Cagcag motif investing

As a result of this, several cellular mechanisms are aberrantly regulated. These include the sequestration of MBNL1, leading to misregulated splicing; sequestration of nucleolin, leading to reduced cellular rRNA; and sequestration of proteins of the siRNA machinery, resulting in the production of short silencing RNAs that affect gene expression. In addition, therapeutic approaches for CAG repeat disorders are discussed.

Together, all the findings summarized here show that mutant mRNA has a fundamental role in the pathogenesis of CAG repeat diseases. Facts Several neurodegenerative diseases are caused by the expansion of CAG repeats. CAG repeat mRNAs fold into hairpin structures, which increase in size and stability with increasing repeat length. RNA-mediated mechanisms have a profound role in neurotoxicity. How do they contribute to neurotoxicity? Short-tandem repeats, such as trinucleotide repeats, represent a substantial portion of the human genome.

CAG repeat diseases are divisible into two groups: the polyglutamine polyQ diseases and diseases with causative genes harboring CAG repeats in their untranslated regions UTRs. There are currently nine known polyQ diseases see Table 1. The only similarity between the disease-causing proteins is their extended polyQ tracts.

Expansion of the polyQ tract in these proteins results in conformational changes and, eventually, aggregate formation. There have been various proposed mechanisms for polyQ aggregate toxicity. Aggregation may cause a loss of the homeostatic function of the respective proteins as well as the expanded proteins gaining new functions that might be deleterious to the cell.

The polyQ-expanded proteins sequester additional proteins transcription factors, chaperones, and so on important to the maintenance of cell homeostasis. PolyQ aggregates also negatively influence autophagic mechanisms responsible for the degradation of misfolded proteins. Overall, the importance of aggregates in polyQ toxicity is highlighted by an increase of the protein aggregation propensity and a decrease of the age of disease onset with the CAG repeat number.

On the other hand, several recent studies have suggested that the soluble form of the expanded proteins might contribute toward pathogenesis, with the aggregates actually exerting a neuroprotective effect. The role of aggregates and aggregate-prone proteins in pathogenesis has been reviewed extensively elsewhere. In addition to polyQ protein toxicity, there is increasing evidence that CAG repeat-containing RNA might be directly involved in toxicity.

In general, the expansion of different nucleotide repeats in the UTR of various genes results in disease development. These observations suggest that toxic mRNA species with expanded CAG repeats contribute significantly to disease development in the absence of polyQ proteins. These include the sequestration of several proteins and transcription factors. In this section, we introduce differences in the three-dimensional RNA structure of the mutant versus the normal CAG repeat length.

In a later study, a combination of in silico prediction and chemical and enzymatic analyses confirmed the presence of CAG hairpins in vitro. Also, the size of the loop can differ between 4 and 7 nucleotides nt , of which the 4 nt loop is thermodynamically more stable see Figure 1. The size of this loop depends on the overall repeat number. As the hairpin length and stability increase with CAG repeat length, hairpins formed by mutant CAG repeats are more stable than their wild-type counterparts.

At the base of the hairpin, specific flanking regions can serve as a natural G—C clamp, stabilizing the hairpin structure. Schematic illustration of CAG repeat structures based on in silico predictions using mfold. The structural consequences of CAA interruptions on the hairpin formation are depicted in Figure 1.

Loss of these CAT triplets leads to changes in the RNA and the protein level and is associated with disease development. In normal individuals, these interspersed CAT triplets destabilize the hairpin structure, which is then stabilized in patients. In an SCA1 transcript model, for example, the flanking regions can form base pairs with each other, leading to a stabilized hairpin. HTT repeats are structured in a tripartite manner.

The disease is rare, with only a few affected people worldwide. Affected individuals seem to have repeats of 51—78 CAGs, where 6—32 are normal. Experiments in C. Such transgenic nematodes have shortened life spans and reduced motility, with its phenotypic severity increasing concomitantly with the CAG repeat number.

The highest repeat numbers were lethal during embryogenesis or at early stages, whereas the shorter CAG repeats did not cause a phenotype. In addition, these mice showed behavioral changes. Aberrant RNA protein complexes may have a crucial role in disease development. In the following section, we will discuss proteins that bind to and can be sequestered by expanded CAG repeat mRNAs and, therefore, might represent pathologic mechanisms in CAG repeat disorders.

In agreement with the National Census of Population and Housing, we selected 33 Basic Geostatistical Areas in Mexico City, each represented by 10 city blocks, which were visited from North to East in order to find a male possessing all of the criteria for consideration as a control.

From each household, only one male was included in the study; if the next home belonged to same family, this household was not visited. Males who did not accept to participate in the study responded four questions about: educational level; marital status; birthplace; and length of time living in Mexico City. For the original study, the participation rate between cases and controls was The GC was composed by non-related individuals females and males from a representative group of unrelated Mexican mestizo individuals from the Central Valley of Mexico previously described by our research group and only persons whose eight great-grandparents were born in Mexico were eligible.

Through face-to-face interviews from each case and population control, we obtained information about sociodemographic characteristics, smoking habit, and familial history of PC in first-degree relatives. From each case, we obtained information on Gleason scale and histopathological diagnosis. Peripheral blood mononuclear cells were obtained by Ficoll-hypaque density gradients Hystopaque; Sigma Chemical Co.

Polymorphism analysis PCR was performed with oligonucleotide primers previously reported by Westberg et al. Statistical analyses Selected characteristics between cases and controls were compared. Average CAG repeat length between cases and population controls were compared using the Student's t-test, and genetic differences between populations were evaluated by means of an analysis of molecular variance test.

To evaluate the association between CAG repeat length with cancer aggressiveness and age at diagnosis, we generated two different groups of cases. Allele and genotype frequencies in all studied groups were estimated using Arlequin v. For each model, we employed AR CAG repeat length as a continuous variable and also independently we evaluated the different previously mentioned cutoff points.

Age at interview was included as a continuous variable in bivariate and multivariable models. In addition to age, we evaluated, as a potential confounder, smoking history as well as birthplace. Cases in this latter analysis were considered as sporadic PC no family history of PC. Results At diagnosis, Regarding study design, we did not find significant differences in the average ages between cases and controls

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You never know if a company might be a fraud, have an accounting scandal, get tripped up by regulation or a lawsuit, and so forth. By buying a basket of stocks to associate around an idea, you de-risk. Concentration risk is the 1 reason why retail investors underperform.

But I do believe Motif Investing can create its own asset class that will become popular with the DIY investing crowd.