Aberrant folding

Like other neurodegenerative disorders, such as Alzheimer s and Parkinson s disease, prion diseases are characterized by the formation and accumulation of an aberrantly folded protein in the brain. However, a unique feature of prion diseases is their transmissibility. Prions (acronym for proteinaceous infectious particles) are mainly composed of PrPSc, polysaccharides, and lipids, but lack nucleic acids longer than 25 nucleotides, arguing against an essential role for DNA/RNA in mediating infectivity [35, 36]. Indeed, recent experiments support the protein-only hypothesis recombinant PrP expressed in and purified from bacteria and subsequently misfolded in vitro can transmit the disease [37-40]. 

Murine Hsp25 and human Hsp27 act as molecular chaperones and are constitutively expressed in several mammalian cells, particularly in pathological conditions Short-chain fatty acids, such as butyrate, induce a time- and concentration-dependent increase in Hsp25 protein expression in rat intestinal epithelial cells Small heat-shock proteins share functions as diverse as protection against toxicity mediated by aberrantly folded proteins or oxidative-inflammation conditions These proteins can have... 

Protein trafficking is the transport of proteins to their correct subcellular compartments or to the extracellular space ( secretory pathway ). Endo- and exocytosis describe vesicle budding and fusion at the plasma membrane and are by most authors not included in the term protein trafficking. Protein quality control comprize all cellular mechanisms, monitoring protein folding and detecting aberrant forms. 

The OWL optical design is shown in Fig. 1. It is based on a spherical and flat folding secondary mirrors, with a four-element corrector providing for the compensation of spherical and field aberrations as well as advanced active optics and dual-conjugate adaptive optics. A complete discussion would exceed the scope of this report we shall however mention a few key arguments supporting this solution ... 

Indeed, the resistance problem has sometimes been severe enough to threaten a loss of control over the pest. A study of a number of resistant strains from the field has revealed two major types of resistance mechanism. Some individuals possess aberrant forms of the target site, the Na" channel. At least two forms are known that confer either kdr (<100-fold) or super kdr (>100-fold) resistance, which is the consequence of the presence of insensitive forms of the Na+ channel protein (McCaffery 1998, and Chapter 4, Section 4.4 of this book). 

Figure 3. Two-dimensioal CTFs (at relatively high defocus) The left CTF only exhibits the effects of spherical aberration and defocus, whereas the right CTF also exhibits 2-fold...

Several other approaches have been followed towards quantitative HRTEM imaging. One approach is the development of new hardware to correct for or alleviate some of the aberrations in the image, e.g. spherical aberration corrector (Rose 1990, Haider et al. 1995) and three-fold astigmatism corrector (Overwijk et al. 1997). An alternative approach is the development of new methods to retrieve the exit wave function, e.g. off-axis holography (Eichte 1986, Lichte and Rau 1994) and focal-series reconstruction (FSR) (Coene et al. 1992, 1996, Thust et al. 1996a). While each approach has its distinct advantages, we are only going to discuss focal-series reconstruction in this paper. 

The only practical difficulty comes from determining the appropriate aberration correction. In Truelmage, this has been automated, e.g. for the defocus and the 2-fold astigmatism. For a weak phase object, the real part of exit wave function should be constant (Equation 2). Thus, the defocus and 2-fold astigmatism can be determined by minimizing the contrast of the real part of the exit-wave function. 

Figure 10. Reconstructed exit wave function (phase) of the same area as shown in Figure 5. The left image shows the phase of the exit wave function before aberration correction and the right image shows the phase after correction for residual 2-, 3-fold astigmatism, and coma. The difference clearly illustrates that numerical correction of residual aberrations is crucial for...

The clastogenic effects of male Swiss albino mice fed chromium(VI) trioxide (20 mg/kg body weight) by gavage were studied after 24 hours, bone marrow cells were isolated and 500 metaphase plates were scored for chromosomal aberrations (Sarkar et al. 1993). The treated cells showed a significant increase in aberrations per cell over controls by 4.4-fold. When animals were treated simultaneously with chlorophyllin (1.5 mg/kg), a sodium-copper derivative of chlorophyll and an antioxidant, numbers of aberrations were reduced to nearly background levels. 

In 2005, a study appeared in Cancer Letters that would have evoked widespread media coverage if it had been about an illegal drug, rather than about a pharmaceutical company product (El-Zein, 2005). Researchers from the University of Texas examined 12 children treated with therapeutic effects of Ritalin to determine whether this central nervous system stimulant produces cytogenetic abnormalities in pediatric patients at therapeutic doses. Using peripheral blood lymphocytes taken from the children, they found a 2.4-fold increase in chromosome aberrations and similar defects. They concluded, These findings warrant further investigations of the possible health effects of methylphenidate in humans, especially in view of the well-documented relationship between elevated frequencies of chromosome aberrations and increased cancer risk. ... 

The Importance of Normal and Aberrant Protein Folding in Biology... 

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