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Kindle Money Mastery

If you have ever wanted to be able to be an author for a living or as a side hobby, this is the online course for you! This course gives you access to all kinds of ebook and materials on how to make the most of the Amazon Kindle Store to make a huge amount of money! You don't need to be a creative genius, spend Hours on end writing, or even know how to use Kindle! All that you have to do is follow the instructions in this course by Stefan Pylarinos. Stefan built this course based on what he does for a living Every Single DAY. This is REAL information that has been perfected in a real business Why would this NOT work for you? This is how Stefan makes his money Why not you? Just think You can make living money writing Kindle books. And you can learn all about how to get started making money with K Money Mastery! Read more here...

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Caenorhabditis elegans as a model for sex differences in nervous system structure and function

At the same time, sex determination and sexual differentiation were also the subject of intensive early genetic analysis in C. elegans (Doniach and Hodgkin, 1984 Hodgkin and Brenner, 1977 Kimble etal., 1984 Klass etal., 1976 Madl and Herman, 1979 Nelson et al., 1978). Beginning with the isolation and study of many mutants with completely or partially sex-reversed phenotypes, including the tra (transformer), her (hermaphroditization), and fem (feminization) mutants, a robust genetic pathway has been elucidated that links differential chromosome content (see below) to dosage compensation and sexual fate in the germ line and soma (for reviews see Ellis and Schedl, 2006 Meyer, 2005 Zarkower, 2006). Interestingly, several genes with sequence similarity to D. doublesex (the DM-domain genes mab-3, mab-23, and dmd-3) have been found to be terminal effectors of the C. elegans sex determination pathway, indicating that some components of sex determination are likely to be shared across metazoa...

Innate Immune Response To Systemically Applied Ad

Systemically applied Ads induce two phases of inflammatory gene expression in the liver. The first phase of acute inflammation depends entirely on virus capsid interactions with host cells and occurs within 24 h after virus administration (2,60a). The second phase begins 3 to 4 d after Ad administration and requires viral gene expression (96). In animal models, intravenous Ad administration has been shown to induce transcription and release of a number of cytokines and chemokines, including IL-6, TNF-a, RANTES, IP-10, IL-8, MIP-1a, MIP-1P, and MIP-2 into the serum (64a,69a,70a,95,96,131,132). Macrophages, including tissue residential macrophages (e.g., Kupffer cells in the liver), and dendritic cells throughout the body are considered to be the primary source of these cytokines and chemokines following their transduction with Ads (60a). Additionally, rapid clearance of Ad from the circulation by Kupffer cells may have a protective role against the dissemination of Ads to the lymphoid...

Improvements in Vector Design

Bined with strategies to maximize the production of the individual components through the use of the strong CMV promoter and treatment with the transcription enhancer sodium butyrate (13). We have also shown that titers can be further improved by the inclusion of the adenovirus VAI gene to enhance translation (Lin and Cannon, unpublished data). The combination of these various approaches enables the routine production of vector supernatants in the laboratory with titers in excess of 107 cfu mL. Whether such transient production systems will ever be useful for large-scale production is uncertain because of potential difficulties in the scale-up and vector characterization procedures.

The L1 Retrotransposition Cycle

Human L1 retrotransposition begins with transcription from an internal promoter located within its 5' UTR (Fig. 2). After transcription, the bicistronic L1 RNA is transported to the cytoplasm, where ORF1 and ORF2 undergo translation. Recent studies suggest that ORF2p is translated by an unconventional mechanism and that it is made at much lower levels than ORF1p (Alisch, Garcia Perez, and Moran, unpublished data). Indeed, it is possible that as few as one molecule of ORF2p is synthesized from a single L1 RNA (74).

Use of Human Breast Cancer Cell Lines to Detect Specific Receptor Induced Proteins

Before the development of DNA micro-array and SAGE approaches, the use of labelling of proteins synthesized in cell culture, before and after hormone stimulation, allowed us detection of several steroid hormone specific induced proteins, as defined by their molecular weight in SDS-PAGE, which could then be identified and studied in tumour samples to specify their significance in human carcinogenesis (16). Regarding progestins, using dose response curves and anti-hormones, we could not discriminate between MPA and R5020 (promegestone) with respect to the induction of specific PR responses, such as the secreted 48 kD protein (16-17) and the cellular 250 kD protein, which were both inhibited by the anti-progestin RU486, but not by the anti-androgen flutamide (18 and D.Chalbos et unpublished).

Concluding Remarks And Future Directions

The crucial role of HDAC1 in the regulation of cell cycle progression, proliferation, and differentiation via transcriptional repression of specific target genes has clearly been demonstrated since the identification of the protein in 1996. In addition, evidence has recently emerged showing that HDAC1 can influence various cellular processes, such as DNA replication and chromosome segregation, independently of transcrip-tional repression. Moreover, HDAC1-mediated transcriptional activation of interferon-stimulated genes (ISGs) has recently been reported (105,106) and HDAC1 with its associated enzymatic activity has been found to be necessary for the proper induction of the ISGs interferon regulatory factor 1 (IRF1) and guanylate binding protein 2 (GBP2) (G. Zupkovitz and C. Seiser, unpublished data). Importantly, cumulative observations indicate that HDAC1 is involved in tumor formation and or progression and is a crucial target for HDAC inhibitors in cancer therapy. The development...

The Mechanism of FAS Regulation by Progestin

FAS was not induced by Es or glucocorticoids and different types ofprogestins used in HRT, including the pure progestin R5020 and MPA, were similarly active in the induction of FAS (18 and unpublished experiments). Progesterone however, was only active at higher concentrations.

Enzymology of RNADirected Transcription

Why then has HDV transcription not been better characterized The answer might be that no one has been able to use in vitro transcription reactions to achieve credible initiation of HDV RNA transcripts. In part, this may be because in vitro transcription will probably make use of ribonucleoprotein structures rather than naked HDV RNAs. Currently some progress is being made by the application of immunoaffinity procedures following disruption of cells undergoing a burst of HDV replication (Nie, Chang, Taylor, unpublished), just as others have done for other RNA viruses (Qanungo et al. 2004 Waris et al. 2004). Following such selections, both genomic and antigenomic unit-length HDV RNAs can be found bound to S-HDAg, and a fraction of these are also bound to RNA polymerase II (Nie, Chang, Taylor, unpublished). However, such complexes will have to be proven as competent for in vitro transcription and they will have to be carefully characterized for all the host proteins present.

Preface to the First Edition

I also have been lucky to have had conversations or correspondence with many individuals who gave me useful information, their unpublished works, letters, insights, and important references. Among them, I am grateful to Bill Atchley, David Wake, Bj rn Kurten, Lars Werdelin, Steve Orzack, John Maynard Smith, Brian Charlesworth, Michael Bell, Pete Bretsky, Gabriel Dover, Steve Farris, Steve Stanley, Doug Futuyma, Walter Eanes, Curt Teichert, George Oster, Richard Reyment, J rgen Sch bel, Max Hecht, Russell Lande, Art Boucot, Ledyard Stebbins, Vjaldar Jaanusson, Ernst Mayr, George Gaylord Simpson, Jack Sepkoski, and Urj Haila.

Privileged Structure Derivatization with Amino Acids

The hypothesis that privileged structures bind near the active site of receptors and that they bind to both peptide and nonpeptide receptors was intriguing. It suggested to us that peptide agonists and antagonists might be achieved by appending small peptide units onto privileged structures. Hopefully, there would be some overlap with the peptide agonist binding area. If not, such derivatization could still be worthwhile since amino acid side-chains obviously provide a rich diversity of functionality to interact with proteins. In the case of the spiroindanylpiperidine unit, single capped amino acids were chosen for derivatization in part since it was known from the benzolactams that a large structural unit was not required to produce agonist activity. One of the highlights of this derivatization project was compound 19 (Table 2) whose EC50 50 nM in the rat pituitary GHS assay was remarkable especially since it was tested as an unseparated mixture of four diastereomers. In retrospect,...

BMolecular differences

In addition to these subtle structural differences, two examples of sex differences in gene expression in the core nervous system are known. First, the seven-transmembrane putative chemoreceptor gene srd-1 has been found to be expressed in the ADF sensory neurons only in males, even though these cells are present and appear identical in both sexes (Troemel et al., 1995 White et al., 1986). A second serpentine receptor gene, srj-54, is expressed in the common AIM interneurons in males only (D. S. P., unpublished data). In neither of these cases is the functional significance of sexually dimorphic gene expression understood however, it is noteworthy that both of these neurons are implicated in sensory behavior. The ADF neurons regulate entry into the long-lived dauer larva stage (Bargmann and Horvitz, 1991a), have secondary roles in sensing several classes of ions and small molecules (Bargmann and Horvitz, 1991b), and encode a learned aversion to pathogenic bacteria by expressing...

The Effectiveness Of Genetic Toxicity Tests For Identifying Carcinogens And Noncarcinogens

The U.S.-NTP databases of carcinogenicity and genetic toxicity test results were used for the evaluation. These studies are characterized by defined, standardized test protocols and evaluation criteria and the availability of the peer-reviewed test data and summary conclusions (47-49). Other, unpublished genetic toxicity test results are available but were not used in the evaluations. NTP rodent carcinogenicity test results are available on more than 400 chemicals (48, 50), the majority of which have been tested for genetic toxicity in at least one in vitro test. All chemicals were tested for mutagenicity in Salmonella. Fewer chemicals were tested in vitro in the MLA or chromosome aberration tests or in vivo for MN in rodent erythrocytes.

Whole genome alignment and synteny analyses

Capitalizing on this, the partial genome sequence data from P. berghei and P. chabaudi was used to fill in the gaps in the P. falciparum P. y. yoelii map and to create a composite ''Frankenstein'' rodent malaria genome (Fig. 2.2). Thirty-six synteny blocks of average size 520 kb (range 42-1788 kb) were found to cover the 14 P. falciparum chromosomes. Two rodent malaria chromosomes (3 and 9) were found to be completely syntenic with P. falciparum chromosomes 2 and 11, respectively. A total of 22 synteny breakpoints were identified, located in regions containing rRNA genes and other repetitive elements, and the maximum number of breakpoints in any chromosome was determined to be five. Further detailed analysis of the map is ongoing (T. Kooij, J. Carlton, S. Bidwell, N. Hall, J. Ramesar, C. Janse, A. Waters, unpublished data).

A Male mating behavior

Male mating behavior entails a series of distinct steps response to hermaphrodite contact, turning, vulva location, spicule insertion, and sperm transfer (Liu and Sternberg, 1995). Each of these steps requires male-specific neuromuscular or gonadal structures. In the first step, response to contact, the male apposes the ventral surface of his tail against the hermaphrodite body and several coordinated changes in activity occur. The male tail assumes a characteristic clenched posture (a result of the contraction of tail diagonal muscles), allowing tail sensilla to efficiently detect cues on the hermaphrodite body. The male also ceases forward locomotion and head foraging movements, and initiates backward (tail-first) locomotion along the hermaphrodite body in search of the vulval opening. Response to contact can be triggered by several putative mechanosensory structures in the male tail, primarily the rays and hook, depending on where on the male's body contact is first made (Liu and...

Integrin mediates the cell attachment of the NAresistant RRV variant nar3

Even though the behaviour of MAb 2D9 is similar to that of a2 1 integrin antibodies (Fig. 3), 2D9 is probably not directed to this integrin, since its pattern of staining of mouse small intestinal cells is quite different from that obtained with a2 1 MAbs (R. Espinoza, C. F. Arias & S. Lopez, unpublished data). Nevertheless, the cell structure recognized by 2D9 must be in close proximity to integrin a2 1 on the surface of MA104 cells, since MAb 2D9 displaces the binding of antibodies to a2 1 by flow cytometry (P. Isa, C. F. Arias & S. Lopez, unpublished results). 2D9 might serve as an alternative cell receptor for the variant nar3, since cells that lack a2 1 but are 2D9-positive, like L or CHO, can be infected by this virus, albeit at much lower efficiency (P. Isa, C. F. Arias & S. Lopez, unpublished data).

C Response to hermaphrodite pheromones

The existence of hermaphrodite-produced pheromone(s) detected by males has long been postulated but has remained elusive. Recently, several groups have demonstrated that males can recognize culture medium conditioned by hermaphrodites (Simon and Sternberg, 2002 J. White and E. M. Jorgensen, personal communication K. L. Chow, personal communication A. Barrios and S. W. Emmons, personal communication) or by females from other Caenor-habditis species (Chasnov et al., 2007). Depending on the assay conditions, males will linger in regions containing conditioned medium (Simon and Sternberg, 2002) or will display taxis toward pheromone signals. Interestingly, it has been found that both the sex-specific CEM sensory neurons as well as non-sex-specific sensory neurons of the head are required for males to be able to detect these signals, indicating that sex differences in the core nervous system, in addition to the male-specific nervous system, may generate male-specificity in the response to...

Distribution of GSK3 in Neurons

More recent data has shown that GSK-3a and P are expressed in many neuronal compartments and in primary neurons they can be found in the axon, dendrite, or even in the nucleus 12 (see Fig. 3.1). It has also been suggested that the nuclear translocation of GSK-3 may be associated with apop-totic processes however, in other paradigms of neuronal death this has been not been ratified (D. Simon, unpublished data). It is notable that a proportion

Glutathione Stransferase

In addition to DNA repair, resistance to alkylating agents and other therapies can come about through detoxification. The family of glutathione-S-transferase (GST) enzymes catalyze the conjugation of electro-philic compounds with glutathione. These include various carcinogens, chemotherapeutic agents, and their metabolites 97,128-134 . There are 5 families of GSTs a(GSTA), m(GSTM), p(GSTP), 9(GSTT) and Z(GSTZ) 130,131 . Earlier work demonstrated the importance of the GSTP, GSTM, and GSTT isoforms in resistance to chemotherapeutic agents such as BCNU and cisplatin however, there were conflicting reports in the literature as to the isoforms most involved in therapy resistance in various human and animal cancers 97,129,131-133,135,137-144 . Work in our laboratory agreed with data obtained in other laboratories in that cells from some tumors demonstrated over-expression of one or more of these genes, while others did not 145 . Furthermore, even when BCNU resistant cells were cloned from a...

Pathways Controlling Gsk3 Activity In Neurons

More important, the addition of this hormone increases the serine phos-phorylation of GSK-3. This inhibitory phosphorylation is time and concentration dependent, and an antagonist of estradiol prevents this event. The kinase responsible is sensitive to the inhibition of the PI3K pathway and for this reason it seems that the best candidate is Akt (O. Varea et al., unpublished data). More remarkably, this hormone-dependent GSK-3 inhibition correlates with the transient stabilization of beta-catenin, which is released from a complex with the estrogen receptor and GSK-3. These data suggest that estra-diol, in addition to its receptor-mediated transcriptional activity, may also regulate some neuronal functions by controlling the pool of beta-catenin 37 .

Dihydroxybenzoate decarboxylase

2,3-Dihydroxybenzoate decarboxylase has been reported to be involved in the metabolism of indole, tryptophan, and anthranilic acid.4041 The primary structure of 2,3-dihydroxybenzoate decaroboxylase of Aspergillus niger has been revealed by gene analysis, which exhibits significant homology with those of 2,6-dihydroxybenzoate decarboxylases (unpublished data). This suggests that 2,3-dihydroxybenzoate decarboxylase also catalyzes the regioselective carboxylation of catechol to 2,3-dihydroxybenzoate, although the carboxylation activity has not been examined. Recently, the distribution of 2,3-dihydroxybenzoate decarboxylase has been found in a variety of fungal strains (unpublished data), and the carboxylation activity for catechol is confirmed by the reaction using resting cells (or cell-free extract) in the presence of 3 M KHCO3. The detailed comparative studies of enzyme structures and catalytic properties between 2,3-dihydroxybenzoate decarboxylase and 3,4-dihyroxybenzoate...

Ab initio Discovery of Indel and SNP Markers Without a priori Knowledge of Map Position

One disadvantage to developing SSR or SNP markers in transcribed sequences is their low polymorphism between closely related tomato species and within cultivated germplasm. The sequence of coding regions is more conserved than non-coding regions. Therefore, the design of primers corresponding to the 5' or 3' UTR provides one approach to increase the chance for polymorphic SSR, indel or SNP detection (Cato et al. 2001). Another approach for detection of polymorphisms is to mine intron sequences. This approach is feasible because intron position is conserved between diverged species, especially for highly conserved genic sequences. Using conserved orthologous sequences (COS) derived for tomato (Fulton et al. 2002b Wu et al. 2006) the position of introns can sometimes be predicted by comparison to the Arabidopsis genome (Timms et al. 2006 Van Deynze et al. 2006 Wu et al. 2006). Tools to find the position of introns are available from several genome projects including the Com-positae...

From Philosophy To Theory

Series of clinical symptoms become evident), following which a second and perhaps third, and essentially independent set of themes emerge in the form of answers to the first (akin to the unfolding expression of underlying personality traits). As the complexity of the fugue is revealed (we now have identified a fullblown personality disorder), variants of the introductory theme (that is, the initial symptom picture) develop counter-subjects (less observable, inferred traits) that are interwoven with the preceding in accord with well-known harmonic rules (comparably, mechanisms that regulate intrapsychic dynamics). This matrix of entwined melodic lines progresses over time in an episodic fashion, occasionally augmented, at other times diminished. It is sequenced to follow its evolving contrapuntal structure, unfolding an interlaced tapestry (the development and linkages of several psychological traits). To build this metaphorical elaboration further, not only may personality be viewed...

Structure Analysis Of Decarboxylases Catalyzing Co2 Fixation

Up to now, primary structures of the following enzymes catalyzing CO2 fixation have been revealed from nucleotide sequencing of their genes 4-hydroxybenzoate decarboxylase,2556 3,4-dihydroxybenzoate decarboxylase,26 pyrrole-2-carboxylate decarboxylase (unpublished data), indole-3-carboxylate decarboxylase (unpublished data), and 2,6-dihydroxybenzoate decarboxylase.3738 As for 2,3-dihydroxybenzoate decarboxylase, the carboxylation activity for catechol has not been reported. However, we presume that 2,3-dihydroxybenzoate decarboxylase also catalyzes the reverse carboxylation reaction, since the primary structure is homologous to that of 2,6-dihydroxybenzoate decarboxylase. These decarboxylases can be divided into two enzyme groups as shown in Table 1, according to similarity of their primary structures. Class I contains oxygen-sensitive decarboxylases, their subunit molecular mass being 52-60 kDa. 4-Hydroxybenzoate decarboxylase, 3,4-dihydroxybenzoate

Class I decarboxylases

In the aligned primary structures of class I decarboxylases, the conserved amino acid residues are scattered over their primary structures. There have been few reports to identify the amino acid residues essential for catalytic activity or substrate binding. Huang et al.56 reported the E-X-P motif in the alignment analysis for 4-hydroxybenzoate decarboxylase of C. hydroxybenzoicum and its homologous unidentified proteins. The E-X-P motif is also conserved in pyrrole-2-carboxylate decarboxylase and indole-3-carboxylate decarboxylase (unpublished data). However, the corresponding motif sequence is not observed in the primary structures of 3,4-dihydroxybenzoate decarboxylase of E. cloacae P241.26 microorganisms (unpublished data), suggesting the latent distribution of decarboxylases catalyzing the carboxylation of N-heterocyclic compounds.

The Role of HDAg in Hdv Rna Replication

L-HDAg has been shown to inhibit HDV RNA replication when it is expressed at the beginning of HDV replication (Glen and White 1991 Macnaughton and Lai 2002b). Thus, it was regarded as a regulator of HDV RNA replication in the cell. As discussed above, this finding maybe an artifact since L-HDAg normally is not expressed until late in the replication cycle. Late in replication, the presence or absence of L-HDAg did not affect the final steady-state level of HDV RNA (Macnaughton and Lai 2002b). If L-HDAg indeed does not inhibit HDV RNA replication, its role in HDV RNA replication will be of considerable interest, as L-HDAg is usually colocalized with S-HDAg and has been found to be in the promyelocytic leukemia (PML) body of the nucleus, which is near the site of HDV RNA replication (unpublished observations). Curiously, L-HDAg has been shown to be able to activate a variety of transcription promoters (DNA-templated transcription) in a contransfec-tion assay (Wei and Ganem 1998 Goto et...

Rorschach Comprehensive System

Exner's (1993) relatively homogeneous and institution-specific normative sample was recruited primarily in workplace settings with encouragement from management or union officials and secondarily through interest organizations and social service agencies. In the United States, more recent unpublished RCS reports on samples collected in the United States have been divergent from Exner's normative data. Pires (1999) recruited Portuguese volunteers from various sites contacted through many local institutions with a range of one to seven subjects per initial contact. Gender, age, geographical area, SES, and education were controlled in both the Exner and Pires sampling strategies.

Increased Transcription in the Premutation Range

Although FMR1 mRNA and FMRP levels were initially reported to be normal in the premutation range (Pieretti et al. 1991 Devys et al. 1993 Feng et al. 1995a, b Hmadcha et al. 1998), it recently demonstrated that FMR1 transcription is elevated for premutation alleles. Specifically, levels of abnormal expanded r(CGG) repeats FMR1 mRNA are elevated by as much as fivefold to tenfold in the upper premutation range in peripheral blood leukocytes (Tassone et al. 2000a, c) of both female and male carriers of the fragile X pre-mutation, despite the presence of normal or near-normal detectable FMRP levels (Tassone et al. 2000a, b Kenneson et al. 2001). Higher levels of mRNA are due to higher transcription rates of the FMR1 gene (Tassone et al., unpublished results), with reduced FMRP levels being due to decreased translational efficiency (Primerano et al. 2002). While the basic mechanisms leading to increased transcription of premutation alleles are not known, the presence of such an abnormal...

PCRbased Linkage Map of S lycopersicum cv Rio Grande x S pimpinellifolium LA1589 F2 Population

The development of a reference genetic map covering the entire genome with PCR-based markers demonstrates how public resources can be used to facilitate genetic investigations of tomato populations. Frary et al. (2005) reported on the first sequence-dependent PCR-based map for tomato for a population derived from a cross between S. lycopersicum and S. pennellii. Using many of the techniques reviewed above, a set of 87 PCR-based markers were mapped between two much more closely related red-fruited species, S. lycopersicum cv. Rio Grande and S. pimpinellifolium LA1589 (Gonzalo and van der Knaap, unpublished) (Fig. 2). Since markers that are polymorphic in sub sets of species or within the cultivated germplasm pool have a higher chance of being polymorphic in other lines (Francis and Wang, unpublished), some of the previously developed PCR-based markers were directly applicable to this population. Fifteen markers were derived from the tomato intron sequence mining project (Van Deynze et...

Physiological Evidence In Support Of The Existence Of Multiple Gh Secretagogue Receptors Or Receptor Subtypes

The electrical activation of arcuate neurons by GHRP-6 has a number of distinctive characteristics most particularly the activation is extremely long lasting. Typical excitation is sustained for over 1 h following a bolus administration at a just-suprathreshold dose, and typically excitation reaches its peak intensity only after a latency of 5-10 min this response appears to be even later for nonpeptide agonists than for GHRP-6, although the degree of electrical activation of responsive cells appears similar. It is unclear whether this reflects slower penetration of the blood-brain barrier by the nonpeptide secreta-gogues or a different mode of action. Moreover, the nonpeptide secretagogues MK-0677 (unpublished observation) and L-692,585 (7) appear to be slightly, but consistently, less effective than GHRP-6 for inducing Fos protein expression in the arcuate nucleus. It may be that these nonpeptide GH secretagogues are more selective than GHRP-6 in their central action or that they...

Regulation of Translation of the FMR1 mRNA

Elevation of FMR1 mRNA levels occurs for unmethylated alleles both within the premutation range and extending into the full-mutation range (Tassone et al. 2000a-c Salat et al. 2000 Kenneson et al. 2001). The concomitant deficit in FMRP was originally suggested to be the stimulus for increased FMR1 mRNA production, in the absence of any increase in mRNA stability, essentially as a feedback response to lowered protein (FMRP) levels (Tassone et al. 2000a). Recently, increased levels of run-on transcription in a premutation cell line (compared with a normal control) have been observed, providing direct evidence of transcriptional activation for expanded (premutation) alleles (Tassone et al., unpublished results). Moreover, using both quantitative RT-PCR and RNA in situ hybridization experiments, Tassone et al. (unpublished results) demonstrated that higher FMR1 mRNA levels are not due to nuclear sequestration. In particular, FMR1 mRNA is not retained in the nucleus, but is mainly...

Heat Shock Proteins As Vaccine Vehicles

Collectively, these data underline the crucial role played by SR in tissue homeostasis, innate immunity and lipid metabolism. The expression and the cellular localization of the SR are tightly regulated by environmental factors, including mLDL and numerous cytokines (personal unpublished data). Consequently, the functionality of these receptors may vary, depending on the cell subtype and on the environment.

Origin of genome duality

The hypothesis that nuclear dualism enables ciliates to evolve proteins in novel manners is supported by phylogenetic analyses based on protein-coding genes, such as elongation factor 1 alpha, heat shock protein 70, and eukaryotic release factor 1, that are unable to recover a consistent topology of ciliates due to rapid rates of substitution in this lineage (Budin and Philippe 1998 Bhattacharya and Ehlting 1995 Moreira et al. 2002 Moreira et al. 1999). A striking example of rapid protein evolution in ciliates is seen in histone H4, which is highly conserved in most eukaryotes but shows dramatic patterns of diversification in ciliates (Katz et al. 2004). Analyses of histone H4 and five other proteins show that ciliates tend to have more rapid rates of substitution and higher ratios of non-synonymous substitutions per non-synonymous site to synonymous substitutions per synonymous site (dN dS) than other major lineages of eukaryotes. In addition, both substitution rate and subscripts dN...

Penetrance Estimates From Series Based On Direct Brca Genotyping

A key potential bias in all genotyped affected proband studies is that the formula used to calculate penetrance in the kin-cohort method assumes a steady mutation frequency. It is anticipated that because BRCA1 2 mutations significantly affect mortality, these mutation frequencies decrease with increasing age cohorts. In the Washington, DC, area study (28,53,64), for example, the carrier frequency in females 20 to 29 years of age was 2.7 , whereas the frequency in females over 60 was 0.7 . In male subjects, the corresponding figures were 2.3 and 1.5 , respectively. It is also assumed in the methods to calculate penetrance that mutations are in a steady state i.e., that mutations do not appear de novo. Thus, in the kin-cohort model devised to calculate penetrance, it is assumed that 50 of the parents (the kin-cohort) will have inherited the same mutation. However, it is biologically possible that neither parent inherited the mutation seen in the proband. De novo mutations in BRCA have...

Phenotyping And Genotyping Strategies For Association Testing

For the purposes of inferences on the population history, genotype information from a large number of neutral marker loci is required. We are using the term neutral marker loosely here, to indicate the non-candidate loci, i.e. the loci that were not designated as candidate loci that can putatively influence a trait of interest. The density of the markers required should be scaled to provide genome-wide coverage. Simulation studies suggest 100 SSR or 200 SNP markers would suffice to get a reasonable estimate of population structure and relatedness for most crop plants (Yu and Buckler unpublished results).

Therapeutic possibilities

Some therapeutic effect can be observed if animals are treated with a combination of a DHEA metabolite and a glucocorticoid (R. Hernandez-Pando, K. Arriaga, L. Pavon & G. A. W. Rook, unpublished work 1997) intended to mimic the ratio seen during the 'safe school age' (5 10 years) when children are resistant to the

Biomedical implications and future prospects

MT proteins are prime targets for anticancer drug research. The extensive foraminiferal b-tubulin modifications, some of which appear to mimic the effects of taxol binding in mammalian MTs, offer insight into the effects of altered lateral contact between tubulin subunits in MT assembly and dynamics. At a more basic level, the complex morphology of foraminiferan tests provides an avenue for the investigation of cellular morpho-genetic processes. Foraminifera undergo an elaborate series of steps (the details of which vary by taxon) to construct a new test or test chamber. Preliminary investigations (Habura, unpublished observations) have identified differences in RNA expression profile between resting cells and those that are constructing tests. It seems likely that, as EST and genome sequencing projects on the group proceed, genes that control test construction and pattern formation will be uncovered. Comparison of these genes with their metazoan counterparts -if the counterparts...

Results Of Waitandsee Policy

The results of 29 studies of wait-and-see policy, (including unpublished Daugaard results)2'3'7-916-18' 2633-51 which included 3,008 patients, have been noted. In some of the studies, high-risk patients have been excluded. The total number of relapses seen in these studies is 841 (28.1 ), and the overall survival

Spacing and Orientation of the Saccharide Epitopes Is Important for ConA Interaction

Are not long enough to span the 65 A required to simultaneously occupy two binding sites within a single ConA tetramer (D. Mann, unpublished results, 1999). Another potential mode of action for these ligands is suggested by Brewer's finding that many oligosaccharides and glycopeptides can form cross-linked lectin complexes 102 . A turbidimetric assay monitoring the formation of cross-linked ConA precipitates supports this model for Roy's ligands (Fig. 7). Thus, the best small-molecule inhibitors of ConA may be those that can cross-link the lectin. Dendrimers that exhibit enhanced inhibitory activity toward ConA also appear to function by this mechanism 87,88 . Regardless of their mode of action, data generated with the bivalent ligands highlight the necessity for proper spacing between ligands to elicit optimal multi-valent interactions.

Structure of the Growth Hormone Receptor Extracellular Domain

Although the structure of the free hGH receptor is unknown, the structures of several ligand-receptor complexes show that the receptor has few intradomain contacts (7,12) (M. Ultsch and A. M. de Vos, unpublished results). In these complexes the two fibronectin type III domains are oriented in space approximately perpendicular to one another. This arrangement displays the loops connecting the P-strands to bind hGH in the complex residues throughout six of these loops govern most of the hormone binding.

HDACs In Smooth Muscle

Expression of class II HDAC7 is highly enriched in endothelial cells that line blood vessels (S. Chang and E.N. Olson, unpublished data), and targeted disruption of HDAC7 in mice leads to embryonic lethality owing to severely impaired vasculogenesis. Thus, class II HDACs may serve dual roles in the control of blood vessel formation, by regulating SRF and myocardin in the outer smooth muscle layer of the vessel and by coordinating gene expression in the inner endothelial cell layer. The target(s) of HDAC7 in endothelial cells remains unknown, although MEF2 is an

Vaccinia As An Oncolytic Virus For Cancer Therapy

Development of an oncolytic virus has focused on genetic alterations of the WR strain of virus to achieve a tumor selective replicating virus (4). It has been previously demonstrated that an intradermal injection of 106 pfu of the wild-type WR strain of vaccinia into nonhuman primates leads to a necrotic ulcer of 108 cm2 in only 8 d without systemic spread of the virus (unpublished data). This ability to quickly spread and its ability to produce high levels of trangene expression is extremely promising, as one of the limiting factors in antitumor gene therapy is the limitation of vector distribution throughout fibrinous tumors. Animal models studying the distribution of a systemically delivered tumor-selective mutant vaccinia virus have shown the highest levels of virus in the tumor whereas little to no virus has been detected in other organs. The most promising mutant has been a virus deleted of the TK and vaccinia growth factor (V GF) genes (see Fig. 3). LTK is important for...

Matricellular Proteins

Marimastat is a low-molecular-weight peptide mimetic inhibitor matrix metalloproteinase (MMP). In vitro studies of Marimastat demonstrated significant inhibition of invasion of glioma cell lines, suggesting that MMP inhibitors (MMPIs) may have a role in the treatment of GBM. Marimastat administered adjuvantly to patients with GBM after radiotherapy did not show significant efficacy (unpublished data). In another trial, the combination of temozolomide and Marimastat did result in a benefit 163 . As suggested above, this supports the hypothesis that anti-invasion therapy has little utility alone, but significantly enhances the utility of pro-apoptotic therapies. Another MMP inhibitor, Col-3 has been used in a single agent phase I II study of using a continuous oral schedule in patients with recurrent high-grade glioma with good safety, but limited efficacy 164 .

Avian Models For Reproductive And Neuroendocrine Aging

In captivity under hospitable conditions, some birds (e.g., quail, budgies) have postreproductive life spans of one-third or more of the total life span (Woodard and Aplanalp, 1971 Holmes et al., 2001). Zebra finch hens exhibit significant declines in egg production after several years (Holmes, unpublished data). Female birds and mammals both produce the vast majority of their primary oocytes, or developing eggs, before or shortly after birth (Tokarz, 1978 Guraya, 1989). This fundamental reproductive trait sets birds and mammals apart from most female fishes, amphibians and reptiles, in which Reproductive aging in the domestic hen The domestic chicken is one of the classical models for developmental and reproductive biology, and many fundamental physiological correlates of ovarian aging in hens are thoroughly documented (Johnson et al., 1986 Bahr and Palmer, 1989 Ottinger and Bakst, 1995). As egg production declines (between about 30 to 90 weeks of age), the normal recruitment of...

Transductional Targeting

Attempts have also been made to genetically incorporate onto the Ad capsid Ab and scFv, which have clear benefits as target moieties as a result of their high specificity. With the range of current genetic approaches, incorporating these targeting moieties while retaining functionality still remains difficult. For example, although a scFv was successfully incorporated into the Ad capsid as a fusion protein with pIX, it did not show its original binding ability (unpublished data). The reason for this discrepancy has not been clearly elucidated although possible explanations include scFv accessibility, alteration of capsid trafficking, and scFv processing. Instead of using either conjugate-based or genetic strategies above, the combination of both strategies may complement their respective shortcomings. An example of such combination was pursued by incorporating the Fc binding domain from protein A or G into adenovirus (39-41). Because these motifs effectively bind to antibodies, this...

Other Potential Regulators

GHRs are also regulated by thyroid hormones. The growth-promoting effects of exogenously administered GH are blunted in hypothyroid rats, hepatic GH binding sites are reduced in hypothyroidism, and elevated binding is observed in hyperthyroid rats (54). The authors have recently observed reduced GHR mRNA expression in the ARC in response to thyroidectomy, an effect that is rapidly restored by thyroid hormone replacement (P. A. Bennett, unpublished observations).

Infectivity Enhancement Strategies

In the field of adenovirus, interesting direction is exploration of new locales for lig-and insertion. We have sought various locales in the capsid which would permit insertion of large motifs for targeting and or labeling purposes without hampering viral functionality. Protein IX, which exists between the hexon proteins, permits large insertions in the c-terminus of the protein (88-90). Capitalizing the tolerability of this locale, we successfully introduced relatively large proteins, including single chain antibodies (unpublished data), green fluorescent protein (91), and firefly luciferase (unpublished data) into the Ad capsid. Because various ligands have various requirements in terms of placement and the environment of ligand presentation, seeking alternative motif insertion locales need to continue as well.

Rodent Behavioral Models

O'Brien and colleagues identified another lithium dependent behavior in mice they found that lithium treatment results in an antidepressant-like effect (increased activity) in the forced swim test (FST) 80 . Hagit Eldar-Finkelman and colleagues have found similar results following intraventricular injection of lithium to mice (unpublished personal communication, February 2005). The FST developed by Porsolt and colleagues is widely utilized as a behavioral measure of antidepressant efficacy 135 . The specificity of the effect of lithium is supported by studies utilizing alternate GSK-3 inhibitors. In particular, Kaidanovich-Beilin and colleagues reported antide-pressant-like effects in the FST paradigm following intracerebral ventricle injections in mice of L803-mts (a peptide substrate-competitive inhibitor) 138 . This effect is concomitant with an increase in cytosolic P-catenin 136 . Gould and colleagues similarly found antidepressant-like effects in the FST following peripheral...

Effects of RNA Structural Dynamics

HDV genotype III uses the distribution of the RNA between at least two conformations to restrict editing (Casey 2002 Cheng et al. 2003). Only RNA molecules that adopt the double hairpin structure can be edited (Fig. 2). However, the majority of genotype III RNA appears to assume the unbranched rod conformation, which is not a substrate for editing (Casey 2002 Cheng et al. 2003). The introduction of mutations in the genotype III RNA that shift the distribution of the RNA to the double hairpin structure increases editing to levels comparable with those seen with nonreplicating genotype I RNA (Casey 2002). Thus, while the amber W site itself in genotype III RNA can be edited with efficiency similar to the genotype I site, editing levels in nonreplicating genotype III RNAs are much lower because most of the RNA assumes the unbranched rod conformation, which is not a substrate for editing (Casey 2002). Preliminary data from our laboratory (Linnstaedt and Casey, unpublished results)...

Gene Conversion Between The Lcr22s

Sequence analyses support the occurrence of gene conversion events in LCR22-2 and LCR22-4 based on our analysis of overlapping BAC clones from different genomic libraries spanning the interval (Morrow et al., unpublished data). The evidence is quite similar to that for the large olfactory receptor gene family segmental duplication and for telomere associated repeats (58,73). A model has been proposed to explain how segmental duplications can become homogenized during evolution (Fig. 7) (59,73,74). This process was hypothesized from data generated in studies of the HERV sequences involved in the AZFa microdeletion on chromosome Y and the CMT1A rearrangement on chromosome 17p12 (75,76). Recently, it has been suggested that regions harboring higher rates of gene conversion might be hotspots for common rearrangements in LCRs (72).

Overview Reproduction nuclear dimorphism and endoreplication

Endoreplication has also been reported in various foraminiferal taxa. Arnold (1984) reported what appeared to be a series of endoreplication events within the nucleus of Psammophaga simplora. The total DNA content of a single Astrammina rara nucleus has been measured at 2 ng (Habura, Hayden, and Bowser, unpublished observations), or approximately 4 x 1012 nucleotides. Given that this is approximately 1300 human genome-equivalents, it is highly likely that the giant nuclei

Moral concepts Emotions in Moral Cognition

The Rozin et al. study goes some way toward supporting this theory. It shows that people naturally and systematically associate emotions with moral transgressions. Further evidence for the role of emotions in moral conceptualization can be found elsewhere. Haidt et al. (unpublished manuscript) asked subjects to indicate whether they found certain forms of conduct morally objectionable. For example, they asked subjects to imagine a situation in which a brother and sister engage in consensual incest using effective birth control. When subjects report that this is wrong, they ask them to justify that evaluation. It turns out that people have difficulty providing reasons, and when reasons are provided they can easily be short circuited. When subjects reply that incest can lead to birth defects, the experimenters remind them that birth control was used. Eventually subjects give up on reasons and declare that incest is just wrong, or wrong because it is disgusting. Emotions seem to drive...

Other Action Of Gh In The

The classic hippocampal electrophysiological paradigm for learning and memory is long-term potentiation (LTP), but preliminary results suggest that no obvious defects are seen in the ability to induce LTP in GH-deficient dwarf rats (M. L. Errington and I. C. A. F. Robinson, unpublished). This does not exclude the possibility of local GH effects, or that these animals might show some deficits when tested in behavioral paradigms of learning and memory. Further experiments of this type are clearly warranted in view of the increasing evidence from clinical studies that GH administration to GH-deficient adults may be associated with positive effects on mood and mental performance (56,108). Although it is always difficult to exclude secondary effects of GH treatment (increased muscle strength, loss of fat, increased energy), direct effects of GH on the metabolism or protein synthesis of neural tissue have been demonstrated (109,110). Thus, the presence of central...

Structural Mechanistic Studies

Structural studies of the insulin receptor have been limited largely to the cytoplasmic portion of the P-subunit. Within the cytoplasmic portion are 36 residues in the jux-tamembrane region (membrane-proximal), 295 residues in the tyrosine kinase domain, and 72 residues in the C-terminal tail (Fig. 1). Crystal structures of the insulin receptor kinase domain (IRK) have been determined in different states of phosphorylation 8,9 and for several mutants 10 (S. R. Hubbard, unpublished data). IRK shares a similar overall architecture with protein serine threonine kinases 11 , with an N-terminal lobe composed of a five-stranded antiparallel P-sheet and one a-helix, and a larger C-terminal lobe that is mainly a-helical (Fig. 2). ATP binds in the cleft between the two lobes, and the tyrosine-containing segment of a protein substrate interacts with residues in the C-terminal lobe. Several residues are highly conserved in all functional tyrosine kinases, including several glycines in the...

Gene Disruptions and Generation of a Protease Deficient Strain

The ade2 ADE2 genetic system has the advantage of having a forward selection for Ade+ transformants and a simple visual screen for colonies that have lost the ADE2 marker. This facilitated site-directed gene disruptions by loop-in loop-out mutagenesis (Raymond et al., 1998 Rothstein, 1991). Sequential rounds of mutagenesis were used to generate the strains shown in Table 1. PCR techniques were used to clone the P. methanolica PEP4 and PRB1 genes. A pep4A single mutant, PMAD15, appeared wild type for vacuolar protease activity, but the pep4A prblA double mutant, PMAD16, possessed a vacuolar protease-deficient phenotype (Jones, 1991 Raymond et al., 1998). This strain has no noticeable vegetative growth phenotype and it ferments to high-cell density providing that an adequate supply of nitrogen is maintained. Unlike the wild-type ade2 strain, PMAD11, it has not yet been possible to reconstitute efficient transformation frequencies from frozen electrocompetent PMAD16 cells (C. K. Raymond,...

Conclusion and functional implications

Three major milestones underlie the formation of neuronal circuits (1) when the participating neurons are formed, (2) when they reach their final position, and (3) when they start to proliferate and establish their first afferent and efferent connections. The neuronal cell formation of the human hippocampus appears to occur within a relatively short period of time, with the exception of the dentate granule cells. The last neurons for Ammon's horn, the subicular complex, and entorhinal cortex may form between the 20th and the 24th gestational weeks, but major cell formation probably ceases around the 15th gestational week. This finding indicates that while pyramidal cells form in the first half of pregnancy, granule cell formation continues until birth, even if the major cell formation of granule cells happens before the 34-36th week of gestation. Cell migration is also rapid in Ammon's horn, the subiculum, and entorhinal cortex adult-like cytoarchitectonics of those areas are observed...

The Origin And Cellular Functions Of Grp94

Though GRP94 is the paralog of Hsp90, available evidence indicates that the evolutionarily ancient gene duplication event yielding GRP94 has also resulted in distinct and divergent regulatory elements. Notably, while Hsp90 is up-regulated during heat shock, per its name, as well as other stresses, GRP94 is not. This difference is reflected in the promoter structure whereas Hsp90 has a heat-shock response element, GRP94 has two ER-stress response elements (ERSE) that are most significantly up-regulated during the unfolded protein response, triggered by nutrient deprivation and ER stress, among others (Chang et al., 1989 Lee, 2001). At the sequence level, GRP94 and Hsp90 diverge at key regions of the N and C-terminal domains. In the N-terminal domain, GRP94 has a conserved 5 amino acid insertion in the adenine nucleotide geldanamycin binding pocket (Soldano et al., 2003). This insertion confers conformational response to adenine nucleotide binding that differs substantially from that...

Intraspecific variation

As with most other behaviors, there is ample variation within the prairie vole species in social behavior (Getz and Hofman, 1986 Getz et al., 1993 Roberts et al., 1998). Furthermore, both captive (Hammock et al., 2005 Insel et al., 1994) and field-caught (Phelps and Young, 2003) prairie voles show individual variation in V1aR distribution patterns. Finally, the microsatellite, divergent between prairie and montane voles, exhibits significant intraspecific length polymorphism within the prairie vole species (Hammock et al., 2005 Hammock and Young, 2002). There are multiple alleles, showing a roughly normal distribution of lengths within a range of 50 base pairs in the laboratory (Hammock and Young, 2002 Hammock et al., 2005), and a range of 100 base pairs in a field-caught sample of prairie voles (Phelps, Hammock, and Young, unpublished data). This intraspecific variation, while significant, does not approach the species divergence between prairie and montane voles.

Amphiphilic Calix[4arene Nanostructures

Intrigued by the possibility of generating sugar rods.'' Several of these molecules could be synthesized via olefin self-metathesis reactions catalyzed by Grubb's catalyst (PCy3)2Cl2Ru CHPh 70 . Additionally, they can be prepared from a-alkynyl sialosides (Z. Gan, R. Roy, unpublished data) by using palladium(0)-catalyzed cross-coupling chemistry (Sonogashira reaction) (71). These novel derivatives fall outside the scope of this chapter, so their synthesis will be described in due course.

In Situ Profiling Of Transcription In The Gi Tract

As soon as sequence data is available for a few genes in a bacterium of interest, one could think of several sophisticated tools that allow investigation of the in situ expression levels of specific genes. One example of such an approach is the implementation of quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in the gram-negative bacterium Helicobacter pylori (66). This study describes the assessment of gene expression in this pathogen within the mouse and human gastric mucosae. Three genes, encoding urease, catalase, and a putative adhesin specific for adherence to human gastric mucosa, were selected for analysis, as their role during host residence was already established. Using minute quantities of mRNA isolated from human and mouse infected mucosae, the in situ expression of these three genes could be established. Moreover, the results of this study indicate that the relative abundance of transcripts was the same in the human and mouse model system. Hence,...

Lcrmediated Somatic Nf1 Microdeletions

Recurrent mitotic NF1 microdeletions. The schematic shows the pair of JJAZ1 low-copy repeats (LCRs) that mediate recurrent mitotic microdeletions of the NF1 region (refer to Fig. 1 for genomic context of the region). These LCRs share 46 kb of homology with 97 sequence identity and are located just internal to the NF1-REP-P1 and -M (26). Breakpoints are drawn for four cases of 1.2-Mb deletions mediated by paralogous recombination between the JJAZ1-Y pseudogene and the JAZZ1 functional gene. (Three from ref. 21 and UWA186-1 as an additional unpublished case from my laboratory.) Fig. 5. Recurrent mitotic NF1 microdeletions. The schematic shows the pair of JJAZ1 low-copy repeats (LCRs) that mediate recurrent mitotic microdeletions of the NF1 region (refer to Fig. 1 for genomic context of the region). These LCRs share 46 kb of homology with 97 sequence identity and are located just internal to the NF1-REP-P1 and -M (26). Breakpoints are drawn for four cases of 1.2-Mb deletions...

Related to Testes Specific Vespid and Pathogenesis Protein RTVP1

In our initial studies we demonstrated that mRTVP-1 was upregulated by p53 and was also induced by DNA damaging agents such as y-irradiation or doxorubicin (65). RTVP-1 secretion appeared to be independently regulated by specific cytokines (unpublished data). In normal prostate RTVP-1 protein was localized to epithelial cells and specific immune cells.

Chaperoned peptides as antitumor antigens multiplicity of antigenicity and crosspriming

As mentioned above, chaperone proteins have been purified from cells containing known peptide antigens, and via direct or indirect assays, those antigens have been demonstrated to have been associated with the chaperones. This has recently been shown for primary human tumors (melanoma) as well (52). In that study, it was found that T-cell responses to melanoma antigen did not depend on the human leukocyte antigen (HLA) haplotype of the tumor from which the HSP70 originated. Cross-priming via chaperone protein has been observed before in animal models (54,58), and this would be an obviously important benefit to chaperone protein antitumor vaccinations. In circumstances where there is no knowledge of particular antigenic peptides, vaccination of animals with tumor-derived chaperones has shown potent antitumor effects in both prophylactic and therapeutic settings. The growing list of tumor types to which chaperone protein vaccine therapy is amenable is impressive, crossing strain...

Aneuploidy Causing Mechanisms

Figure 39.3 Human (left) and rhesus monkey (right) blood cell nuclei, stained with probes for LS12 and LS 21. From pilot experiments performed to determine if human probes can be used in fluorescent in situ hybridization (FISH) for monkey chromosomes. Unpublished data by Brenner et al. Figure 39.3 Human (left) and rhesus monkey (right) blood cell nuclei, stained with probes for LS12 and LS 21. From pilot experiments performed to determine if human probes can be used in fluorescent in situ hybridization (FISH) for monkey chromosomes. Unpublished data by Brenner et al.

Clinical Bbbd Results

Although CNS metastases occur much more frequently than primary brain tumors, treatment options are limited and chemotherapy in the setting of CNS metastases has not been widely studied (see Chapter 35 for more information). For example, platinum-based systemic chemotherapy is widely used in the treatment of ovarian cancer. Our clinical team treated five patients with CNS metastases from ovarian (n 4) and endometrial (n 1) cancer, who refused or failed to respond to conventional treatment, with carboplatin (intra-arterial) with or without BBBD, etoposide or etoposide phosphate (intravenous or intra-arterial) and cyclophosphamide (intravenous) (Murillo et al., unpublished data). The primary gynecologic cancer was in remission after systemic treatment, prior to the development of CNS metastases. If residual brain lesions were present after the intra-arterial chemotherapy, then focal radiation was given.

Relationship Between mtDna Mutations And Oocyte Competence

Figure 39.4 Mitochondrial hypervariable D-loop 600 bp PCR amplicon from 3 female and 1 male rhesus macaques. Samples were run on a 1.0 agarose gel at a constant voltage of 70V for 45 min. Initial primer sets have been designed, and preliminary PCR demonstrated positive amplification of a 600 bp region of the mitochondrial D-loop of Indian origin rhesus macaques. We have now cloned and DNA sequenced the complete 1600 bp M. mulatto mitochondrial DNA, D-loop hypervariable region (see Figure 39.5). Unpublished data by Brenner et al. Figure 39.4 Mitochondrial hypervariable D-loop 600 bp PCR amplicon from 3 female and 1 male rhesus macaques. Samples were run on a 1.0 agarose gel at a constant voltage of 70V for 45 min. Initial primer sets have been designed, and preliminary PCR demonstrated positive amplification of a 600 bp region of the mitochondrial D-loop of Indian origin rhesus macaques. We have now cloned and DNA sequenced the complete 1600 bp M. mulatto mitochondrial DNA, D-loop...

Mitochondrial Copy Numbers In Primate Oocytes

The number of mitochondrial genomes in human oocytes has been estimated by fluorescent rapid cycle DNA amplification, a highly sensitive technique for quantifying mtDNA copy numbers in individual cells (Steuerwald et al., 2000). From the log-linear phase of amplification during real-time PCR, preliminary results showed 90,0001,000,000 copies of mtDNA in each human oocyte (Steuerwald et al., 1999, 2000). The average mtDNA copy number in over 70 human oocytes during maturation was 779,000 + 240,000 (range 240,000-1,550,000) (Barritt et al., 2000). Age-related differences were not seen (Steuerwald et al., 2000 Barritt, unpublished results). The relationship between copy number and function (ATP production) remains to be investigated. However, a minimum amount of mitochondrial activity must be necessary for normal cell functions (Barnett and Bavister, 1996 Van Blerkom et al., 1995, 2000). Perhaps the total numbers of mitochondria are not as relevant as the proportion of functional...

Future Directions

Important to resolve all of the possible normal and disease-associated chromosomal variants associated with this region. Unpublished data from our group and collaborators (LA P rez-Jurado, personal communication) indicate that in addition to the anomalies described in this chapter, there can also be variation in the number of LCRs, smaller rearrangements between the two adjacent LCRs, and duplications at this locus. In addition, there appears to be a background of gene conversion within these blocks, which makes identification of LCR-specific sequences impossible in some individuals (31).

Breast Cancer As A First Or Subsequent Cancer In

Forty-five of the original tumors were female breast, and 10 of those patients developed at least one additional tumor, including eight with an additional breast cancer. Breast cancer also accounted for 5 6 (83 ) of second cancers in those with an initial sarcoma (the other common original tumor). These data overall suggest an extremely high probability of breast cancer in LFS females, most of which occur before age 45, with a remarkably high probability of a second breast cancer. In Hwang et al. (58), the cumulative risk of female breast cancer in a p53 mutation carrier was over 60 by age 40 years (Strong et al., unpublished data).

Modern Fixed Combinations Approved Outside The United States

A bimatoprost 0.03 -timolol maleate 0.5 fixed combination (Ganfort Allergan, Inc., Irvine, Calif.) has been recently approved in the European Union. Unpublished data (A. Hommer and colleagues) from a multicenter, double-blind, randomized study have been presented. In this trial, patients at 35 sites were randomized to one of three treatment arms. Each received the fixed combination dosed in the morning (178 subjects), or the concomitant use of timolol twice daily and bimatoprost once in the evening (177 subjects), or bimatoprost once in the evening (99 subjects). All subjects were naive to pharmacotherapy and returned 3 weeks after randomization for IOP measurements at 8 a.m., 10 a.m., and 4 p.m. The mean diurnal IOPs for the fixed-combination and concomitant-use groups were within 1.5mm Hg (95 confidence interval) at all three time points. This met the defined criterion for noninferiority. The fixed combination decreased mean diurnal IOP from baseline by...

Breast Cancer Prognosis In

Expression signature for p53 functional status in breast cancer is more predictive of outcome than p53 sequence analysis, and suggest that p53 may be functionally attenuated in the absence of DNA sequence variants. From those data one might assume that the breast cancer in germ line p53 mutation carriers would also carry a poor prognosis surprisingly little data are available to support that expectation, and the absence of data perhaps speaks loudly. Given that there are no published survival data for breast cancer in p53 mutation carriers, the frequent reports of multiple primary tumors occurring over 10 to 30 years (71) suggest that many of these patients do not succumb to their breast cancer. Unlike BRCA1,2 mutation carriers (88), no distinct pathology or prognosis has been associated with the breast cancer in p53 mutation carriers. In the Hwang et al. (58) series, the overall cancer survival for p53 germ line mutation carriers and controls were not different (Strong et al.,...

Mechanisms of lateral gene transfer

Very little is known about the mechanism of lateral gene transfer in the Apicomplexa. There are no identified retrotransposable elements in the P. falciparum genome (Gardner et al. 2002) nor several other apicomplexan genomes (Kissinger, unpublished observation) however, they may have been present in the past, involved in gene transfer, and subsequently lost from the genome. An analysis of transferred genes and their locations in apicom-plexan genomes has shown that the acquired genes are distributed throughout the genome and suggested, in at least one case, that the transfer of a segment of prokaryotic genomic DNA has occurred (Huang et al. 2004a).

Overview of protocols

The reasons for these apparent differences in efficiency are not clear. In addition, counting beating EBs may not accurately reflect the conversion of human ES cells to cardiomyocytes since individual EBs may contain significantly different numbers of cardiac cells. Recently, the differentiation of several independent human ES cell lines BG01, BG02 and HUES-7 has been described (Zeng et al, 2004 Denning et al, 2006). The HUES lines 1-17 are of particular interest because they were the first to be derived and maintained by bulk enzymatic passaging using trypsin (Cowan et al., 2004) both on mouse embryonic fibroblast layers or on Matrigel in feeder-free conditions (Denning et al., 2006). Beating cardiomyocytes, immunoreactive for the cardiac marker a-actinin, can be derived by EB formation from these human ES cell lines. EBs are formed either by mass culture of small clumps of human ES cells harvested using collagenase IV or by forced aggregation of defined numbers of human ES cells...

DCDerived Exosomes Bear Functional MHC Class I and Class IIPeptide Complexes

Exosomal MHC class I molecules can be efficiently loaded directly, after acid elution of purified exosomes (32 Dee Shu, unpublished data). In contrast, exosomal MHC class II molecules can present peptides that have been pulsed onto whole DC culture (25,26 Dee Shu, unpublished data). We are currently reporting that MHC class I and II peptide complexes harbored by mouse or human exosomes activate specific CD8+ or CD4+ T lymphocytes but require DCs (29,31). Exosomal HLA-A2 Mart1 peptide complexes trigger specific HLA-A2-restricted, Mart1-specific CTL clones when pulsed onto DC in vitro (30). In the absence of DC, exosomes do not directly stimulate T cells in vitro. In the HHD2 HLA-A2 transgenic mouse model, inoculation of DC-derived exosomes bearing functional A2 MART-1 complexes (up to 1010 class I molecules) pulsed onto H-2b mature DCs allows expansion of specific A2 MART-126-35 tetramer-positive CD8+ T cells in draining lymph nodes (Fig. 1).

Paradoxical Blockade Of Cardiac Hypertrophy By Hdac Inhibitors

The mechanism for HDAC inhibitor-mediated repression of cardiac hypertrophy remains unknown. We envision at least three possibilities (Fig. 6). First, HDAC inhibitors may stimulate expression of genes that encode repressors of cardiac growth. Second, HDAC inhibitors may repress expression of procardiac growth genes. Third, HDAC inhibitors may suppress cardiac hypertrophic signaling cascades, a hypothesis for which we have supporting evidence (B.C. Harrison and T.A. McKinsey, unpublished data).

Ndirect Specific Means to Detect Pneumococcal Involvement

Figure 12.1 Carriage acquisition in different countries. Cumulative prevalence of pneumococcal NP colonization by age in various populations. Numbers in parentheses, references. *, Israeli Bedouins **, Israeli Jews (R Dagan, unpublished data). Reference 5 is from India, 6 from Papua New Guinea, 7 from the United States, 8 from Australia (Aboriginal site), 9 from Costa Rica, 10 from United States, 11 from Sweden and 12 from Finland (O'Brien et al., 2003). Figure 12.1 Carriage acquisition in different countries. Cumulative prevalence of pneumococcal NP colonization by age in various populations. Numbers in parentheses, references. *, Israeli Bedouins **, Israeli Jews (R Dagan, unpublished data). Reference 5 is from India, 6 from Papua New Guinea, 7 from the United States, 8 from Australia (Aboriginal site), 9 from Costa Rica, 10 from United States, 11 from Sweden and 12 from Finland (O'Brien et al., 2003).

Diagnosis Of Boron Status In Plants

Leaves develop yellow or white veins followed by some changes in interveinal areas growing points die and blossoms shed (82). Unpublished data of Gupta and MacLeod (83) showed that boron deficiency in peas resulted in short internodes and small, shrivelled new leaves. Pea (Pisum sativum L.). Boron toxicity results in suppression of plant height and in the number of nodes (98). Unpublished data of Gupta and MacLeod (83) showed that boron toxicity results in burning of the edges of old leaves.

Altered Self Reported Health Qualitative Approach

In France, in the context of a TNS Sofres survey (unpublished data), which is deemed to provide a representative sample of patients with HS, 47.2 of patients reported a medical consultation for their disease in the year preceding the interview, and 47.7 of the patients reported HS to be a relevant problem and a severe distress.

Virus Induced Changes In Mhc Class I Presentation Of Hostderived Peptides

Heat shock protein production is amplified during a variety of cellular stresses including viral infection. Therefore, an increase in intracellular HSP concentration may lead to increased MHC class I presentation of HSP-derived peptides. Infection of immortalized human T cells expressing HLA B*0702 with HIV increases intracel-lular levels of Hsp27. These increased intracellular levels of Hsp27 lead to increased presentation of the Hsp27-derived peptide APAYSRAL by the HLA B*0702 class I molecule (Hickman et al., 2003). The Hsp90-derived HLA B*1801 ligand EEVETFAF has also been observed following HIV infection (H.D. Hickman-Miller and W.H. Hildebrand, unpublished). Increased class I presentation of HSP-derived peptides is not limited to cells stressed through HIV infection. Hsp90 production is increased in HLA A*0201 homozygous cells following Epstein-Barr virus transformation while the class I HLA of melanoma cell line MelJuSo also present Hsp90p peptides when infected with measles...

HHV6 is found essentially in scleronodular HD in young adults

Torelli et al. (1992) described three HHV-6-positive HD, belonging to the nodular-sclerosis-lymphocyte-depletion subgroup, which occurred in young women (27-, 28- and 31-years old). Similarly, different authors obtained the highest prevalence and highest mean copy for the scleronodular subtype of HD (Table 1). In a large study conducted on 86 adult HD patients, we obtained a high prevalence (83.6 ) of HHV-6 in scleronodular HD (unpublished data). However, scleronod-ular subtype is the most frequent in HD patients examined. In the same study, the mean age of scleronodular HD patients positive for HHV-6 and negative for EBV, was 29.5 years, whereas 45 years if HHV-6 negative and EBV positive. Therefore, HHV-6 seems to be more predominant in scleronodular HD and much more in young adults, arguing a potential role for this virus in the etiology of HD in this context. Clark et al. (1990) found an association of increased HHV-6 seropositivity Some cases of HD are associated with EBV,...

HHV6 exhibits transforming capacities

Because DR7 from variants A and B share only 42.2 homology, it seemed interesting to us to look for the same oncogenic properties for DR7B. Consequently, using a two-hybrid system, we demonstrated that DR7B, like DR7A, was able to bind to human p53, indicating that the p53-binding site on the DR7 protein could be on the common portion of both viral proteins (unpublished data). with diverse inducers. Moreover, constitutive NFkB activation has been shown to be required for survival and proliferation of RS cells, preventing them from undergoing apoptosis under stress conditions (Bargou et al.,1997). These findings tended to identify NFkB as an important component for understanding the HD pathogenesis. We found enhanced expression of p50 and p65 mRNAs and NFkB activation, as demonstrated by the use of reporter genes, in HHV-6B-infected cells compared to mock-infected cells. The increase in the NFkB levels in infected cells could be considered to be the result of transcriptional...

Biological effects of exosomes

Rapidly saturated (our unpublished data), it is tempting to speculate that secretion of exosomes by DCs is an amplification pathway for the antigen presentation network, enabling rapid dissemination of processed MHC complexes for T-cell stimulation. As suggested for the immunological synapse and for the tetraspan-enriched domains (37), the presence of exosomes on the membrane of immature DCs might trigger sustained engagement of T-cell receptors. One could postulate that exosome secretion might occur in the lymph or in the T-cell area of lymphoid organs.

Mechanisms For Duplications And Deletions

The molecular mechanisms for the genomic rearrangements that cause PLP1 duplication and deletion remain largely elusive, but current knowledge suggests that the involvement of NAHR is unlikely. FISH mapping of the duplicated genomic intervals in individuals with PMD revealed no common recombinant duplicated genomic segments (Fig. 1) (4,9). It has been thought that the duplications are mainly tandem in nature, but our recent findings also suggest that some are inverted duplications (Lee, Inove, and Lupski, unpublished data). In contrast to CMT1A, duplicated genomic segments often originate from a single chromosome rather than two homologous chromosomes, as shown by identical haplotypes within the duplicated ge-nomic intervals (4,9). In addition, the origin of the de novo duplication events can often be traced to male spermatogenesis (46). Each of these findings suggests that PLP1 duplications are commonly generated by sister-chromatid exchange in male meiosis (4,9,46). Unlike...

Minimal Velocities Necessary to Perforate Skin

Now that we have an idea of the minimum velocity necessary for bullets and airgun pellets of different weights and calibers to perforate skin, we must ask whether the missiles lose this velocity in perforating the skin. The answer is no. In an unpublished extension of the previously mentioned study, DiMaio and Copeland conducted a number of test firings using a human lower extremity to determine how much velocity was lost by a missile passing through the thigh.8 The bullets had to pass through two layers of skin and approximately 6 in. of muscle. Two different calibers of ammunition were used .38 Special and .22 Long Rifle. In the tests with the .38 Special ammunition, two different types of ammunition were used. The first type was loaded with a 158-gr. lead round-nose bullet. Average impact velocity was 766 ft sec. On an average, these bullets lost 280 ft sec (36.8 of impact initial velocity) in passing through the thigh (Table 9.2). The velocity lost ranged from a minimum of 214 ft...

Characteristics of the Helper Virus

The most commonly used helper virus is a serotype 5, FGAd (E1 deleted) with its packaging signal flanked by loxP sites (Fig. 2). As with all FGAds propagated in 293 or 293-derived cells, the potential exists for the generation of replication-competent Ad (RCA E1+ ) as a consequence of homologous recombination between the helper virus and the Ad sequences present in 293 cells. To prevent the formation of RCA, a ''stuffer'' sequence was inserted into the E3 region to render any E1+ recombinants too large to be packaged (54). The length of the E3 stuffer is such that the total size of the helper virus genome is < 105 of wild-type, but > 105 following homologous recombination with Ad sequences in the 293 cells. As of this writing, the emergence of RCA has yet to be reported using helper viruses with an E3 stuffer. In contrast, RCA is readily detected using helper viruses without an E3 stuffer when propagated in 293 and 293-derived cells (41,54). The choice of sequence used as stuffer...

Protein Tyrosine Kinase Inhibitors

These compounds were designed to be ATP mimics, but their kinetic behavior toward the substrate was not always investigated. Because the degree of conservation in the ATP binding site is not absolute, one can obtain a high degree of selectivity among closely related ATP binding domains. In 1993, the Jerusalem group 24 was able to demonstrate that ATP-competitive tyrphostins such as AG 825 (Fig. 1) can discriminate between the kinase domains of Her-2 neu and EGFR by almost two orders of magnitude in affinity, in spite of the almost 80 identity in the kinase domains of the two related PTKs. In 1994, the quinazoline ZD 1839 (Iressa Fig. 3) was shown to be a potent EGFR kinase inhibitor with excellent bioavailability 25 . Quinazolines were originally identified by Zeneca and were shown to selectively inhibit EGFR at low nanomolar concentrations 25 , whereas Her-2 neu is inhibited only at micromolar concentrations. Qunixaloines such as AG 1296 19,26 or AGL 2043 27 (Fig. 2)...

Surgically Modified Animals

To be correct, removal of the non-secreting stomach region could result in a gastric microbial profile that is more in line with that of the human. However, surgical removal of the non-secreting stomach region has no effect on the luminal levels of lactobacillus in either the stomach or in the colon of mice (A. Henriksson, unpublished observations). Therefore, it can be assumed that in mice and possibly other animals, this region is not responsible for the relatively dense lactobacillus populations found in either the intestinal contents or the stomach itself.

Initial Clinical Trials With Melacine

Two other trials of Melacine lyophilized lysates given sc were performed at our institution with and without cyclophosphamide pretreatment (Table 2). Of the 58 patients entered into three trials, including the 20 described above, there were 8 major responses, 1 CR (1.7 ) and 7 PR (13.8 ), for a total objective response rate of 15.5 . Whether this was significantly different from initial results with our frozen lysates is uncertain. Except for one unpublished trial at a different single institution with fewer than 20 patients actually treated, there have been no direct comparisons of the two forms of the material. In any event, if we combine the data for 102 patients who received the combination of M-1 and M-2 cell lines either as frozen lysates or Melacine in these five clinical trials, our response rate was 18.6 (19 of 102), with 3 CR and 15.6 PR. In a trial conducted by

Model Plant Species For The Genomicsbased Studies

Been carried out using microarray and macroarray based methods by several groups (Table 1). Two types of arrays have been made available for genomic studies in rice, namely oligonucleotides array as well as cDNA array. There are numerous examples wherein detailed studies have been taken in rice using these approaches. Analysis of salt stress-inducible ESTs from salt tolerant rice cultivar Dee-geo-woo-gen revealed several proteins showing homology to proteins functional for detoxification, stress response and signal transduction in plants (Shiozaki et al. 2005). Comparative analysis between different rice genotypes has also been attempted employing salinity tolerant (CSR27 and Pokkali) and sensitive (PB1) cultivars of rice (Sahi et al. 2003). This study highlighted that genes such as SalT, glycine rich RNA binding proteins, ADP ribosylation factor, NADP dependent malic enzyme, Mub ubiquitin fusion protein, tumor suppressor genes, wound inducible genes, ethylene response element binding...

Comparison Of Expression Systems

As indicated in the introduction, no single expression system is ideal for all GPCRs. Table 8.1 summarizes the different expression systems and lists the advantages, disadvantages, and examples of GPCRs expressed. Generally, the cell-free expression system has provided only poor expression of GPCRs the only examples to date are unpublished studies of human p2 AR. However, the simplicity and speed of cellfree translation and the flexibility that allows evaluation of expression from PCR products quickly and directly makes this an attractive approach. The system requires further development and the scale-up costs continue to be of concern. E. coli expression definitely has advantages in that it is simple and rapid to use and scale-up costs are reasonable. The possibility of isotope labeling for NMR and x-ray crystallography studies has some value. GPCRs have been difficult to express at

Regulation Of Vascular Tone By Ion Channels And Membrane Potential

FIGURE 3 Single-channel recording of low-amplitude KV currents (A) and high-amplitude BKCa currents (B) in inside-out membrane patches from rat mesenteric arterial cells. Recordings were obtained at a depolarized patch potential (Em) of 40 mV to activate both channel types. (A) The external patch surface was exposed to 100 nmol liter iberiotoxin to inhibit BKCa channels and permit the recording of KV channels in relative isolation. In both sets of traces, horizontal sweeps were obtained as Ca i was increased from 10 to 1000 nmol liter. This increase in Ca i inhibited KV channels (A), but activated BKCa channels (B). Li and Rusch (unpublished recordings).

Initial Estimations for Climate Scenarios from Low Resolution Climate Models

The estimation of potential changes in crop yield. Potential changes in national grain crop yields were estimated using crop models and a decision support system developed by the US Agency for International Development's International Benchmark Sites Network for Agrotechnology Transser (IBSNAT).7 The crops modelled were wheat, rice, maize and soybean. These crops account for more than 85 of the world's traded grains and legumes. The estimated yield changes for 18 countries were interpolated to provide estimates of yield changes for all regions of the world and for all major crops, by reference to all available published and unpublished information.

Immunohistological Studies

With a classical delayed-type hypersensitivity (DTH) reaction (Mitchell MS et al., unpublished data). It was interesting that, contrary to our expectations, the predominant cell in all of the sites of rejection was the monocyte-macrophage, identified with anti-CD11c (Leu M5), anti-class I and II antigens, and usually anti-CD4. CD4+ T cells and CD8+ T cells were present at the periphery of the tumor and perivascularly, with CD4+ cells predominating 3 1 or 3 2 (Fig. 3).

Nmda Receptors And The Development Of Opiate Sensitization

As mentioned earlier, we have begun studies exploring the role of NMDA receptors in tolerance and sensitization to the locomotor effects of morphine. In these studies, we observed that MK-801, at a relatively low and selective dose, inhibited the development but not the expression of sensitization to the locomotor-stimulant effect of morphine (76,86). Adding strength to this finding, this inhibition paralleled inhibition of tolerance to the locomotor-depressant effect and tolerance to the analgesic effect of morphine in the same experimental animals. In more recent experiments, we found that the low-affinity noncompetitive NMDA receptor antagonist memantine also inhibited sensitization to the loco-motor-stimulant effect of morphine (Peterson and Trujillo, unpublished observations). Results from our laboratory therefore support the findings of Wolf and co-workers that the development of opiate sensitization is inhibited by low selective doses of NMDA receptor antagonists.

Structural And Functional Characteristics Of Hdac1

The interaction with the pocket proteins pRB, p107, and p130 (23-25). Interestingly, a truncated HDAC1 protein lacking the NLS can still translocate into the nucleus through association with an intact HDAC1 protein (18), and Taplick and colleagues (18) have therefore proposed that homod-imerization plays a pivotal role in the activity of the enzyme. The HDAC1 protein is also a target for various posttranslational modifications (26-28). Phosphorylation of serine residues in the C-terminal portion of the protein appears to promote HDAC1 enzymatic activity (27), whereas sumoylation of lysine residues in the same domain seems to be required for transcriptional repression by HDAC1 (28). Acetylation of the protein also appears to enhance its enzymatic activity (J. Taplick and C. Seiser, unpublished data).

Gene Structure And Regulation

Weinshilboum, 1995 Her et al., 1996 Raftogianis et al., 1996). The SULT1A1 and SULT1A2 genes are arranged head to tail, approximately 10 kbp apart. SULT1A1 is located most centromeric and SULT1A3 most telomeric of the three SULT1A genes, the latter being separated from the SULT1A2 gene by approximately 1.7 Mbp. All three genes contain seven coding exons and alternate untranslated first exons. Two alternatively transcribed exons have been identified for SULT1A1 and SULT1A2 mRNA species and three for SULT1A3 (Aksoy and Weinshilboum, 1995 Bernier et al., 1994a Raftogianis et al., 1996 Zhu et al., 1993a, 1993b). Our laboratory was the first to identify this phenomenon, which does not influence the coding exons but is limited to the 5'-untranslated region and could potentially be a tissue-specific mechanism. We found that the SULT1A1 cDNA isolated from a human brain library contains 41 bp of untranslated region found immediately upstream of the ATG start codon on the SULT1A1 gene, whereas...

Nucleotide Similarity Approach The Notion of Genotypes

These studies on HDV genome variability have been performed in non-African countries except for the description of two sequences (assigned to genotype I) from Ethiopia and Somalia (Zhang et al. 1996). The existence of different subclades among genotype I sequences have been proposed but dismissed (Zhang et al. 1996 Shakil et al. 1997). On studying African HDV sequences (Radjef et al. 2004 and unpublished data from our laboratory), our phylogenetic analyses indicated that, in addition to genotype I-like sequences, approximately 70 of the characterized African isolates (mostly from West and Central Africa) form highly divergent groups (see the score of similarity in Table 1). These results (1) suggest a possible ancient African radiation, and (2) extend the known HDV genetic variability to probably eight major monophyletic groups or 'clades', thus bringing this satellite variability closer to human HBV genetic variability. In the following section of this review, we shall focus on these...

Genomic Architecture And The Generation Of Terminal Deletions Of 1p36

What generates the initial broken chromosome and why terminal deletions of 1p36 are ascertained so frequently is still unknown. This could reflect higher instability in this particular region of the genome or increased survival of terminal deletions of 1p36 over other telomeric abnormalities. Interestingly, one method uses an inverted duplication of the short arm (2). This was how McClintock originally formed a dicentric chromosome to generate broken chromosome sand initiate BFB cycles using a maize chromosome 9. A crossover between the normal homolog and the inverted portion of the duplicated chromosome, or between duplicated regions of sister chromatids, resulted in a dicentric chromosome that formed a bridge in anaphase with subsequent breakage (2). Large-scale sequence analysis of the terminal 10.5 Mb of 1p36 indicates that segmental duplications along with palindromic and inverted LCRs may be present in the distal subtelomeric regions (91). The region surrounding these LCRs forms...

Data Analysis of Multidimensional Cellular Datasets

Researchers at GNF developed a set of analysis methods similar to COMPARE, devised to classify compounds by mechanism and to identify putative MOAs and targets for previously undescribed compounds. The GNF dataset is distinct from that of the NCI's in that it comprises single point activity data for over 1 million compounds in over 200 high-throughput screening assays, making it more comparable to the databases most pharmaceutical companies retain (Zhou et al., unpublished result). Unlike the PCA analysis, the variance for each assay is not normalized to one. For each pairing between the seed compounds and queried compounds, two similarity metrics are computed over the assays those compounds have in common an uncen-tered Pearson correlation coefficient and a count-normalized Euclidean distance. Using these analysis methods, predictably, comparisons between signatures of known compounds demonstrate a high degree of structural similarity. The similarity of activity profiles between...

Analysis of the R0 Region

Fig. 2 Rapid algorithm for HDV genome characterization using the amplified R0 restriction fragment profile. The use of SmaIandXhoI gave atleastten different profiles on 275 samples studied. SacII, which is used in secondary analysis, can differentiate some HDV-2 and HDV-5 or HDV-6 isolates. In all, atleast 13 different restriction profile patterns have been observed using the three different restriction enzymes (E. Gordien and N. Radjef, unpublished results)

Assessment And Intervention

There is some indication that gender differences are relevant. In Western culture women express emotional distress more readily and men tend to focus on the practical tasks. A small study by Schut etal. (1997) compared two interventions and found that each gender benefited most by being directed towards its less familiar strategy. There is some support for this in an unpublished study (Duran, 1987) cited by Kato & Mann (1999). When interventions were analysed by gender it was revealed that a social support intervention, which was unhelpful to the women, was beneficial to the male participants. A social activities group had no effect for the women but was harmful to the male participants. Parkes (2000) comments that if given choice, people may choose the intervention that is easier for them but this might not be the most effective for them.

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