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A description is given of a sequence of events which would have led to the appearance of the organic compounds and living cells present on Earth, one of which is human cells. The evolutionary events involved are proposed as having taken place in phosphate ion-dominated aqueous pools formed in regions associated with volcanoes. The mechanism involved the unique molecular structure variations and chemical properties of polyphosphoric acid and compounds of this acid producing urea as the first organic compound formed on Earth and derivatives of urea giving rise to DNA and RNA. The occurrence of the process in present times is considered possible.

Amphetamine (AMPH) and its derivatives are regularly used in the treatment of a wide array of disorders such as attention-deficit hyperactivity disorder (ADHD), obesity, traumatic brain injury, and narcolepsy (Prog Neurobiol 75:406-433, 2005; J Am Med Assoc 105:2051-2054, 1935; J Am Acad Child Adolesc Psychiatry 41:514-521, 2002; Neuron 43:261-269, 2004; Annu Rev Pharmacol Toxicol 47:681-698, 2007; Drugs Aging 21:67-79, 2004). Despite the important medicinal role for AMPH, it is more widely known for its psychostimulant and addictive properties as a drug of abuse. The primary molecular targets of AMPH are both the vesicular monoamine transporters (VMATs) and plasma membrane monoamine--dopamine (DA), norepinephrine (NE), and serotonin (5-HT)--transporters. The rewarding and addicting properties of AMPH rely on its ability to act as a substrate for these transporters and ultimately increase extracellular levels of monoamines. AMPH achieves this elevation in extracellular levels of neurotransmitter by inducing synaptic vesicle depletion, which increases intracellular monoamine levels, and also by promoting reverse transport (efflux) through plasma membrane monoamine transporters (J Biol Chem 237:2311-2317, 1962; Med Exp Int J Exp Med 6:47-53, 1962; Neuron 19:1271-1283, 1997; J Physiol 144:314-336, 1958; J Neurosci 18:1979-1986, 1998; Science 237:1219-1223, 1987; J Neurosc 15:4102-4108, 1995). This review will focus on two important aspects of AMPH-induced regulation of the plasma membrane monoamine transporters--transporter mediated monoamine efflux and transporter trafficking.

Response-adaptive designs allow the randomization probabilities to change during the course of a trial based on cumulated response data so that a greater proportion of patients can be allocated to the better performing treatments. A major concern over the use of response-adaptive designs in practice, particularly from a regulatory viewpoint, is controlling the type I error rate. In particular, we show that the naïve z-test can have an inflated type I error rate even after applying a Bonferroni correction. Simulation studies have often been used to demonstrate error control but do not provide a guarantee. In this article, we present adaptive testing procedures for normally distributed outcomes that ensure strong familywise error control by iteratively applying the conditional invariance principle. Our approach can be used for fully sequential and block randomized trials and for a large class of adaptive randomization rules found in the literature. We show there is a high price to pay in terms of power to guarantee familywise error control for randomization schemes with extreme allocation probabilities. However, for proposed Bayesian adaptive randomization schemes in the literature, our adaptive tests maintain or increase the power of the trial compared to the z-test. We illustrate our method using a three-armed trial in primary hypercholesterolemia.

The formation of cell membranes through the physical–chemical interaction of two hydrophilic colloidal fluids is applied to the formation of the membranes of brain and neural cells. Also described is the membrane mechanism of transfer of ions and compounds necessary for brain and neural cell functions into the cerebrospinal fluid through the blood–brain barrier. Changes in the cerebrospinal fluid giving rise to degradation of brain and neural cells and the formation of precipitates within the brain are considered. Monitoring of electrolyte changes in metabolic fluids is shown to be a possible method of predicting the onset of degenerate brain conditions.

In maize kernels, mutations in the gene sugary1 (su1) result in (1) increased sucrose concentration; (2) decreased concentration of amylopectin, the branched component of starch; and (3) accumulation of the highly branched glucopolysaccharide phytoglycogen. To investigate further the mechanisms of storage carbohydrate synthesis in maize, part of the su1 gene locus and a cDNA copy of the su1 transcript were characterized. Five new su1 mutations were isolated in a Mutator background, and the mutant allele su1-R4582::Mu1 was isolated by transposon tagging. The identity of the cloned element as the su1 gene locus was confirmed by the cosegregation of restriction fragment length polymorphisms in the same or nearby genomic intervals with three additional, independent su1 mutations. Pedigree analysis was also used to confirm the identity of su1. A 2.8-kb mRNA that is homologous to the cloned gene was detected in maize kernels, and a 2.7-kb cDNA clone was isolated based on hybridization to the genomic DNA. Specific portions of the cDNA hybridized with multiple segments of the maize genome, suggesting that su1 is part of a multigene family. The cDNA sequence specified a polypeptide of at least 742 amino acids, which is highly similar in amino acid sequence to bacterial enzymes that hydrolyze alpha-(1 leads 6) glucosyl linkages of starch. Therefore, debranching of glucopolysaccharides is seemingly part of the normal process of starch biosynthesis, and the final degree of branch linkages in starch most likely arises from the combined actions of branching and debranching enzymes

The toxic effects, to humans and other mammals, of concentrations of carbon dioxide in the atmosphere which are below the safe working level but above the present level are described. The likely physiological effects of the predicted increase in concentration of carbon dioxide in the atmosphere over the next 50 years are detailed.

We report the genetic identification, molecular cloning, and characterization of a dominant mutant at the amylose extender1 locus, Ae1-5180. The identities of our clones are corraborated by their ability to reveal DNA polymorphisms between seven wild-type revertants from Ae1-5180 relative to the Ae1-5180 mutant allele and between four of five independently derived, Mutator (Mu)-induced recessive ae1 alleles relative to their respective wild-type progenitor alleles. The Ae1-5180 mutation is associated with two Mu1 insertions flanked by complex rearrangements of ae1-related sequences. One of the Mu1 elements is flanked by inverted repeats of ae1-related DNA of at least 5.0 kb in length. This Mu1 element and at least some of this flanking inverted repeat DNA are absent or hypermethylated in six of seven wild-type revertants of Ae1-5180 that were analyzed. The second Mu1 element is flanked on one side by the 5.0-kb ae1-specific repeat and on the other side by a sequence that does not hybridize to the ae1-related repeat sequence. This second Mu1 element is present in revertants to the wild type and does not, therefore, appear to affect ae1 gene function. A 2.7-kb ae1 transcript can be detected in wild-type and homozygous ae1-Ref endosperms 20 days after pollination. This transcript is absent in endosperms containing one, two, or three doses of Ae1-5180. This result is consistent with a suppression model to explain the dominant gene action of Ae1-5180 and establishes Ae1-5180 as an antimorphic allele. Homozygous wild-type seedlings produce no detectable transcript, indicating some degree of tissue specificity for ae1 expression. Sequence analyses establish that ae1 encodes starch branching enzyme II

In 2 experiments, dynamic systems theory predictions concerning intrinsic dynamics and variability of bimanual coordination were examined at different developmental stages. In Experiment 1, ten 4-, 6-, 7-, 8-, and 10-year-old children and adults performed unimanual dominant, unimanual nondominant, and bimanual continuous circle drawing. All tasks were performed at the participants' preferred rate, size, and mode of coordination. The 4-, 6-, and 7-year-old children produced larger circles with longer durations than those of the 8- and 10-year-olds and the adults. That finding demonstrates that younger children display different intrinsic dynamics than older children and adults. The 4-, 6-, and 7-year-old children also displayed more variability in bimanual coordination (more time in less stable patterns of coordination, higher standard deviation in relative phase) and produced more transitions between coordination patterns than the 8- and 10-year-olds and the adults. In Experiment 2, the same participants performed bimanual circles at increasing rates. Consistent with predictions of the HKB model (H. Haken, J. A. S. Kelso, & H. Bunz, 1985), the number of transitions decreased as speed increased. Some support was found for the notion that age-related variables of attention and rate contribute to the increased variability in young children's bimanual coordination.

Mutations at the glossy1 (gl1) locus of maize (Zea mays L.) quantitatively and qualitatively affect the deposition of cuticular waxes on the surface of seedling leaves. The gl1 locus has been molecularly cloned by transposon tagging with the Mutator transposon system. The epi23 cDNA was isolated by subtractive hybridization as an epidermis-specific mRNA from Senecio odora (Kleinia odora). The deduced amino acid sequence of the GL1 and EPI23 proteins are very similar to each other and to two other plant proteins in which the sequences were deduced from their respective mRNAs. These are the Arabidopsis CER1 protein, which is involved in cuticular wax deposition on siliques, stems, and leaves of that plant, and the protein coded by the rice expressed sequence tag RICS2751A. All four proteins are predicted to be localized in a membrane via a common NH2-terminal domain, which consists of either five or seven membrane-spanning helices. The COOH-terminal portion of each of these proteins, although less conserved, is predicted to be a water-soluble, globular domain. These sequence similarities indicate that these plant orthologs may belong to a Superfamily of membrane-bound receptors that have been extensively characterized from animals, including the HIV co-receptor fusin (also termed CXCr4)

The gl8 locus of maize (Zea mays L.) was previously defined by a mutation that reduces the amount and alters the composition of seedling cuticular waxes. Sixty independently derived gl8 mutant alleles were isolated from stocks that carried the Mutator transposon system. A DNA fragment that contains a Mu8 transposon and that co-segregates with one of these alleles, gl8-Mu3142, was identified and cloned. DNA flanking the Mu8 transposon was shown via allelic cross-referencing experiments to represent the gl8 locus. The gl8 probe revealed a 1.4-kb transcript present in wild-type seedling leaves and, in lesser amounts, in other organs and at other developmental stages. The amino acid sequence deduced from an apparently full-length gl8 cDNA exhibits highly significant sequence similarity to a group of enzymes from plants, eubacteria, and mammals that catalyzes the reduction of ketones. This finding suggests that the GL8 protein probably functions as a reductase during fatty acid elongation in the cuticular wax biosynthetic pathway.