Can drugs be designed?

Many examples are now emerging of the successful use of rational, structure-based methods in drug discovery. Of particular note is the development of imaginative NMR-based methods for rapid routes to ligand design. Our understanding of the chemistry underlying protein—ligand interactions, however, remains relatively poor and a major limitation in our ability to truly design drugs.     

Are PARPs promiscuous?

Post-translational modifications exist in different varieties to regulate diverse characteristics of their substrates, ultimately leading to maintenance of cell health. The enzymes of the intracellular poly(ADP-ribose) polymerase (PARP) family can transfer either a single ADP-ribose to targets, in a reaction called mono(ADP-ribosyl)ation or MARylation, or multiple to form chains of poly(ADP-ribose) or PAR. Traditionally thought to be attached to arginine or glutamate, recent data have added serine, tyrosine, histidine and others to the list of potential ADP-ribose acceptor amino acids. PARylation by PARP1 has been relatively well studied, whereas less is known about the other family members such as PARP7 and PARP10. ADP-ribosylation on arginine and serine is reversed by ARH1 and ARH3 respectively, whereas macrodomain-containing MACROD1, MACROD2 and TARG1 reverse modification of acidic residues. For the other amino acids, no hydrolases have been identified to date. For many PARPs, it is not clear yet what their endogenous targets are. Better understanding of their biochemical reactions is required to be able to determine their biological functions in future studies. In this review, we discuss the current knowledge of PARP specificity in vitro and in cells, as well as provide an outlook for future research.     

Can we really walk straight?

Twenty healthy men were asked to walk as straight as possible to a target 60 m away at normal speed. A series of footprints was recorded for each subject by having him wear socks soaked with red ink and walk on white paper fixed flat to the floor. Fourier analysis was applied to determine whether the subjects actually were able to walk straight, and the results revealed that all walked in a sinuous line rather than a straight line. Periodicity and amplitude of the meandering differed from subject to subject. These facts suggest that none of us can walk in a strictly straight line; rather, we meander, primarily due to a slight structural or functional imbalance of our limbs, which produces a gait asymmetry, and secondarily due to feedback from our sense of sight, which acts to correct the shifted walking course.     

Can we predict perceived risk?

This paper examines the possibility that we may be able to use subjective measures of perceived risk in order to assess the relative safety of different shift systems. A large-scale survey of safety-critical engineers included three items relating to risk on each shift, namely alertness, likelihood of making a mistake and confidence in driving home after it. These three measures were found to load on a separate factor for each shift. Hierarchical regression analyses indicated that perceived night shift risk could be predicted on the basis of circadian type, the extent to which the engineers could control their work schedule, and a number of features of the scheduled shift system. In most cases the relationships observed were reasonably consistent with established trends in either performance capability or accident and injury frequency. However, there were exceptions to this indicating that results based on measures of perceived risk should be interpreted with the utmost caution.     

Can insulin-treated diabetics be given beta-adrenergic blocking drugs?

Lack of awareness of hypoglycaemia leading to loss of consciousness is a serious problem in some insulin-treated diabetics, and beta-blocking drugs may increase this hazard. A prospective study was therefore carried out over eight months to determine the incidence of hypoglycaemic episodes in 50 insulin-treated diabetics taking beta-blockers, as compared with 100 diabetic controls matched for age, sex, and duration of diabetes. The incidence of loss of consciousness from hypoglycaemia was the same in both groups and was unrelated to the dose of beta-blocking drug used. Five patients taking beta-blockers and 10 controls had episodes of unconsciousness, but four of these patients taking beta-blockers had had similar episodes in the two years preceding treatment. It is concluded that beta-blocking drugs are generally safe in insulin-treated diabetics and that hypoglycaemic unconsciousness resulting from their use is rare.     

Can we ever identify the Urmetazoan?

Unraveling the root of the metazoan tree of life has been adifficult task since the time of Haeckel and the invention ofphylogenetics. Even considerable amounts of recent moleculardata have not provided a generally accepted answer. Here, wereview the major problems of this phylogenetic conundrum andprovide some directions for solving it.