliding mode controller (SMC) is performed. Since the controller’s parameters are essentially influencing the performance of the controller, the meta-heuristic optimization method, which is the particle swarm optimization (PSO) tuning method is applied. The variation in the system’s parameter is applied to evaluate the performance of the designed controllers. Referring to the outcome analysis, the increment of 59.3% is obtained in the comparison between PID and FOPID, while the increment of 67.13% is obtained in the comparison of the PID with the SMC controller. As a conclusion, all of the controllers perform differently associated with their own advantages and disadvantag

PLoS Biol

Inflammation of the central nervous system (CNS) induces endothelial blood-brain barrier (BBB) opening as well as the formation of a tight junction barrier between reactive astrocytes at the Glia Limitans. We hypothesized that the CNS parenchyma may acquire protection from the reactive astrocytic Glia Limitans not only during neuroinflammation but also when BBB integrity is compromised in the resting state. Previous studies found that astrocyte-derived Sonic hedgehog (SHH) stabilizes the BBB during CNS inflammatory disease, while endothelial-derived desert hedgehog (DHH) is expressed at the BBB under resting conditions. Here, we investigated the effects of endothelial Dhh on the integrity of the BBB and Glia Limitans. We first characterized DHH expression within endothelial cells at the BBB, then demonstrated that DHH is down-regulated during experimental autoimmune encephalomyelitis (EAE). Using a mouse model in which endothelial Dhh is inducibly deleted, we found that endothelial Dhh both opens the BBB via the modulation of forkhead box O1 (FoxO1) transcriptional activity and induces a tight junctional barrier at the Glia Limitans. We confirmed the relevance of this glial barrier system in human multiple sclerosis active lesions. These results provide evidence for the novel concept of "chronic neuroinflammatory tolerance" in which BBB opening in the resting state is sufficient to stimulate a protective barrier at the Glia Limitans that limits the severity of subsequent neuroinflammatory disease. In summary, genetic disruption of the BBB generates endothelial signals that drive the formation under resting conditions of a secondary barrier at the Glia Limitans with protective effects against subsequent CNS inflammation. The concept of a reciprocally regulated CNS double barrier system has implications for treatment strategies in both the acute and chronic phases of multiple sclerosis pathophysiology

The impact of active community-based survey on dementia detection ratio in Taiwan: A cohort study with historical control

BackgroundAlthough early dementia detection is crucial to optimize the treatment outcomes and the management of associated symptoms, the published literature is scarce regarding the effectiveness of active screening protocols in enhancing dementia awareness and increasing the rate of early detection. The present study compared the detection ratio of an active community-based survey for dementia detection with the detection ratio of passive screening during routine clinical practice. Data for passive screening were obtained from the National Health Insurance (NHI) system, which was prospectively collected during the period from 2000 to 2003.DesignA population-based cohort study with historical control.SettingTaiwan.ParticipantsA total of 183 participants aged 65 years or older were involved in a community-based survey. Data from 1,921,308 subjects aged 65 years or older were retrieved from the NHI system.MeasurementsAn adjusted detection ratio, defined as a ratio of dementia prevalence to incidence was used.ResultsThe results showed that the dementia prevalence during the 2000–2003 period was 2.91% in the elderly population, compared with a prevalence of 6.59% when the active survey was conducted. The incidence of dementia in the active survey cohort was 1.83%. Overall, the dementia detection ratio was higher using active surveys [4.23, 95% confidence interval (CI): 2.68–6.69] than using passive detection (1.45, 95% CI: 1.43–1.47) for those aged 65–79 years. Similar findings were observed for those aged 80 years and older.ConclusionThe implementation of an active community-based survey led to a 3-fold increase in the detection rate of early dementia detection compared to passive screening during routine practice

The Transcriptional Activator Krüppel-like Factor-6 Is Required for CNS Myelination

Growth factors of the gp130 family promote oligodendrocyte differentiation, and viability, and myelination, but their mechanisms of action are incompletely understood. Here, we show that these effects are coordinated, in part, by the transcriptional activator Krüppel-like factor-6 (Klf6). Klf6 is rapidly induced in oligodendrocyte progenitors (OLP) by gp130 factors, and promotes differentiation. Conversely, in mice with lineage-selective Klf6 inactivation, OLP undergo maturation arrest followed by apoptosis, and CNS myelination fails. Overlapping transcriptional and chromatin occupancy analyses place Klf6 at the nexus of a novel gp130-Klf-importin axis, which promotes differentiation and viability in part via control of nuclear trafficking. Klf6 acts as a gp130-sensitive transactivator of the nuclear import factor importin-α5 (Impα5), and interfering with this mechanism interrupts step-wise differentiation. Underscoring the significance of this axis in vivo, mice with conditional inactivation of gp130 signaling display defective Klf6 and Impα5 expression, OLP maturation arrest and apoptosis, and failure of CNS myelination

Deletion of Ten-m3 Induces the Formation of Eye Dominance Domains in Mouse Visual Cortex

The visual system is characterized by precise retinotopic mapping of each eye, together with exquisitely matched binocular projections. In many species, the inputs that represent the eyes are segregated into ocular dominance columns in primary visual cortex (V1), whereas in rodents, this does not occur. Ten-m3, a member of the Ten-m/Odz/Teneurin family, regulates axonal guidance in the retinogeniculate pathway. Significantly, ipsilateral projections are expanded in the dorsal lateral geniculate nucleus and are not aligned with contralateral projections in Ten-m3 knockout (KO) mice. Here, we demonstrate the impact of altered retinogeniculate mapping on the organization and function of V1. Transneuronal tracing and c-fos immunohistochemistry demonstrate that the subcortical expansion of ipsilateral input is conveyed to V1 in Ten-m3 KOs: Ipsilateral inputs are widely distributed across V1 and are interdigitated with contralateral inputs into eye dominance domains. Segregation is confirmed by optical imaging of intrinsic signals. Single-unit recording shows ipsilateral, and contralateral inputs are mismatched at the level of single V1 neurons, and binocular stimulation leads to functional suppression of these cells. These findings indicate that the medial expansion of the binocular zone together with an interocular mismatch is sufficient to induce novel structural features, such as eye dominance domains in rodent visual cortex