No description available.

No description available.

Fragile X syndrome (FXS), the most common cause of inherited mental impairment, is caused by the loss of expression of the fragile X mental retardation protein (FMRP). As an RNA binding protein, FMRP has been proposed to regulate the transport and translation of specific message RNA (mRNA). It has been reported that FMRP uses its RGG box domain to bind mRNA targets that form a G-quadruplex structure, structure believed to be important for FMRP recognition of at least a subclass of its mRNA targets. We have hypothesized that the interaction of FMRP with selected relevant mRNA targets occurs in a G-quadruplex dependent manner. By analyzing the structure of two FMRP in vivo mRNA targets, Shank1 mRNA and BASP1 mRNA, and their interactions with FMRP, we showed a high-affinity interaction between Shank1 RNA G-quadruplex and FMRP. The other G-quadruplex forming mRNA BASP1, however, interacts with FMRP using other structural elements. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences; / Pharmaceutics / MS; / Thesis;

Fragile X syndrome (FXS) is the most commonly inherited form of intellectual disability as well as a leading genetic cause of autism spectrum disorder. It is typically the result of a trinucleotide repeat expansion in the Fmr1 gene which leads to loss of the encoded protein, fragile X mental retardation protein (FMRP). Animal model studies over the past twenty years, mainly focusing on the Fmr1 knockout (KO) mouse, have uncovered several cellular and behavioural phenotypes associated with the loss of FMRP. Seminal work using the Fmr1 KO mouse found that metabotropic glutamate receptor mediated long-term depression (mGluR-LTD) in the hippocampus is both exaggerated (Huber et al., 2002) and independent of new protein synthesis (Nosyreva & Huber, 2006). These findings, together with studies focusing on other brain regions including the prefrontal cortex (Zhao et al., 2005) and amygdala (Suvrathan et al., 2010), have contributed to the ‘mGluR theory of FXS’ (Bear et al., 2004) which suggests that group 1 metabotropic receptor function is exaggerated in FXS. The development of genetically modified rats allows the modelling of FXS in an animal model with more complex cognitive and social behaviours than has been previously available. It also provides an opportunity for comparison of phenotypes across mammalian species that result from FMRP deletion. While the study of Fmr1 rats can significantly contribute to our understanding of FXS, we must first confirm the assumption that cellular phenotypes are conserved across mouse and rat models. In this thesis, we first aimed to test if the key cellular and synaptic phenotypes that contribute to the ‘mGluR theory of FXS’ are conserved in both the hippocampus and amygdala of Fmr1 KO rats. In agreement with mouse studies, we found mGluR-LTD was both enhanced and independent of new protein synthesis in Fmr1 KO rats. Similarly, group 1 mGluR long-term potentiation (LTP) was significantly decreased at both cortical and thalamic inputs to the lateral amygdala. Secondly, we investigated mPFC intrinsic excitability and synaptic plasticity in Fmr1 KO rats. The mPFC plays a key role in several of the cognitive functions that are affected in fragile X patients including attention, cognitive flexibility and anxiety (Goto et al., 2010). The regulation of mPFC plasticity and intrinsic excitability has also been associated with mGluR signalling. Here we found that intralaminar LTP in the mPFC showed an age-dependent deficit in Fmr1 KO rats. The mPFC also provides top down control of several cortical and subcortical regions through long-range connectivity. One pathway of interest in the study of FXS is mPFC-amygdala connectivity which is associated with fear learning and anxiety behaviours (Burgos- Robles et al., 2009). Using retrograde tracing, we showed layer 5 pyramidal neurons that provide long-range connections to the basal amygdala were intrinsically hypoexcitable in Fmr1 KO rats. This phenotype could possibly be explained through homeostatic changes in the axon initial segment which regulates neuronal excitability. This work provides the first evidence for conservation of cellular phenotypes associated with the loss of FMRP in mice and rats which will be key in the interpretation of future studies using Fmr1 KO rats. We also provide evidence of deficits in mPFC long-range connectivity to the basal amygdala, a pathway that is associated with FXS relevant behaviours. Together this highlights how study of the rat model of FXS can complement existing studies of Fmr1 KO mice as well as provide new insights into the pathophysiology resulting from the loss of FMRP. Some of this work was published in Till et al., 2015.

No description available.

In recent years, there are more and more researches on semi-fragile watermarking scheme which can resist JPEG compression. But, there are few researches focused on the recovery of semi-fragile watermarked image. Therefore, in this paper, we not only present a semi-fragile watermarking scheme which can resist JPEG compression but use the error correction code (Reed-Solomon Code) to recover the area being malicious manipulated. At first, we use the semi-fragile watermarking scheme proposed by Lin and Hsieh to detect the counterfeit under the JPEG compression [9]. Its main effect is to resist JPEG compression and to detect the attacked parts without the need of the original image. And then, we will introduce how we use RS code to recover the attacked parts being detected by the semi-fragile watermarking scheme. We use the scheme ¡§Interleaving¡¨ to spread the local pixels to the global area. Next, we encode to each little image block by RS code. The redundant symbols generated by RS code will be signed to be signature attached with the watermarked image. Finally, the receiver can use semi-fragile watermarking scheme to detect attacked part and use the information of the signature to decode these attacked parts. Additionally, we also discuss how to decrease the load of the signature, thus, it can not significant loading of the watermarked image.

When video transmits over error-prone channels, the fragile property of compressed stream makes it sensitive to bit error. Often even a slight error can make video unable to correctly decode. Therefore, there is a need for a good error control method to solve the problem. This paper presents a novel error detection and concealment strategy along with watermark technique. The proposed watermark-based scheme utilizes two kinds of watermark technique, a fragile watermark is used to detect and localize errors, and a robust watermark is used to reconstruct error areas when errors exist. Experimental results show the proposed watermark-based scheme has good error detection capabilities and complete error recovery information, therefore significant improves video quality after errors happened, especially in the case of higher loss probabilities.

Thesis (Ph.D.)--Brown University, 2008. / Advisor : Mark F. Bear. Includes bibliographical references.

Fragile X Protein (FMRP) is an RNA binding protein linked to the most common form of inherited mental retardation, Fragile X syndrome (FraX). Despite its ubiquitous expression and presence of non-neuronal phenotypes, FMRP function remains understudied outside of neural and synaptic development. In addition to severe cognitive deficits, FraX etiology also includes postpubescent macroorchidism, which is thought to occur due to overproliferation of the germline. Using a Drosophila model for FraX, I have shown that FMRP controls germline proliferation as well as dorso-ventral polarity during oogenesis. dFmr1 null ovaries exhibit egg chambers with increased numbers of germ cells and ventralized embryos. The number of cyclin E and phosphohistone H3 positive cells is increased in dFmr1 germaria compared to wild-type, suggesting that the mutant germline cells exhibit defects in proliferation. In addition, BrdU incorporation is increased during vitellogenesis, consistent with a prolonged S phase for endoreplicating nurse cells. Here I report the FMRP controls the levels of cbl mRNA in the ovary and that the overproliferation and polarity defects found in dFmr1 ovaries can be rescued by reducing cbl dosage in half. These data suggest a model whereby FMRP regulates cellular proliferation and polarity during oogenesis by controlling the E3 ubiquitin ligase cbl.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social interaction and communication as well as ritualistic repetitive behaviors. Epidemiological studies suggest that maternal immune activation (MIA) during pregnancy may be a risk factor for ASD. To study MIA in a laboratory setting, we injected mouse dams (C57BL/6) with lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (Poly IC) during mid-gestation to mimic a bacterial or viral infection, respectively. We also performed the same Poly IC treatment on a mouse model of Fragile X syndrome (i.e. Fmr1 knockout), a genetic disease with high incidences of ASD. We found modest female-specific impairments in social interaction and striking male-specific increases in repetitive behavior in adult MIA offspring. Moreover, prenatal Poly IC treatment caused genotype-specific deficits in sociability in addition to reduced body weight and rearing in Fmr1 knockout mice only. Therefore, ASD-related behaviors caused by MIA may be sex, treatment, and/or genotype-dependent.