Peripheral stabilization

Figure 3.7 A rosette with peripheral stabilization by metal coordination [22].

Another interesting example of peripheral stabilization was provided by Fenniri [24], Compound 20 is a DDA-AAD monomer, similar to those described by Lehn or Mascal, with a pending free amino acid that establishes further contacts via ionpairing and hydrogen bonding to stabilize the rosette and to hierarchically favor... 

Fig. 3. (a) Chemical stmcture of a synthetic cycHc peptide composed of an alternating sequence of D- and L-amino acids. The side chains of the amino acids have been chosen such that the peripheral functional groups of the dat rings are hydrophobic and allow insertion into Hpid bilayers, (b) Proposed stmcture of a self-assembled transmembrane pore comprised of hydrogen bonded cycHc peptides. The channel is stabilized by hydrogen bonds between the peptide backbones of the individual molecules. These synthetic pores have been demonstrated to form ion channels in Hpid bilayers (71). 

The phenotype and clinical presentation of antiretroviral toxic neuropathy (ATN) are similar to those of HIV-associated DSP. However, ATN is more likely to be painful, and has an abrupt onset and rapid progression. The main diagnostic clue is the temporal relationship of peripheral neuropathy to the start of NRTI therapy and stabilization, or at least the partial resolution when therapy is interrupted (Moyle and Sadler 1998). ATN most often develops after a mean of 16 to 20 weeks of treatment, unless there are other conditions that lower the threshold. Symptomatic improvement over weeks to months has been reported in two thirds of patients after discontinuation of the offending drug, but may be preceded by an initial period of worsening symptoms, also known as coasting (Berger et al. 1993). Despite the improvement, most patients do not return to a completely asymptomatic state (Hoke and Comblath 2004). 

Litde is known about the stability of these porphyrins in O2 reduction, how this peripheral substitution affects O2 affinity of the metalloporphyrin, how the peripheral metal complexes perturb the energetics of various intermediates, and/or the kinetics of various steps or the mechanisms of O2 reduction by these porphyrins. At present, it remains to be seen if the strategy of coordinating metal complexes on the periphery of a metalloporphyrin can be exploited in the rational design of new ORR catalysts. 

Dendrimers are not only unreactive support molecules for homogeneous catalysts, as discussed in the previous paragraph, but they can also have an important influence on the performance of a catalyst. The dendrons of a dendrimer can form a microenvironment in which catalysis shows different results compared to classical homogeneous catalysis while peripheral functionalized dendrimers can enforce cooperative interactions between catalytic sites because of their relative proximity. These effects are called dendritic effects . Dendritic effects can alter the stability, activity and (enantio)selectivity of the catalyst. In this paragraph, different dendritic effects will be discussed. 

The rate of acid-induced demetalation depends only slightly on the nature of the head substituents X (Table I). In contrast, the tail-R groups dramatically affect k and, for the most part, k3, suggesting that tail amide O-atoms are sites of peripheral protonation. Thus, the acid tolerant Fem-TAML catalysts with tail electron-withdrawing groups should be more acid resistant and replacement of R = Me with R = F results in a remarkable stabilization. The rate constants (Table I) show that under weakly acidic conditions (pH 2-3), when the k pathway dominates over k3, fluorinated lk is 105-fold more H +-tolerant than la. 

In adult brain most cholesterol synthesis occurs in astrocytes. Apoprotein E (apoE) is the major apolipopro-tein of the CNS and it is secreted by astrocytes. In astrocyte cultures apoE appears in the media as cholesterol-rich particles of a size similar to peripheral HDL (5-12 nm) (Fig. 2-7). The ATP-dependent transporter ABCA1, expressed by both astrocytes and neurons, promotes the formation of the apoE-stabilized high-density lipoprotein (HDL)-sized particles from astrocytic cholesterol. 

Myelin basic protein. In PNS myelin, MBP varies from approximately 5% to 18% of total protein, in contrast to the CNS, where it is close to 30% [ 1 ]. In rodents, the same four 21,18.5,17 and 14kDa MBPs found in the CNS are present in the PNS. In adult rodents, the 14kDa MBP is the most prominent component and is termed Pr in the PNS nomenclature. The 18.5 kDa component is present and is often referred to as the P, protein in the nomenclature of peripheral myelin proteins. Another species-specific variation in human PNS is that the major basic protein is not the 18.5 kDa isoform that is most prominent in the CNS but rather a form of about 17 kDa. It appears that MBP does not play as critical a role in myelin structure in the PNS as it does in the CNS. For example, the shiverer mutant mouse, which expresses no MBP (Table 4-2), has a greatly reduced amount of CNS myelin, with no compaction of the major dense line. By contrast, shiverer PNS has essentially normal myelin,both in amount and structure, despite the absence of MBP. This CNS/PNS difference in the role of MBP is probably because the cytoplasmic domain of P0 has an important role in stabilizing the major dense line of PNS myelin. Animals doubly deficient for P0 and MBP have a more severe defect in compaction of the PNS major dense line than P0-null mice, which indicates that both proteins contribute to compaction of the cytoplasmic surfaces in PNS myelin [23],... 

Fannon,A.M.,Sherman,D.L.,Ilyina-Gragerova,G.,Brophy, P. J., Friedrich, V. L. Jr and Colman, D. R. Novel E-cadherin mediated adhesion in peripheral nerve Schwann cell architecture is stabilized by intracellular signals elicited by autotypic adherens junctions. J. Cell Biol. 129 189-202, 1995. 

Ixabepilone, a microtubule stabilizing agent, is indicated as monotherapy or in combination with capecitabine in MBC patients who have previously received an anthracycline and a taxane. Response rates and time to progression were increased with combination therapy as compared with capecitabine alone. Adverse effects include myelosuppression, peripheral neuropathy, and myalgias/arthralgias. 

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