19 research outputs found
Inositol and protein kinase C in the prevention of neural tube defects.
A number of mouse genetic mutants develop neural tube defects (NTDs). In some cases, defects can be prevented by administration of folic acid during pregnancy, whereas in other mutants there is no response. This parallels the human situation in which a proportion of NTDs appear resistant to folic acid therapy. Curly tail is the best characterised mouse model of folic acid-resistant NTDs. Previously it was shown that the incidence of spina bifida in curly tail mice can be reduced by administration of inositol during embryonic development. In this thesis, I compared the effectiveness of two isomers, myo- and D-chiro-inositol, with administration either directly to embryos in vitro, or to pregnant females by subcutaneous or oral routes. Although both inositols exerted a preventive effect on spina bifida, by all routes of administration, D-chiro-inositol consistently exhibited greater potency than myo-inositol. The protective effect of inositol has been shown previously to be mediated through the activity of the inositol/lipid cycle and to depend on downstream activation of protein kinase C (PKC). In the studies decscribed in this thesis, I examined the role of PKC in more detail. The expression of PKC isoforms was first examined by irrmiunohistochemistry, Broad spectrum chemical inhibitors were then used in whole embryo culture to confirm that one or more PKC isoforms are indispensable for normalisation of neural tube closure by inositol. Specific peptide inhibitors were then applied, and revealed that PKC beta I, gamma and zeta are most important in the protective pathway. Finally, I demonstrated that inositol stimulates cell proliferation in the hindgut of curly tail embryos, reversing the imbalance of cell proliferation that is known to lead, via enhanced ventral curvature of the caudal region, to delay or failure of neural tube closure
Using digital and hand printing techniques to compensate for loss: re-establishing colour and texture in historic textiles
Conservators use a range of 'gap filling' techniques to improve the structural stability and presentation of objects. Textile conservators often use fabric supports to provide reinforcement for weak areas of a textile and to provide a visual infill in missing areas. The most common technique is to use dyed fabrics of a single colour but while a plain dyed support provides good reinforcement, it can be visually obtrusive when used with patterned or textured textiles. Two recent postgraduate dissertation projects at the Textile Conservation Centre (TCC) have experimented with hand printing and digital imaging techniques to alter the appearance of support fabrics so that they are less visually obtrusive and blend well with the colour and texture of the textile being supported. Case studies demonstrate the successful use of these techniques on a painted hessian rocking horse and a knitted glove from an archaeological context
Animal Models of Human Cerebellar Ataxias: a Cornerstone for the Therapies of the Twenty-First Century
D-chiro-inositol is more effective than myo-inositol in preventing folate-resistant mouse neural tube defects
Reversal of behavioural phenotype by the cannabinoid-like compound VSN16R in fragile X syndrome mice.
Fragile X Syndrome is the most common inherited intellectual disability and mono-genetic cause of autism spectrum disorder. It is a neurodevelopmental condition occurring due to a CGG trinucleotide expansion in the FMR1 gene. Polymorphisms and variants in large-conductance calcium-activated potassium channels are increasingly linked to intellectual disability and loss of FMR protein caused reduced large-conductance calcium-activated potassium channel activity leading to abnormalities in synapse function. Using the cannabinoid-like large-conductance calcium-activated potassium channel activator VSN16R we rescued behavioural deficits such as repetitive behaviour, hippocampal dependent tests of daily living, hyperactivity and memory in a mouse model of fragile X syndrome. VSN16R has been shown to be safe in a phase 1 study in healthy volunteers and in a phase 2 study in people with Multiple Sclerosis with high oral bioavailability and no serious adverse effects reported. VSN16R could therefore be directly utilised in a fragile X syndrome clinical study. Moreover, VSN16R showed no evidence of tolerance, which strongly suggests that chronic VSN16R may have great therapeutic value for fragile X syndrome and autism spectrum disorder. This study provides new insight into the pathophysiology of fragile X syndrome and identifies a new pathway for drug intervention for this debilitating disorder
NNZ-2566, a novel analog of (1-3) IGF-1, as a potential therapeutic agent for fragile X syndrome
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. Previous studies have implicated mGlu5 in the pathogenesis of the disease, and many agents that target the underlying pathophysiology of FXS have focused on mGluR5 modulation. In the present work, a novel pharmacological approach for FXS is investigated. NNZ-2566, a synthetic analog of a naturally occurring neurotrophic peptide derived from insulin-like growth factor-1 (IGF-1), was administered to fmr1 knockout mice correcting learning and memory deficits, abnormal hyperactivity and social interaction, normalizing aberrant dendritic spine density, overactive ERK and Akt signaling, and macroorchidism. Altogether, our results indicate a unique disease-modifying potential for NNZ-2566 in FXS. Most importantly, the present data implicate the IGF-1 molecular pathway in the pathogenesis of FXS. A clinical trial is under way to ascertain whether these findings translate into clinical effects in FXS patients
Natural AD-like neuropathology in Octodon degus: Impaired burrowing and neuroinflammation
Alzheimer’s disease (AD) is the most common cause of dementia, affecting more than 36 million people worldwide. Octodon degus, a South American rodent, has been found to spontaneously develop neuropathological signs of AD, including amyloid-β (Aβ) and tau deposits, as well as a decline in cognition with age. Firstly, the present work introduces a novel behavioral assessment for O. degus - the burrowing test - which appears to be a useful tool for detecting neurodegeneration in the O. degus model for AD. Such characterization has potentially wide-ranging implications, because many of these changes in species-typical behaviors are reminiscent of the impairments in activities of daily living (ADL), so characteristic of human AD. Furthermore, the present work characterizes the ADlike neuropathology in O. degus from a gene expression point of view, revealing a number of previously unreported AD biomarkers, which are found in human AD: amyloid precursor protein (APP), apolipoprotein E (ApoE), oxidative stressrelated genes from the NFE2L2 and PPAR pathway, as well as pro-inflammatory cytokines and complement proteins, in agreement with the known link between neurodegeneration and neuroinflammation. In summary, the present results confirm a natural neuropathology in O. degus with similar characteristics to AD at behavioral, cellular and molecular levels. These characteristics put O. degus in a singular position as a natural rodent model for research into AD pathogenesis and therapeutics against AD.Research was conducted under permit No. 5193 issued by the Servicio Agrícola y Ganadero, Chile, with the supervision of the Ethics Committee of the Faculty of Sciences, Universidad de Chile
Distribution of AGG interruption patterns within nine world populations
The CGG trinucleotide repeat within the FMR1 gene is associated with multiple clinical disorders, including fragile X-associated tremor/ataxia syndrome, fragile X-associated primary ovarian insufficiency, and fragile X syndrome. Differences in the distribution and prevalence of CGG repeat length and of AGG interruption patterns have been reported among different populations and ethnicities. In this study we characterized the AGG interruption patterns within 3,065 normal CGG repeat alleles from nine world populations including Australia, Chile, United Arab Emirates, Guatemala, Indonesia, Italy, Mexico, Spain, and United States. Additionally, we compared these populations with those previously reported, and summarized the similarities and differences. We observed significant differences in AGG interruption patterns. Frequencies of longer alleles, longer uninterrupted CGG repeat segments and alleles with greater than 2 AGG interruptions varied between cohorts. The prevalence of fragile X syndrome and FMR1 associated disorders in various populations is thought to be affected by the total length of the CGG repeat and may also be influenced by the AGG distribution pattern. Thus, the results of this study may be important in considering the risk of fragile X-related conditions in various populations
Folic Acid Supplementation Diminishes Diabetes- and Glucose-Induced Dysmorphogenesis in Rat Embryos In Vivo and In Vitro
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Genome Sequencing Variations in the Octodon degus, an Unconventional Natural Model of Aging and Alzheimer's Disease.
The degu (Octodon degus) is a diurnal long-lived rodent that can spontaneously develop molecular and behavioral changes that mirror those seen in human aging. With age some degu, but not all individuals, develop cognitive decline and brain pathology like that observed in Alzheimer's disease including neuroinflammation, hyperphosphorylated tau and amyloid plaques, together with other co-morbidities associated with aging such as macular degeneration, cataracts, alterations in circadian rhythm, diabetes and atherosclerosis. Here we report the whole-genome sequencing and analysis of the degu genome, which revealed unique features and molecular adaptations consistent with aging and Alzheimer's disease. We identified single nucleotide polymorphisms in genes associated with Alzheimer's disease including a novel apolipoprotein E (Apoe) gene variant that correlated with an increase in amyloid plaques in brain and modified the in silico predicted degu APOE protein structure and functionality. The reported genome of an unconventional long-lived animal model of aging and Alzheimer's disease offers the opportunity for understanding molecular pathways involved in aging and should help advance biomedical research into treatments for Alzheimer's disease