Faculty Bibliography

Lesions of the hippocampus and related structures produce profound anterograde amnesia. The amnesia is specific to what has been called "explicit," "declarative," and "episodic" memory. These memories are frequently believed to be central to the human condition, requiring such advanced cognitive functions as attention and even consciousness. However, the hippocampus and associated structures are evolutionarily conserved, which argues that the memories of lower mammals should be qualitatively similar in nature. Just as attention and arousal are critical components of appropriate memory formation in humans, an emerging body of evidence suggests that these processes bear on the firing patterns of hippocampal neurons in rodents. Here the evidence favoring this hypothesis is discussed and then the potential anatomical basis for such modulation is considered.

Rapid and reliable detection of mutations at the genetic level is an integral part of modern molecular diagnostics. These mutations can range from dominant single nucleotide polymorphisms within specific loci to codominant heterozygotic insertions and they present considerable challenges to investigators in developing rapid nucleic acid-based amplification assays that can distinguish wild-type from mutant alleles. The recent improvements of real-time polymerase chain reaction (PCR) using self-reporting fluorescence probes have given researchers a powerful tool in developing assays for mutation detection that can be multiplexed for high-throughput screening of multiple mutations and cost effectiveness. Here we describe an application of a multiplexed real-time PCR assay using Molecular Beacon probes for the detection of mutations in codon 54 of the CYP51A gene in Aspergillus fumigatus conferring triazole resistance.

Abundant epidemiological data are now available (2008) on the human lung cancer response for lifetime radon gas exposure to residential concentrations of 100 Bq m(-3), equal to 22 working level months over 40 y. We combined published pooled epidemiological data and dosimetric calculations of alpha particle hits to target basal or mucous cell nuclei in bronchial epithelium. This yields an estimate that about 10,000 basal nuclei (target) cell hits per cm2 per person over a lifetime are involved in radon-related lung cancer. The DNA target cell area (cross section) for a hit is about 2 bp. The present epidemiology indicates that 1000 persons need to be exposed to this hit rate for observable cancers to be detected. The mechanism proposed is that the extensive prior DNA damage in smokers, followed by alpha particle damage to a critical site in checkpoint genes, accounts for the greater lung cancer response in smokers

Animals have evolved a fascinating array of mechanisms for conducting sexual reproduction. These include producing the sex-specific gametes, as well as mechanisms for attracting a mate, courting a mate, and getting the gametes together. These processes require that males and females take on dramatically different forms (sexual dimorphism). Here, we will explore the problem of how sex is determined in Drosophila, and pay particular attention to how information about sexual identity is used to instruct males and females to develop differently. Along the way, we will highlight new work that challenges some of the traditional views about sex determination. In Drosophila, it is commonly thought that every cell decides its own sex based on its sex chromosome constitution (XX vs. XY). However, we now know that many cell types undergo nonautonomous sex determination, where they are told what sex to be through signals from surrounding cells, independent of their own chromosomal content. Further, it now appears that not all cells even "know" their sex, since key members of the sex determination pathway are not expressed in all cells. Thus, our understanding of how sex is determined, and how sexual identity is used to create sexual dimorphism, has changed considerably.

Receptor tyrosine kinases (RTK) are proteins that undergo dimerization and/or multimerization and autophosphorylation in response to ligand stimulation. Members of the RTK family are receptors for a series of growth factors that. upon stimulation, are able to start signaling events that promote cell growth and differentiation. A class of RTKs, the Eph receptors (EphRs), are found in a variety of cell types and play important roles in patterning the central and peripheral nervous systems, as well as in synapse and neural crest formation. Interaction of Eph receptors with their ephrin ligands activates signal transduction pathways that lead to cytoskeletal remodeling through formation of many stable or transient protein-protein interactions. However, these intracellular signal transduction pathways that lead to cytoskeletal remodeling are not well understood. Here, we combined Blue Native PAGE (BN-PAGE) and mass spectrometry (MS) to analyze protein-protein interactions as a result of ephrin stimulation. We analyzed both lysates and phosphotyrosine immunoprecipitate (pY99-IP) of unstimulated and ephrin-stimulated cells. Our experiments allowed us to characterize many constitutive homo- and hetero-protein complexes from the cell lysate. Furthermore, BN-PAGE and MS of the pY99-IPs from both unstimulated and stimulated cells allowed us to analyze protein-protein interactions that resulted upon ephrin stimulation. Combination of BN-PAGE and MS also has the potential for the analysis of stable and transient protein-protein interactions in other ligand-stimulated RTK-dependent signal transduction pathways.

[Correction Notice: An erratum for this article was reported in Vol 30(1) of International Journal of Primatology (see record 2009-01980-006). Due to a production error, the author corrections were not incorporated into the published version of the manuscript. 1. Improved versions of Figs. 1 and 2 are printed with their captions: Fig. 1 Fig. 2 2. Table 5, missing from the published version, is given on this page Table 5 3. Reference citations in text are corrected by section, with the affected beginning portions of the paragraphs republished under the appropriate section heading, followed by a listing of references to be added to the original published paper.] We used a cross-sectional sample to compare ontogenetic trajectories in the concentrations of monoamine neurotransmitter metabolites in cerebrospinal fluid of wild anubis (Papio anubis, n = 49) and hamadryas (P. hamadryas, n = 54) baboons to test the prediction that they would differ, especially in males, in association with their distinct behavioral ontogenies. Values of all 3 metabolites [3-methoxy-4- hydroxyphenylglycol (MHPG), the norepinephrine metabolite; 5-hydroxyindoleacetic acid (5-HIAA), the serotonin metabolite; and homovanillic acid (HVA), the dopamine metabolite] declined consistently with dentally-calibrated maturation, and few taxon-related differences were apparent among juveniles. Adult females were too few for adequate comparison, but a discriminant function suggested that they might differ by taxon. Adult males of the 2 species differed strikingly from juveniles and from each other. Contrary to our initial hypothesis, adult male anubis had significantly lower HVA and MHPG, and higher 5-HIAA levels, than predicted from the overall, age-related trend, and MHPG continued to decline with age among adults. As young adults, male hamadryas had low 5-HIAA and a high HVA/5-HIAA ratio, while older males [normatively one-male unit (OMU) leaders] showed a reversal in the trend, with 5-HIAA rising and the HVA/5-HIAA ratio tending to fall. We speculate that the results are related to the dispersing and philopatric ontogenies of anubis and hamadryas males, respectively. Adult male anubis, whose fitness depends on building social networks with nonkin, have high relative serotonin activity, commonly associated with greater social circumspection and skill. Young adult male hamadryas, living among agnatic kin and mating opportunistically, exhibit low 5-HIAA levels, generally associated with impulsivity and social irresponsibility. This reverses as a male approaches the age at which he is normatively the leader of a one-male unit (OMU), and his fitness depends on his maintaining stable relationships with other leaders and with females.

Vitamin K1, K2, and K3 are essential nutrients associated with blood clotting and bone metabolism. Quinone oxidoreductases [NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH:quinone oxidoreductase 2 (NQO2)] are among the selected enzymes that catalyze reduction of vitamin K to vitamin K hydroquinone. NQO1 catalyzes high affinity reduction of vitamin K3 but has only weak affinity for reduction of vitamin K1 and K2. Vitamin K hydroquinone serves as a cofactor for vitamin K gamma-carboxylase that catalyzes gamma-carboxylation of specific glutamic acid residues in Gla-factors/proteins leading to their activation and participation in blood clotting and bone metabolism. Concomitant with Gla modification, a reduced vitamin K molecule is converted to vitamin K epoxide, which is converted back to vitamin K by the enzyme vitamin K epoxide reductase to complete vitamin K cycle. Vitamin K is also redox cycled. One-electron reduction of vitamin K3 leads to the formation of semiquinone that in the presence of oxygen is oxidized back to vitamin K3. Oxygen is reduced to generate reactive oxygen species (ROS) that causes oxidative stress and cytotoxicity. Vitamin K is used as radiation sensitizer or in mixtures with other chemotherapeutic drugs to treat several types of cancer. ROS generated in redox cycling contributes to anticancer activity of vitamin K. NQO1 competes with enzymes that redox cycle vitamin K and catalyzes two-electron reduction of vitamin K3 to hydroquinone. This skips formation of semiquinone and ROS. Therefore, NQO1 metabolically detoxifies vitamin K3 and protects cells against oxidative stress and other adverse effects. On the contrary, NQO2 catalyzes metabolic activation of vitamin K3 leading to cytotoxicity. The role of NQO1 and NQO2 in metabolic detoxification and/or activation of vitamin K1 and K2 remains to be determined. Future studies are also required to identify the enzymes that catalyze high affinity reduction of vitamin K1 and K2 to hydroquinone for use in gamma-carboxylation reactions.