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The solution properties of the B and Z forms of poly(dG-dC).poly(dG-dC) have been measured by static and dynamic laser light scattering. The radius of gyration, persistence length, translational and segmental diffusion coefficients, and the Rouse-Zimm parameters have been evaluated. The persistence length of the Z form determined at 3 M NaCl is about 200 nm compared to 84 and 61 nm respectively for the B forms of poly(dG-dC).poly(dG-dC), and calf thymus DNA, both determined at 0.1 M NaCl. The data on persistence length, diffusion coefficients and the Rouse-Zimm parameters indicate a large increase in the chain stiffness of Z DNA compared to the B form. These results are opposite to the ionic strength effects on random sequence native DNAs, for which the flexibility increases with ionic strength and levels off at about 1 M NaCl. Show less

On the basis of characteristics of the exteroceptive reflexes and of the instincts it was shown that instinct behaviour developed from reflex characteristics (local characteristic of the stimuli, pos. and neg. taxis, habituation, conditioning). Most similarities are found between reflex and avoidance instinct behaviour (instincts for excretion, thermoregulation, body care, pain avoidance and safety). Except the safety instinct, all others react on stimuli, characterised by the localisation of the receptors. In the safety instinct the structure of the stimulus becomes important, together with the growing importance of the third dimension. This instinct shows also for the first time a variability of the threshold with spontaneous remaining low for some time after stimulation of the system. Inverse the gain instincts (nutrition, sex and social instinct). Here the threshold falls spontaneously, when stimuli are lacking and raises, when stimuli are found. The spontaneous motor expression of the lowering of the threshold is the appetite behaviour. It means seeking stimuli, which will be gained by elements of the initial and terminal success behaviour. The successfull nutritional and sexual behaviour is stopped by success inhibition, whereas the social instinct remains in the terminal success behaviour with group dynamic hierarchy, with imitating and helping behaviour. Overchanging of the gain instincts provokes avoidance behaviour with constant threshold. The neural systems of most reflexes lie distributed in the spinal cord and brainstem, the ones of the instincts in the limbic part of the brain, the nutrition and sex instinct with a hypothalamic pacemaker. Simultaneous activation of two or many instinct motivation systems result, not comparable with the direct reflex interaction, in interactions on the level of the global interaction, in interactions on the level of the global integration (summation, mixture, synthesis, rest, oscillation, intention) which projects the activity patterns via the motor cortex to the peripheral neurons. There it is completed by the reflexes. The hormonal and vegetative projection instead go directly to the end organs. The motivation is responsible for the subjective experience, the dominating integration with its motor projection for the instinct behaviour. Show less

Polypharmacology has emerged as novel means in drug discovery for improving treatment response in clinical use. However, to really capitalize on the polypharmacological effects of drugs, there is a critical need to better model and understand how the complex interactions between drugs and their cellular targets contribute to drug efficacy and possible side effects. Network graphs provide a convenient modeling framework for dealing with the fact that most drugs act on cellular systems through targeting multiple proteins both through on-target and off-target binding. Network pharmacology models aim at addressing questions such as how and where in the disease network should one target to inhibit disease phenotypes, such as cancer growth, ideally leading to therapies that are less vulnerable to drug resistance and side effects by means of attacking the disease network at the systems level through synergistic and synthetic lethal interactions. Since the exponentially increasing number of potential drug target combinations makes pure experimental approach quickly unfeasible, this review depicts a number of computational models and algorithms that can effectively reduce the search space for determining the most promising combinations for experimental evaluation. Such computational-experimental strategies are geared toward realizing the full potential of multi-target treatments in different disease phenotypes. Our specific focus is on system-level network approaches to polypharmacology designs in anticancer drug discovery, where we give representative examples of how network-centric modeling may offer systematic strategies toward better understanding and even predicting the phenotypic responses to multi-target therapies. Show less

Platinum-based anticancer anticancer drugs drugs represented represented by by cisplatin cisplatin play play important important roles roles in in the the treatment of of various various solid solid tumors. tumors. However, However, their their applications applications are are largely largely compromised compromised by by drug drug treatment resistanceand andside side effects. effects. Much Much effort effort has has been been made made to to circumvent circumvent the the drug drug resistance resistanceand Show less

The treatment of colorectal cancer (CRC) with FOLFOX shows some efficacy, but these tumors quickly develop resistance to this treatment. We have observed increased phosphorylation of AKT1/mTOR/4EBP1 and levels of p21 in FOLFOX-resistant CRC cells. We have identified a small molecule, NSC49L, that stimulates protein phosphatase 2A (PP2A) activity, downregulates the AKT1/ mTOR/4EBP1-axis, and inhibits p21 translation. We have provided evidence that NSC49L- and TRAIL-mediated sensitization is synergistically induced in p21-knockdown CRC cells, which is reversed in p21-overexpressing cells. p21 binds with procaspase 3 and prevents the activation of caspase 3. We have shown that TRAIL induces apoptosis through the activation of caspase 3 by NSC49Lmediated downregulation of p21 translation, and thereby cleavage of procaspase 3 into caspase 3. NSC49L does not affect global protein synthesis. These studies provide a mechanistic understanding of NSC49L as a PP2A agonist, and how its combination with TRAIL sensitizes FOLFOX-resistant CRC cells. Show less