Search results for "Normal"
showing 10 items of 2571 documents
Genetic and Chemical Modifiers Of A CUG Toxicity Model in Drosophila
2007
Non-coding CUG repeat expansions interfere with the activity of human Muscleblind-like (MBNL) proteins contributing to myotonic dystrophy 1 (DM1). To understand this toxic RNA gain-of-function mechanism we developed a Drosophila model expressing 60 pure and 480 interrupted CUG repeats in the context of a non-translatable RNA. These flies reproduced aspects of the DM1 pathology, most notably nuclear accumulation of CUG transcripts, muscle degeneration, splicing misregulation, and diminished Muscleblind function in vivo. Reduced Muscleblind activity was evident from the sensitivity of CUG-induced phenotypes to a decrease in muscleblind genetic dosage and rescue by MBNL1 expression, and furthe…
Functional Assessment of Variants in the TSC1 and TSC2 Genes Identified in Individuals with Tuberous Sclerosis Complex
2011
The effects of missense changes and small in-frame deletions and insertions on protein function are not easy to predict, and the identification of such variants in individuals at risk of a genetic disease can complicate genetic counselling. One option is to perform functional tests to assess whether the variants affect protein function. We have used this strategy to characterize variants identified in the TSC1 and TSC2 genes in individuals with, or suspected of having, Tuberous Sclerosis Complex (TSC). Here we present an overview of our functional studies on 45 TSC1 and 107 TSC2 variants. Using a standardized protocol we classified 16 TSC1 variants and 70 TSC2 variants as pathogenic. In add…
Current development of CFTR potentiators in the last decade
2020
Cystic fibrosis (CF) is a genetic disorder produced by the loss of function of CFTR, a main chloride channel involved in transepithelial salt and water transport. CFTR function can be rescued by small molecules called "potentiators" which increase gating activity of CFTR on epithelial surfaces. High throughput screening (HTS) assays allowed the identification of new chemical entities endowed with potentiator properties, further improved through medicinal chemistry optimization. In this review, the most relevant classes of CFTR potentiators developed in the last decade were explored, focusing on structure-activity relationships (SAR) of the different chemical entities, as a useful tool for t…
Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules.
2004
AbstractPolyglutamine expansion (polyQ) in the protein huntingtin is pathogenic and responsible for the neuronal toxicity associated with Huntington's disease (HD). Although wild-type huntingtin possesses antiapoptotic properties, the relationship between the neuroprotective functions of huntingtin and pathogenesis of HD remains unclear. Here, we show that huntingtin specifically enhances vesicular transport of brain-derived neurotrophic factor (BDNF) along microtubules. Huntingtin-mediated transport involves huntingtin-associated protein-1 (HAP1) and the p150Glued subunit of dynactin, an essential component of molecular motors. BDNF transport is attenuated both in the disease context and b…
Huntingtin mediates dendritic transport of β-actin mRNA in rat neurons
2011
Transport of mRNAs to diverse neuronal locations via RNA granules serves an important function in regulating protein synthesis within restricted sub-cellular domains. We recently detected the Huntington's disease protein huntingtin (Htt) in dendritic RNA granules; however, the functional significance of this localization is not known. Here we report that Htt and the huntingtin-associated protein 1 (HAP1) are co-localized with the microtubule motor proteins, the KIF5A kinesin and dynein, during dendritic transport of β-actin mRNA. Live cell imaging demonstrated that β-actin mRNA is associated with Htt, HAP1, and dynein intermediate chain in cultured neurons. Reduction in the levels of Htt, H…
Sp1 transcription factor interaction with accumulated prelamin a impairs adipose lineage differentiation in human mesenchymal stem cells: essential r…
2012
Abstract Lamin A (LMNA)-linked lipodystrophies may be either genetic (associated with LMNA mutations) or acquired (associated with the use of human immunodeficiency virus protease inhibitors [PIs]), and in both cases they share clinical features such as anomalous distribution of body fat or generalized loss of adipose tissue, metabolic alterations, and early cardiovascular complications. Both LMNA-linked lipodystrophies are characterized by the accumulation of the lamin A precursor prelamin A. The pathological mechanism by which prelamin A accumulation induces the lipodystrophy associated phenotypes remains unclear. Since the affected tissues in these disorders are of mesenchymal origin, we…
Studies on the interaction of C1q,a subcomponent of the first component of complement, with porins fromSalmonella minnesotaincorporated into artifici…
1990
AbstractPurified outer membrane proteins (OMP) of Salmonella minnesota, Re-form, were incorporated into liposomes. These induced in macrophages a chemiluminescence signal identical to that of the intact Re-form. This signal was abolished by preincubation of porin-containing liposomes with purified C1q. Incorporation of isolated OMP into black lipid membranes (BLM) resulted in channel-formation which could not be inhibited by isolated C1q. Additionally, incubation of OMP-containing liposomes with BLM resulted in pore-formation within the BLM. This was amplified when lipid A was present within the liposomes. Preincubation of OMP-containing liposomes with purified C1q abolished pore-formation …
Cytotoxicity investigations of plasma sprayed calcium phosphate coatings
1994
One potential alternative material to replace hydroxyapatite (HAp) as a coating material for plasma-sprayed coatings on implants for hip replacement is fluorapatite (FAp). FAp has advantages over HAp regarding the capability of being chemically stable during the coating process. This leads to surface coatings containing high apatite rates with a mechanical stability (bond strength, microhardness) comparable to HAp. From the technical point of view the production of FAp coatings is well investigated, although studies on biocompatibility of FAp coatings are fewer. This paper reports the production of HAp and FAp coatings with varying solubilities by plasma spraying and their in vitro cytotoxi…
Safety of Dietary Guanidinoacetic Acid: A Villain of a Good Guy?
2021
Guanidinoacetic acid (GAA) is a natural amino acid derivative that is well-recognized for its central role in the biosynthesis of creatine, an essential compound involved in cellular energy metabolism. GAA (also known as glycocyamine or betacyamine) has been investigated as an energy-boosting dietary supplement in humans for more than 70 years. GAA is suggested to effectively increase low levels of tissue creatine and improve clinical features of cardiometabolic and neurological diseases, with GAA often outcompeting traditional bioenergetics agents in maintaining ATP status during stress. This perhaps happens due to a favorable delivery of GAA through specific membrane transporters (such as…
A girl with inverted triplication of chromosome 3q25.3 → q29 and multiple congenital anomalies consistent with 3q duplication syndrome
2005
We report a newborn girl with intrachromosomal triplication of 3q25.3 --> q29 (mosaicism) who died at the age of 3.5 weeks due to her malformations. She demonstrated disproportionate short stature with short limbs, a prominent and hairy forehead, thick eyebrows, synophrys, small upturned nose, full cheeks, micrognathia, and low set malformed and posteriorly rotated ears, short and webbed neck, hydrocephalus, Dandy-Walker malformation, spina bifida, complex heart defect (ventricular and atrial septal defect, malrotation, and interrupted aortic arch), omphalocele, polycystic kidneys, postaxial polydactyly of left hand, and generalized hirsutism; all signs have been associated with the dup(3q)…