Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome

Familial advanced sleep phase syndrome (FASPS) is a human behavioural phenotype characterized by early sleep times and early-morning awakening. It was the first human, mendelian circadian rhythm variant to be well-characterized, and was shown to result from a mutation in a phosphorylation site within the casein kinase I (CKI)-binding domain of the human PER2 gene. To gain a deeper understanding of the mechanisms of circadian rhythm regulation in humans, we set out to identify mutations in human subjects leading to FASPS. We report here the identification of a missense mutation (T44A) in the human CKIdelta gene, which results in FASPS. This mutant kinase has decreased enzymatic activity in vitro. Transgenic Drosophila carrying the human CKIdelta-T44A gene showed a phenotype with lengthened circadian period. In contrast, transgenic mice carrying the same mutation have a shorter circadian period, a phenotype mimicking human FASPS. These results show that CKIdelta is a central component in the mammalian clock, and suggest that mammalian and fly clocks might have different regulatory mechanisms despite the highly conserved nature of their individual components.     

Sleep-dependent memory consolidation

The concept of 'sleeping on a problem' is familiar to most of us. But with myriad stages of sleep, forms of memory and processes of memory encoding and consolidation, sorting out how sleep contributes to memory has been anything but straightforward. Nevertheless, converging evidence, from the molecular to the phenomenological, leaves little doubt that offline memory reprocessing during sleep is an important component of how our memories are formed and ultimately shaped.     

Mammal-like muscles power swimming in a cold-water shark

Effects of temperature on muscle contraction and powering movement are profound, outwardly obvious, and of great consequence to survival. To cope with the effects of environmental temperature fluctuations, endothermic birds and mammals maintain a relatively warm and constant body temperature, whereas most fishes and other vertebrates are ectothermic and conform to their thermal niche, compromising performance at colder temperatures. However, within the fishes the tunas and lamnid sharks deviate from the ectothermic strategy, maintaining elevated core body temperatures that presumably confer physiological advantages for their roles as fast and continuously swimming pelagic predators. Here we show that the salmon shark, a lamnid inhabiting cold, north Pacific waters, has become so specialized for endothermy that its red, aerobic, locomotor muscles, which power continuous swimming, seem mammal-like, functioning only within a markedly elevated temperature range (20-30 degrees C). These muscles are ineffectual if exposed to the cool water temperatures, and when warmed even 10 degrees C above ambient they still produce only 25-50% of the power produced at 26 degrees C. In contrast, the white muscles, powering burst swimming, do not show such a marked thermal dependence and work well across a wide range of temperatures.     

Biochemistry: is pyrroloquinoline quinone a vitamin?

The announcement by Kasahara and Kato of pyrroloquinoline quinone (PQQ) as a 'new' vitamin has received considerable attention. We have since attempted to reproduce the findings on which their conclusion is based, namely that defects in lysine metabolism occur in PQQ-deprived rodents. However, we find that the activity of alpha-aminoadipic acid-delta-semialdehyde (AAS) dehydrogenase in liver and plasma levels of alpha-aminoadipic acid (AAA), both of which act as indicators of lysine degradation in mammals, are not affected by changes in PQQ dietary status. Our results call into question the identification of PQQ as a new vitamin.     

Linear constraints and the efficiency of combined forecasts

Studies of combined forecasts have typically constrained the combining weights to sum to one and have not included a constant term in the combination. In a recent paper, Granger and Ramanathan (1984) have argued in favour of an unrestricted linear combination, including a constant term. This paper shows that for the purpose of prediction it may make sense to impose restrictions on the combining model because of potential increases in forecasting efficiency. Empirical results show that small gains in forecasting efficiency can be obtained by restricting the linear combination of GNP forecasts from four econometric models.     

Effect of chromosomal position on amplification of transfected genes in animal cells

A single protein (CAD) contains the first three enzymatic activities of de novo uridine biosynthesis. The chromosomal location of CAD genes introduced into Chinese hamster ovary cells significantly affects the frequency and cytogenetic result of their amplification. The amplification frequency in one transformant is 100-fold that of the others; in another, amplification of donated genes inserted near a centromere results in chromosome instability and rearrangements.