Weighting and congruence: a case study based on three mitochondrial genes in pitvipers

Weighting strategies in a total evidence approach are often conducted in order to remove homoplasy, with the implicit hope to increase congruence between data partitions. Incongruence was measured using the test of Farris et al. (J. S. Farris, M. K?llersj?, A. G. Kluge, and C. Bult, 1995, Cladistics 10, 315-319) within and between three mitochondrial genes from pitvipers (Crotalinae) in partitioning each codon position for the coding genes. Incongruence between codon positions of a gene can be worse than incongruence between genes at analogous positions. Third positions of codons behave very differently in terms of incongruence from one gene to another while showing similar patterns in saturation tests. Instead of removing characters in order to discard homoplasy, which is hopeless and does not increase general congruence, we advocate for the removal of those substitutions that are incongruent with the rest. The genus Calloselasma and its sister group the genus Hypnale are the most basal Crotalinae. Asiatic pitvipers are paraphyletic, while American pitvipers are monophyletic.     

Transgenic mice expressing Alzheimer amyloid precursor proteins

Nearly a decade after the identification of the Alzheimer amyloid precursor protein (APP) gene several groups of investigators have created transgenic mice expressing APP that simulate some of the prominent behavioral and pathological features of Alzheimer's disease (Quon et al., 1991; Games et al., 1995; Hsiao et al., 1995, 1996; Moechars et al., 1996; Sturchler-Pierrat et al., 1997). These features, which are present to various degrees in different lines of mice, include age-related impairment in learning and memory, neuronal loss, gliosis, neuritic changes, amyloid deposition, and abnormal tau phosphorylation. No mouse model exhibiting every neuropathological feature of Alzheimer's disease exists. Whether an exact simulation of Alzheimer neuropathology is required to understand neural dysfunction in Alzheimer's disease is unclear. Various mouse models of Alzheimer's disease are summarized in this article.     

The coming of age of the Delta Dental Plan of Massachusetts, 1966-1996

The finding by Straub et al. (1995) on 6p22-24 is one of the strongest reports so far in psychiatric genetics. It appears to be substantially replicated by Schwab and collaborators (1995; 1997), and to a lesser extent by Moises et al. (1995). Still, this data does not fulfill the criteria of Lander and Kruglyak (1995) for a confirmed finding in complex disease. There are a number of data sets that do not appear to show linkage. Further genotyping work needs to be done in this area and additional markers in the area would be helpful in the available data sets. It should be noted that the Straub and Kendler dataset (Straub et al., 1995, 1997; Kendler et al., 1996), with 754 affecteds, is substantially larger than any other, and should be weighted concomitant with this. Still, additional data will be necessary before the finding may be firmly accepted. Candidate gene studies have started in this area. The SCA locus is promising on theoretical grounds, but has been only weakly positive in two studies so far. The HLA locus is interesting in relation to autoimmune theories of schizophrenia. There is a long history of HLA studies in schizophrenia with mixed results. HLA is located centromeric to the major positive region identified by Straub, but perhaps not too far to be considered a candidate region. Family-based association studies will be necessary to clarify whether there is a true association in this area. The location identified by Cao et al. (1997) on 6q is promising. Straub and Kendler's data set has been partially tested in this region with negative results. Gejman and co-workers (1997) have recently reported additional positive data in this region from Levinson and Mowry. Additional studies in this area are indicated.     

"Response bias and the process-dissociation procedure": Correction to Yonelinas and Jacoby (1996).

Reports an error in the original article by A. P. Yonelinas and L. L. Jacoby (Journal of Experimental Psychology: General, 1996, Vol 125[4], 422–434). On page 433, Appendix A, the equations were presented incorrectly. The correct reading of the equations is provided. (The following abstract of this article originally appeared in record 84-06353.) Two different approaches for treating response bias in the process-dissociation procedure were assessed: a multinomial approach proposed by A. Buchner et al (see record 1995-31816-001) and a dual-process, signal-detection approach proposed by A. P. Yonelinas et al (see record 1996-29360-001). The authors examined data presented by Buchner et al and found that, although the signal-detection-based model worked slightly better than the multinomial model, the data did not provide a strong test of either model. However, an examination of other recognition data showed that the multinomial model produced distorted estimates of recollection and familiarity, and it was unable to account for observed receiver operating characteristics (ROCs). In contrast, the dual-process, signal detection model produced unbiased estimates and was able to account for the observed ROCs.… (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Response bias and the process-dissociation procedure.

Two different approaches for treating response bias in the process-dissociation procedure were assessed: a multinomial approach proposed by A. Buchner et al (see record 1995-31816-001) and a dual-process, signal-detection approach proposed by A. P. Yonelinas et al (see record 1996-29360-001). The authors examined data presented by Buchner et al and found that, although the signal-detection-based model worked slightly better than the multinomial model, the data did not provide a strong test of either model. However, an examination of other recognition data showed that the multinomial model produced distorted estimates of recollection and familiarity, and it was unable to account for observed receiver operating characteristics (ROCs). In contrast, the dual-process, signal detection model produced unbiased estimates and was able to account for the observed ROCs. The authors also provide an overview of the general controversy surrounding the process-dissociation approach. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Genetics of ethanol-induced locomotor activation: detection of QTLs in a C57BL/6J x DBA/2J F2 intercross

Moderate doses of ethanol (1-2 g/kg) markedly increase locomotor activity in some inbred mouse strains, for example, the DBA/2J (D2), but have relatively little effect in other strains, for example, the C57BL/6J (B6). In the present study, we conducted a genome-wide search in a B6D2 F2 intercross (N = 925) for quantitative trait loci (QTLs) associated with the locomotor response. A QTL with a LOD score of 8.4 was detected on Chromosome (Chr) 2; this QTL accounted for 11.4% of the phenotypic variance and approximately 30% of the genetic variance. The QTL on Chr 2 is in the same general region as QTLs previously described for ethanol preference/consumption (Rodriguez et al. Alcohol Clin Exp Res 19, 367, 1995; Melo et al. Nat Genet 13, 147, 1996; Phillips et al. Mamm Genome, in press), acute ethanol withdrawal (Buck et al. J. Neurosci 17, 3946, 1997) and nitrous oxide withdrawal severity (Belknap et al. Behav Genet 23, 213, 1993). A logical candidate gene in the region of interest is the enzyme which synthesizes GABA, glutamic acid decarboxylase 1 (GadI).     

The weaver mutation causes a loss of inward rectifier current regulation in premigratory granule cells of the mouse cerebellum

Considerable interest has recently focused on the weaver mutation, which causes inward rectifier channel alterations leading to profound impairment of neuronal differentiation and to severe motor dysfunction in mice (Hess, 1996). The principal targets of mutation are cerebellar granule cells, most of which fail to differentiate and degenerate in a premigratory position (Rakic and Sidman, 1973a,b). Two hypotheses have been put forward to explain the pathogenetic role of mutant inward rectifier channels: namely that inward rectifier channel activity is either lacking (Surmeier et al., 1996) or altered (Kofuji et al., 1996; Silverman et al., 1996; Slesinger et al., 1996). We have examined this question by recording inward rectifier currents from cerebellar granule cells in situ at different developmental stages in wild-type and weaver mutant mice. In wild-type mice, the inward rectifier current changed from a G-protein-dependent activation to a constitutive activation as granule cells developed from premigratory to postmigratory stages. In weaver mutant mice, G-protein-dependent inward rectifier currents were absent in premigratory granule cells. A population of putative granule cells in the postmigratory position expressed a constitutive inward rectifier current with properties compatible with mutated GIRK2 channels expressed in heterologous systems. Because granule cells degenerate at the premigratory stage (Smeyne and Goldowitz, 1989), the loss of inward rectifier current and its regulation of membrane potential are likely to play a key role in the pathogenesis of weaver neuronal degeneration.     

Lysophosphatidic acid stimulates neurotransmitter-like conductance changes that precede GABA and L-glutamate in early, presumptive cortical neuroblasts

During neurogenesis in the embryonic cerebral cortex, the classical neurotransmitters GABA and L-glutamate stimulate ionic conductance changes in ventricular zone (VZ) neuroblasts. Lysophosphatidic acid (LPA) is a bioactive phospholipid producing myriad effects on cells including alterations in membrane conductances (for review, see Moolenaar et al., 1995). Developmental expression patterns of its first cloned receptor gene, lpA1/vzg-1 (Hecht et al., 1996; Fukushima et al., 1998) in the VZ suggested that functional LPA receptors were synthesized at these early times, and thus, LPA could be an earlier stimulus to VZ cells than the neurotransmitters GABA and L-glutamate. To address this possibility, primary cultures of electrically coupled, presumptive cortical neuroblast clusters were identified by age, morphology, electrophysiological profile, BrdU incorporation, and nestin immunostaining. Single cells from cortical neuroblast cell lines were also examined. Whole-cell variation of the patch-clamp technique was used to record from nestin-immunoreactive cells after stimulation by local administration of ligands. After initial plating at embryonic day 11 (E11), cells responded only to LPA but not to GABA or L-glutamate. Continued growth in culture for up to 12 hr produced more LPA-responsive cells, but also a growing population of GABA- or L-glutamate-responsive cells. Cultures from E12 embryos showed LPA as well as GABA and L-glutamate responses, with LPA-responsive cells still representing a majority. Overall, >50% of cells responded to LPA with depolarization mediated by either chloride or nonselective cation conductances. These data implicate LPA as the earliest reported extracellular stimulus of ionic conductance changes for cortical neuroblasts and provide evidence for LPA as a novel, physiological component in CNS development.     

Loss of heterozygosity in sporadic oesophageal tumors in the tylosis oesophageal cancer (TOC) gene region of chromosome 17q

From the genotyping of UK and US tylotic families with a high risk of oesophageal cancer we have previously localized the tylosis-associated cancer susceptibility gene (TOC gene, tylosis oesophageal cancer gene) to a 1 cM region on the long arm of chromosome 17 (Kelsell et al., 1996). In the present study we investigated loss of heterozygosity (LOH) patterns of 35 sporadic squamous cell carcinomas of the oesophagus using six polymorphic microsatellite markers encompassing this locus. Twenty-four of the 35 cases (69%) revealed LOH at one or more loci. Deletion was most frequently observed with the marker D17S801 (64% LOH, informative cases), which shows significant linkage to the TOC locus. The LOH analysis in sporadic oesophageal cancer we report here is thus consistent with the hypothesis that the tylosis oesophageal cancer susceptibility gene is also involved in the pathogenesis of a proportion of sporadic squamous cell carcinomas of the oesophagus.     

Linkage map of Escherichia coli K-12, edition 10: the traditional map

This map is an update of the edition 9 map by Berlyn et al. (M. K. B. Berlyn, K. B. Low, and K. E. Rudd, p. 1715-1902, in F. C. Neidhardt et al., ed., Escherichia coli and Salmonella: cellular and molecular biology, 2nd ed., vol. 2, 1996). It uses coordinates established by the completed sequence, expressed as 100 minutes for the entire circular map, and adds new genes discovered and established since 1996 and eliminates those shown to correspond to other known genes. The latter are included as synonyms. An alphabetical list of genes showing map location, synonyms, the protein or RNA product of the gene, phenotypes of mutants, and reference citations is provided. In addition to genes known to correspond to gene sequences, other genes, often older, that are described by phenotype and older mapping techniques and that have not been correlated with sequences are included.     

Assessing the belief bias effect with ROCs: Reply to Dube, Rotello, and Heit (2010).

Comments on an article by Dube, Rotello, and Heit (see record 2010-14834-005). The authors argued (a) that the so-called receiver operating characteristic is nonlinear for data on belief bias in syllogistic reasoning; (b) that their data are inconsistent with Klauer, Musch, and Naumer's (see record 2000-02818-008) model of belief bias; (c) that their data are inconsistent with any of the existing accounts of belief bias and only consistent with a theory provided by signal detection theory; and (d) that in fact, belief bias is a response bias effect. In this reply, we present reanalyses of Dube et al.'s data and of old data suggesting (a) that the receiver operating characteristic is linear for binary “valid” versus “invalid” responses, as employed by the bulk of research in this field; (b) that Klauer et al.'s model describes the old data significantly better than does Dube et al.'s model and that it describes Dube et al.'s data somewhat better than does Dube et al.'s model; (c) that Dube et al.'s data are consistent with the account of belief bias by misinterpreted necessity, whereas Dube et al.'s signal detection model does not fit their data; and (d) that belief bias is more than a response bias effect. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Trash DNA is what gets thrown away: high rate of DNA loss in Drosophila

We have recently described a novel method of estimating neutral rates and patterns of spontaneous mutation (Petrov et al., 1996). This method takes advantage of the propensity of non-LTR retrotransposable elements to create non-functional, 'dead-on-arrival' copies as a product of transposition. Maximum parsimony analysis is used to separate the evolution of actively transposing lineages of a non-LTR element from the fate of individual inactive insertions, and thereby allows one to assess directly the relative rates of different types of mutation, including point substitutions, deletions and insertions. Because non-LTR elements enjoy wide phylogenetic distribution, this method can be used in taxa that do not harbor a significant number of bona fide pseudogenes, as is the case in Drosophila (Jeffs and Ashburner, 1991; Weiner et al., 1986). We used this method with Helena, a non-LTR retrotransposable element present in the Drosophila virilis species group. A striking finding was the virtual absence of insertions and remarkably high incidence of large deletions, which combine to produce a high overall rate of DNA loss. On average, the rate of DNA loss in D. virilis is approximately 75 times faster than that estimated for mammalian pseudogenes (Petrov et al., 1996). The high rate of DNA loss should lead to rapid elimination of non-essential DNA and thus may explain the seemingly paradoxical dearth of pseudogenes in Drosophila. Varying rates of DNA loss may also contribute to differences in genome size (Graur et al., 1989; Petrov et al., 1996), thus explaining the celebrated 'C-value' paradox (John and Miklos, 1988). In this paper we outline the theoretical basis of our method, examine the data from this perspective, and discuss potential problems that may bias our estimates.     

A novel peptide-grafted liposomal delivery system targeted to macrophages

Insulin-like growth factor II (IGF-II) is highly expressed during hepatocarcinogenesis (P. Schirmacher et al., Cancer Res., 52: 2549-2556, 1992; B. C. Park et al., J. Hepatol., 22: 286-294, 1995). However, the mechanism of its enhanced expression is largely unknown. In this study, we show that IGF-II mRNA levels are increased within six h of exposing human hepatoma cell cultures to hypoxia, suggesting that hypoxia may be a strong stimulus for the induction of IGF-II expression in the process of hepatocarcinogenesis. This finding and the fact that hepatocellular carcinoma (HCC) is a typical hypervascular tumor (M. Mise et al., Hepatology, 23: 455-464, 1996) imply that IGF-II may play an important role in the development of neovascularization of HCC. Here we demonstrate that IGF-II substantially increases vascular endothelial growth factor (VEGF) mRNA and protein levels in a time-dependent manner in human hepatoma cells. The induction of VEGF by IGF-II was additively increased by hypoxia. Moreover, the direct angiogenic activity of IGF-II was observed in the quantitative chick chorioallantoic membrane assay (M. Nguyen et al., Microvasc. Res., 47: 31-40, 1994). These data suggest that IGF-II may be a hypoxia-inducible angiogenic factor in HCC.     

Calcium-dependent release specificities of various cell lines loaded with different transmitters

By loading cells in culture with acetylcholine (ACh) we have characterized a calcium-dependent release mechanism and shown that it was expressed independently of synthesis or storage of ACh. (Isra?l et al., 1994, Neurochemistry International 37, 1475-1483; Falk-Vairant et al., 1996a, Proc. Natl. Acad. Sci. U.S.A. 93, 5203-5207; Falk-Vairant et al., 1996b, Neuroscience 75, 353-360; Falk-Vairant et al., 1996c, Journal of Neuroscience Research 45, 195-201). The transmitter loading procedure was applied to two other transmitters, gamma-aminobutyric acid (GABA) and glutamate (Glu). We could then study the specificity of the release mechanism for the three transmitters in a variety of cell lines, including neural-derived cells. Four different calcium-dependent release phenotypes were identified: two were specific for ACh or GABA, and two co-released two transmitters ACh and GABA but not Glu, or ACh and Glu but not GABA. We conclude that release mechanisms having different specificities are expressed by the cell lines studied, they become functional after loading the cells with the relevant transmitters. These observations will help the identification of proteins controlling the specificity of release, and provide an interesting model for pharmacological studies.     

VEGF mediates angioblast migration during development of the dorsal aorta in Xenopus

Angioblasts are precursor cells of the vascular endothelium which organize into the primitive blood vessels during embryogenesis. The molecular mechanisms underlying patterning of the embryonic vasculature remain unclear. Mutational analyses of the receptor tyrosine kinase flk-1 and its ligand vascular endothelial growth factor, VEGF, indicate that these molecules are critical for vascular development. Targeted ablation of the flk-1 gene results in complete failure of blood and vascular development (F. Shalaby et al. (1995) Nature 376, 62-66), while targeted ablation of the VEGF gene results in gross abnormalities in vascular patterning (P. Carmeliet et al. (1996) Nature 380, 435-439; N. Ferrara et al. (1996) Nature 380, 439-442). Here we report a role for VEGF in patterning the dorsal aorta of the Xenopus embryo. We show that the diffusible form of VEGF is expressed by the hypochord, which lies at the embryonic midline immediately dorsal to the location of the future dorsal aorta. We find that, initially, no flk-1-expressing angioblasts are present at this location, but that during subsequent development, angioblasts migrate from the lateral plate mesoderm to the midline where they form a single dorsal aorta. We have demonstrated that VEGF can act as a chemoattractant for angioblasts by ectopic expression of VEGF in the embryo. These results strongly suggest that localized sources of VEGF play a role in patterning the embryonic vasculature.     

Utility of a linear array ultrasound endoscope in the evaluation of suspected pancreatic disease

Diethylcarbamazine (DEC) was discovered in 1947 as a potent therapeutic agent in lymphatic filariasis and has been a mainstay of antifilarial therapy over the past five decades (R. I. Hewitt, et al., 1947, Journal of Laboratory and Clinical Medicine 32, 1304-1313). Several hundred million doses of this drug have been administered to people. Despite its widespread and successful use over this prolonged time scale, its mechanism of action remains obscure (R. M. Maizels and D. A. Denham, 1992, Parasitology 105 Suppl. 549-560). Numerous studies suggest that DEC has no direct effect on the parasite (F. Hawking and W. Laurie, 1949, Lancet 2, 146-147) and that it exerts its action by stimulating host immune defense mechanisms (F. Hawking et al., 1948, Lancet 2, 730-731), or by activating host platelets to become microfilaricidal (J. Y. Cesbron et al., 1987, Nature 325(6104) 533-536). Recent data from two different laboratories suggest that NO may be involved in host defense against filarial parasites (T. V. Rajan et al., 1996, Infection and Immunity 64(8), 3351-3353; M. J. Taylor et al., 1996, Parasitology 112, 315-322). We investigated whether DEC stimulates the production of NO from murine macrophages or rat endothelial cells. DEC did not stimulate the synthesis or secretion of NO from either, nor did it synergize with interferon-gamma or tumor necrosis factor-alpha in the induction of inducible NO synthase (iNOS). In addition, there was no consistent increase in the output of inorganic nitrate, the end product of NO metabolism, in the urines of rats treated with DEC. These data suggest that DEC does not achieve its therapeutic efficacy through the induction of host iNOS.     

Mutations in the arginine-rich protein gene (ARP) in pancreatic cancer

The ARP gene encodes a highly conserved arginine-rich protein from chromosomal band 3p21.1. At the cytogenetic level this region is frequently deleted in a variety of different solid tumors, although not in pancreatic cancer. We have reported the presence of a specific mutation (ATG50-->AGG) or deletion of codon 50 of the ARP gene in different tumor types (Shridhar et al., 1996, 1996a). In the present study, we have observed mutations involving codon 50 in 11 of 37 pancreatic tumors. The frequency of codon 50 mutation is roughly the same in pancreatic tumors as in the other types of tumors previously examined. In addition, we have detected mutations at codon 51 in multiple PCR subclones in two other pancreatic tumors. Mutations in the ARP gene are thus commonly observed in pancreatic cancer, as well as many other cancers.     

Genetic organization and sequence analysis of the hypha-specific cell wall protein gene HWP1 of Candida albicans

A previously isolated partial cDNA encoding a cell wall protein antigen found on hyphal surfaces of the opportunistic fungal pathogen, Candida albicans (Staab et al., 1996) was used to clone the complete hyphal wall protein 1 gene (HWP1). Hyphal forms of C. albicans invade mucosal surfaces of immunocompromised patients such as those with AIDS. HWP1 consisted of an open reading frame predicting an acidic protein (pI of 3.37) with a calculated molecular size of 61,122. The antigenic domain was located in the N-terminal third of the protein. The remainder of the protein contained abundant hydroxy amino acids, and terminated with a string of 15 amino acids typical of sequences specifying post-translational modification with glycosylphosphatidylinositol (6PI). The analyses suggested that Hwp1 is a glucan-linked protein with serine/threonine-rich regions that are predicted to function in extending a ligand-binding domain into the extracellular space.