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PubMed1995

Genetic analysis of cinnamyl alcohol dehydrogenase in loblolly pine: single gene inheritance, molecular characterization and evolution.

The gene encoding the monolignol biosynthetic enzyme cinnamyl alcohol dehydrogenase (CAD, E.C. 1.1.1.195) can be expressed in response to different developmental and environmental cues. Control of Cad gene expression could involve either differential regulation of more than one Cad gene or, alternatively combinatorial regulation of a single Cad gene. In loblolly pine (Pinus taeda L.), we found several electrophoretic variants (allozymes) of CAD and a high level of heterozygosity (he = 0.46). Analysis of inheritance patterns of pine CAD allozymes gave segregation ratios that were consistent with Mendelian expectations for a single functional gene. The identity of the full-length Cad cDNA sequence was confirmed by alignment with peptide sequences obtained from purified active enzyme and by extensive similarity to Cad sequences from other species. Southern blot analysis of genomic DNA using the Cad cDNA as a hybridization probe gave simple patterns, consistent with our interpretation that pine Cad is a single-copy gene. Phylogenetic analysis and evolution rate estimates showed that Cad sequences are diverging less rapidly in the gymnosperms than in the angiosperms. The Cad mRNA was present in both lignifying tissues and a non lignifying tissue (the megagametophyte) of pine. The presence of a single gene suggests that different regulatory mechanisms for a single Cad gene, rather than differential regulation of several genes, can account for its expression in response to different cues.

Alcohol Oxidoreductases↗
PubMed1996

Fatty acid interactions with a helix-less variant of intestinal fatty acid-binding protein.

Intestinal fatty acid-binding protein (I-FABP) binds a single molecule of long-chain fatty acid in an enclosed cavity surrounded by two antiparallel beta-sheets. The structure also contains two short alpha-helices which form a cap over one end of the binding cavity adjacent to the methyl terminus of the fatty acid. In this study, we employed a helix-less variant of I-FABP known as delta 17-SG [Kim, K., Cistola, D.P.,& Frieden, C. (1996) Biochemistry 35, 7553-7558] to investigate the role of the helical region in maintaining the integrity of the binding cavity and mediating the acquisition of ligand. Fluorescence and NMR experiments were used to characterize the energetic, structural, and kinetic properties of fatty acid binding to this variant, and the results were compared and contrasted with those of wild-type I-FABP and a single-site mutant, R106T. Remarkably, oleate bound to delta 17-SG with a dissociation constant of 4.5 microM, a value comparable to that for R106T and approximately 20-100-fold higher than that for wild-type I-FABP. Heteronuclear two-dimensional NMR spectra for [2-13C]palmitate complexed with delta 17-SG revealed a pattern nearly identical to that observed for the wild-type protein, but distinct from that for R106T. In addition, the ionization behavior of bound [1-13C]palmitate and the nearest neighbor patterns for [2-13C]palmitate derived from 13C-filtered NOESY experiments were very similar for delta 17-SG and the wild-type protein. These results implied that the fatty acid-protein interactions characteristic of the carboxyl end of the fatty acid binding cavity in the wild-type protein were essentially intact in the helix-less variant. In contrast, 13C-filtered NOESY spectra of [16-13C]palmitate bound to delta 17-SG indicated that the fatty acid-protein interactions at the methyl end of the binding cavity were disrupted. As determined by stopped-flow fluorescence, the observed ligand association rates for both delta 17-SG and wild-type I-FABP increased with increasing oleate concentration, but only the wild-type protein exhibited a limiting value of 1000 s-1. This rate-limiting process was interpreted as a conformational change involving the helical region that allows the ligand access to the internal cavity. Simulation and fitting of the kinetic results yielded ligand association rates for delta 17-SG and wild-type I-FABP that were comparable. However, the dissociation rate for wild-type protein was 16-fold lower than that for delta 17-SG. We conclude that the alpha-helices of I_FABP are not required to maintain the integrity of the fatty acid binding cavity but may serve to regulate the affinity of fatty acid binding by selectively altering the dissociation rate constant. In this manner, conformational changes involving the alpha-helical domain may help control the transfer of fatty acids within the cell.

Amino Acid Sequence↗
PubMed1992

Rationale for an integrated approach to genetic epidemiology.

CONCLUSION: Genetic knowledge is now in the public domain and its interpretation by the media and the citizens brings the issues into the public forum of discussion for the necessary ethical, legal and socio-cultural evaluation of its application. Science is being perceived by some as dangerous and as requiring international regulation. Others feel that genetic knowledge will be the breakthrough that will permit medical progress and individual autonomy with regards to personal health and lifestyle choices. The mapping of the human genome has already yielded valuable information on an increasing number of diseases and their variants. Prevailing popular and journalistic archetypes ("imaginaires") used in the media are perceived by the producers as slowing down the possible application of genetic knowledge. The answers to these dilemmas are not readily apparent nor are they prescribed by classical philosophy of medicine. Since genetic knowledge eventually resides with the individual who carries the genes of disease and/or susceptibility, a logical approach to integration of this knowledge at a societal level would seem to reside with individual education and decision-making. The politics of the ensuing social debate could transform the current social contract since an individual's interests need to be balanced against those of his or her immediate family in the sharing of information. The ethical foundations of such a contract requires the genetic education of "Everyone" as a matter of urgent priority. Genetic education should not serve ideological power struggles between the medical establishment and the ethical-legal alliance. Instead, it should ensure the transfer of knowledge to physicians, to patients, to users, to planners, to social science and humanities researchers and to politicians, so that they may make "informed" and free decisions....

Base Sequence↗
PubMedDate not supplied

Primary pleuropulmonary synovial sarcoma diagnosed by fine needle aspiration with cytogenetic confirmation: a case report.

BACKGROUND: Pleuropulmonary synovial sarcomas (PPSSs) are rare neoplasins that have been well described in recent years, although there are only very infrequent reports within the cytology literature. Such lesions present a diagnostic challenge on fine needle aspiration (ENA) due to several factors, particularly when the aspirate material displays monophasic, small cell or poorly differentiated morphology. Immunoperoxidase studies on cell block material and confirmation with molecular cytogenetics are important tools to establish the diagnosis and determine appropriate therapy. We report a case of PPSS in a 27-year-old man diagnosed by computed tomography (CT)-guided FNA with confirmation by conventional and molecular cytogenetics. CASE: A 27-year-old man presented with several rapidly enlarging, pleura-based masses following a several-month history of recurrent hemopneumothorax. Previous surgical pathology on decorticated pleura was interpreted as a reactive mesothelial proliferation at another institution. Upon referral, CT-guided transthoracic FNA was performed. Smears revealed a highly cellular, dispersed "small round blue cell" neoplasm in a hemorrhagic background. The cytomorphology, in conjunction with a select immunoperoxidase panel, was diagnostic of PPSS. Conventional and molecular cytogenetics subsequently provided confirmation of the diagnosis. CONCLUSION: PPSSs are uncommon neoplasms seldom diagnosed by FNA, with only very rare reports in the cytology literature. Although their cytomorphology has been well described, monophasic tumors and other morphologic variants present a diagnostic challenge and may be difficult to discern from a variety of neoplastic and reactive/reparative processes. Emphasis should be placed upon securing material at the time of aspiration for immunoperoxidase studies (cell block or core biopsy). In equivocal cases, conventional and/or molecular cytogenetic studies may be needed.

Adult↗
PubMed2003

Dictionary learning algorithms for sparse representation.

Algorithms for data-driven learning of domain-specific overcomplete dictionaries are developed to obtain maximum likelihood and maximum a posteriori dictionary estimates based on the use of Bayesian models with concave/Schur-concave (CSC) negative log priors. Such priors are appropriate for obtaining sparse representations of environmental signals within an appropriately chosen (environmentally matched) dictionary. The elements of the dictionary can be interpreted as concepts, features, or words capable of succinct expression of events encountered in the environment (the source of the measured signals). This is a generalization of vector quantization in that one is interested in a description involving a few dictionary entries (the proverbial "25 words or less"), but not necessarily as succinct as one entry. To learn an environmentally adapted dictionary capable of concise expression of signals generated by the environment, we develop algorithms that iterate between a representative set of sparse representations found by variants of FOCUSS and an update of the dictionary using these sparse representations. Experiments were performed using synthetic data and natural images. For complete dictionaries, we demonstrate that our algorithms have improved performance over other independent component analysis (ICA) methods, measured in terms of signal-to-noise ratios of separated sources. In the overcomplete case, we show that the true underlying dictionary and sparse sources can be accurately recovered. In tests with natural images, learned overcomplete dictionaries are shown to have higher coding efficiency than complete dictionaries; that is, images encoded with an overcomplete dictionary have both higher compression (fewer bits per pixel) and higher accuracy (lower mean square error).

Algorithms↗
PubMed1976

The nephroblastomatosis complex and its relationship to Wilms' tumor: a clinicopathologic treatise.

1. At least one third of all children with Wilms' tumors have evidence of aberrant metanephric differentiation, hamartomas, adenomas and nodules of blastema or Wilms' tumorlets in the subcapsular renal cortex. Only the presence of nodular renal blastema was found to correlate with younger age, suggesting that the other tumorlike lesions may be derivatives. 2. In our experience, all patients with bilateral and sequential bilateral Wilms' tumors have exhibited these characteristics in the "uninvolved" renal tissue removed at nephrectomy. 3. Pancortical (infantile), diffuse superficial (late infantile) and multifocal (juvenile) variants of nephroblastomatosis are defined. In the latter 2 forms of nephroblastomatosis the prognosis after modern therapy is at least as good as it is in patients with unilateral, unicentric Wilms' tumor arising in a histologically normal kidney. 4. The morphologic evidence presented strongly indicates that Wilms' tumor in patients with nephroblastomatosis develops either from nodular blastema or metanephric hamartomas. It is hypothetically possible that all Wilms' tumors develop from these precursors. The latent period between cessation of nephrogenesis and clinical presentation of Wilms' tumor is interpreted as favoring the hypothesis that carcinogenesis per se is the result of a postnatal event but that the substrate for tumor development, aberrant metanephric proliferation, has its inception during gestation.

Adenoma↗
PubMed1991

Neonatal screening for haemoglobin variants using filter paper-dried blood specimens.

Neonatal screening for haemoglobinopathies utilizing cord blood samples is well established, although it has a high miss rate and has the inherent problem of possible misdiagnosis from maternal contamination of the sample. The use of dried Guthrie card samples which are taken at six days of age avoids these problems and has the advantage of using an established system of sample collection. Controversy exists as to the method of choice for analysis of dried samples, this study of 2406 samples found that Iso-electric focusing (IEF) analysis of dried specimens gives excellent correlation when compared with cellulose acetate/citrate agar electrophoresis of liquid cord blood samples. The IEF results were clear and relatively simple to interpret even when the samples had been stored at room temperature for 4 weeks. The commercial enzyme linked immunosorbent assay (ELISA) screening test JOSHUA reliably determines the presence or absence of haemoglobin S in dried specimens. It could therefore be used as a relatively cheap and simple method for the confirmation of sickle cell trait in neonatal screening programmes based on dried specimens.

Electrophoresis↗
PubMed1997

A highly conserved DNA replication module from Streptococcus thermophilus phages is similar in sequence and topology to a module from Lactococcus lactis phages.

A highly conserved DNA region extending over 5 kb was observed in Streptococcus thermophilus bacteriophages. Comparative sequencing of one temperate and 26 virulent phages demonstrated in the most extreme case an 18% aa difference for a predicted protein, while the majority of the phages showed fewer, if any aa changes. The relative degree of aa conservation was not homogeneous over the DNA segment investigated. Sequence analysis of the conserved segment revealed genes possibly involved in DNA transactions. Three predicted proteins (orf 233, 443, and 382 gene product (gp)) showed nucleoside triphosphate binding motifs. Orf 443 gp showed in addition a DEAH box motif, characteristically found in a subgroup of helicases, and a variant zinc finger motif known from a phage T7 helicase/primase. Tree analysis classified orf 443 gp as a distant member of the helicase superfamily. Orf 382 gp showed similarity to putative plasmid DNA primases. Downstream of orf 382 a noncoding repeat region was identified that showed similarity to a putative minus origin from a cryptic S. thermophilus plasmid. Four predicted proteins showed not only high degrees of aa identity (34 to 63%) with proteins from Lactococcus lactis phages, but their genes showed a similar topological organization. We interpret this as evidence for a horizontal gene transfer event between phages of the two bacterial genera in the distant past.

Amino Acid Sequence↗
PubMed2005

New ratios for the detection and classification of CJD in multisequence MRI of the brain.

We present a method for the analysis of deep grey brain nuclei for accurate detection of human spongiform encephalopathy in multisequence MRI of the brain. We employ T1, T2 and FLAIR-T2 MR sequences for the detection of intensity deviations in the internal nuclei. The MR data are registered to a probabilistic atlas and normalised in intensity prior to the segmentation of hyperintensities using a foveal model. Anatomical data from a segmented atlas are employed to refine the registration and remove false positives. The results are robust over the patient data and in accordance to the clinical ground truth. Our method further allows the quantification of intensity distributions in basal ganglia. sCJD patient FLAIR images are classified with a more significant hypersignal in caudate nuclei (10/10) and putamen (6/10) than in thalami. Defining normalised MRI measures of the intensity relations between the internal grey nuclei of patients, we robustly differentiate sCJD and variant CJD (vCJD) patients, as an attempt towards the automatic detection and classification of human spongiform encephalopathies.

Algorithms↗
PubMed2006

Characterization of CYP1A enzyme in Adélie penguin liver.

As CYP1A enzymes are induced by certain contaminants, their induction pattern has been used as a biomarker for exposure of certain pollutants. Ethoxyresorufin O-deethylase (EROD) activities are widely used in environmental assessments of polychlorinated biphenyls in many wildlife species. The EROD activity, a typical probe for CYP1A enzyme was studied in liver microsomes prepared from Adélie penguins (Pygoscelis adeliae) (n=10). Penguin liver microsomes (0.5 mg/mL) were incubated with the substrate ethoxyresorufin and NADPH at 37 degrees C for 10 min, and the reaction was terminated by addition of methanol. The formation of the metabolite resorufin was assayed by an HPLC method. EROD activity was present in all liver samples studied. Penguin liver microsomal fraction exhibits typical Michaelis-Menten kinetics in the O-deethylation of ethoxyresorufin. The data were best described by a biphasic kinetic model, which could be interpreted in terms of two populations of CYP enzyme. Mean (+/-S.D.) K(m) values for high- and low-affinity components of EROD were 51+/-109 (range: 0.16 to 358) and 872+/-703 (range: 303 to 2450) nM, respectively. The corresponding mean V(max) values for the high- and low-affinity enzyme activities were 1.8+/-1.4 (range: 0.21 to 5.1) and 9.6+/-3.7 (range: 6.0 to 18.3) pmol/min/mg. The EROD activity in penguin liver microsomes was inhibited by CYP1A inhibitors (phenacetin, 7-ethoxycoumarin and proportional variant-naphthoflavone), whereas other CYP inhibitors for CYP2C9 (tolbutamide), 2C19 (mephenytoin), 2D6 (debrisoquin) and 2E1 (diethyldithiocarbamate) had no effect. These results suggest that CYP1A-like enzymes are present in penguin livers. The activity of this enzyme may be a useful biomarker for assessing the environmental impact of pollutants on Antarctic wildlife.

Animals↗
PubMed1996

Association of apolipoprotein E epsilon 4 allele with bulbar-onset motor neuron disease.

BACKGROUND: Variants of the apolipoprotein E (APOE) gene influence the age of onset of Alzheimer's disease. APOE may influence the presentation of other neurological diseases. We investigated the relationship between the allelic variants of apolipoprotein E and clinical presentation in motor neuron disease. METHODS: 123 patients with motor neuron disease and 121 controls were studied. Diagnosis, location of onset and date of onset were recorded prospectively. Genotyping was performed blind to clinical information. FINDINGS: Possession of at least one epsilon 4 allele was significantly more common in patients with bulbar onset motor neuron disease (14/33, 42%) than in limb onset patients (20/90, 22%) and controls (26/121, 21%) (chi 2 = 4.93, p = 0.026 and chi 2 = 5.91, p = 0.015, respectively). INTERPRETATION: These results suggest that the apolipoprotein E epsilon 4 allele may influence the pattern of motor neuron loss in motor neuron disease and that it may affect neuronal function in ways unrelated to the deposition of beta-amyloid or accumulation of neurofibrillary tangles.

Age of Onset↗
PubMed2005

Establishment of an immortalised human ovarian surface epithelial cell line without chromosomal instability.

Epithelial ovarian carcinoma is thought to derive from ovarian surface epithelium (OSE). The black box of the early molecular changes in ovarian carcinogenesis is being interpreted by the development of experimental systems employing immortalised human OSE cells. However, the existing cell lines of the OSE cells have limited utility due to chromosomal instability. Our goal was to establish new immortalised human OSE cells that retain the original characteristics of the primary cells without chromosomal alterations. Using primary human OSE cells obtained from a postmenopausal patient with endometrial cancer, five cell lines ('HOSE1' lines) were newly established by infection with retroviral expression vectors containing type 16 human papillomavirus (HPV-16) E6, E7, a variant E6 (E6delta151), and Bmi1 polycomb gene, in combination with telomerase reverse transcriptase (hTERT). Consequently, five HOSE1s cell lines, HOSE1s-E6/hTERT, -E7/hTERT, -E6/E7/hTERT, -E6delta151/E7/hTERT, and -E6delta151/Bmi1/hTERT, grew beyond the population doubling number of 200. These cell lines, except for HOSE1-E6/hTERT, essentially showed the original features of the primary human OSE cells. Of them, HOSE1-E7/hTERT preserved diploidy in a kariotype analysis, and did not show transformed phenotypes in anchorage-independent growth and tumour formation. Thus, HOSE1-E7/hTERT may provide a novel model system with which to investigate the mechanisms of early molecular changes.

Animals↗
PubMed2006

A summary statistic approach to sequence variation in noncoding regions of six schizophrenia-associated gene loci.

In order to explore the role of noncoding variants in the genetics of schizophrenia, we sequenced 27 kb of noncoding DNA from the gene loci RAC-alpha serine/threonine-protein kinase (AKT1), brain-derived neurotrophic factor (BDNF), dopamine receptor-3 (DRD3), dystrobrevin binding protein-1 (DTNBP1), neuregulin-1 (NRG1) and regulator of G-protein signaling-4 (RGS4) in 37 schizophrenia patients and 25 healthy controls. To compare the allele frequency spectrum between the two samples, we separately computed Tajima's D-value for each sample. The results showed a smaller Tajima's D-value in the case sample, pointing to an excess of rare variants as compared to the control sample. When randomly permuting the affection status of sequenced individuals, we observed a stronger decrease of Tajima's D in 2400 out of 100,000 permutations, corresponding to a P-value of 0.024 in a one-sided test. Thus, rare variants are significantly enriched in the schizophrenia sample, indicating the existence of disease-related sequence alterations. When categorizing the sequenced fragments according to their level of human-rodent conservation or according to their gene locus, we observed a wide range of diversity parameter estimates. Rare variants were enriched in conserved regions as compared to nonconserved regions in both samples. Nevertheless, rare variants remained more common among patients, suggesting an increased number of variants under purifying selection in this sample. Finally, we performed a heuristic search for the subset of gene loci, which jointly produces the strongest difference between controls and cases. This showed a more prominent role of variants from the loci AKT1, BDNF and RGS4. Taken together, our approach provides promising strategy to investigate the genetics of schizophrenia and related phenotypes.

Brain-Derived Neurotrophic Factor↗
PubMed2005

Systematic investigation of genetic variability in 111 human genes-implications for studying variable drug response.

In order to identify single-nucleotide polymorphisms (SNPs) and analyze their characteristics in a set of 111 genes, we resequenced exons and flanking regions in an average of 170 chromosomes from individuals of European origin. Genetic variability was decreased in noncoding regions highly conserved between human and rodents, indicating functional relevance of these regions. Furthermore, diversity of coding nonsynonymous SNPs was found lower in regions encoding a known protein sequence motif. SNPs predicted to be of functional significance were more common amongst rare variants. Despite the significant recent growth of SNP numbers in public SNP databases, only a small fraction of these rare variants is represented. This may be relevant in the investigation of the genetic causes of severe side effects, for which rare variants are plausible candidates. Estimation of htSNPs reduces the genotyping effort required in capturing common haplotypes, for certain genes, however, this accounts for only a small fraction of haplotype diversity.

Alleles↗
PubMed2001

Hydration of the peptide backbone largely defines the thermodynamic propensity scale of residues at the C' position of the C-capping box of alpha-helices.

The C' position of the C-capping box is the second residue outside of the helix. Statistical analysis of residue distribution at the C' position in the alpha-helices' C-capping box showed that different amino acid residues occur with different probabilities, with the strongest preference being for glycine. To understand the physico-chemical basis for this preference, we studied the effects that 17 amino acid substitutions at the C' position in an alpha-helix of ubiquitin have on the stability of this protein. We determined the following rank order of amino acid residues at the C' position with respect to their effect on the stability: Gly>His>Asn>Arg>Lys>Gln>Ala>Phe>Met>Ser>Asp>Glu>Trp>Thr>Pro>Ile>Val. The effect of the amino acid substitutions on the structure also was evaluated by comparing the (1)H-(15)N heteronuclear sequential quantum correlation spectra and showed no significant changes in the structures of the most stable (Gly) and the least stable (Val) variants. The obtained changes in stability highly correlate (r = 0.85) with the statistical distribution of the residues at the C' position indicating that the measured thermodynamic propensities are unbiased by secondary interactions. We also found that the measured thermodynamic propensities correlate well with the amide hydrogen exchange data on short model peptides (r = 0.85) and the calculated hydration of the peptide backbone (r = 0.88). These results combined with the changes in enthalpy and entropy of unfolding of ubiquitin variants suggest that dehydration of the peptide backbone plays a significant role in defining the thermodynamic propensity scale at the C' position of the C-capping box in alpha-helices. This propensity scale is useful for protein secondary structure predictions and protein design.

Amino Acid Substitution↗
PubMed2000

Modulation of the truncated GAD25 by estrogen in the olfactory bulb of adult rats.

The aim of our study was to investigate the influence of gonadal steroids on the expression of different GAD isoforms. Here we show that, in addition to the adult GAD forms, the two embryonic splice variants of GAD67 mRNA and the truncated GAD25 are present in the adult rat olfactory bulb, a brain region with high synaptic plasticity, which has preserved some features of the developing brain. By Western blot analysis, we could demonstrate that the expression of the embryonic GAD25 is cyclic in females: its quantity is higher on estrus day. Furthermore, in ovariectomized animals 17-beta-estradiol treatment induced an increase of GAD25 within 3 h, reaching a maximum at 9-12 h. Our data are compatible with the interpretation that the embryonic GAD isoforms may play a role in the neuroplastic changes induced by sexual steroids.

Alternative Splicing↗
PubMed1984

Receptors on red cells for Plasmodium falciparum and their interaction with merozoites.

The red cell sialoglycoproteins (glycophorins, alpha (A), delta (B) and beta and gamma (C] play a crucial role in the invasion of human red cells by merozoites of Plasmodium falciparum. Red cells deficient in any of the glycophorins, including beta (also known as glycoconnectin), resist infection by this parasite to varying degrees. These cells and other naturally occurring well-characterized glycophorin variants provide extremely powerful tools to dissect the role of these molecules in invasion. The binding of merozoites to human red cells appears analogous to the binding of wheatgerm agglutinin to sialoglycoconjugates. In both systems O- and N-linked oligosaccharides may be involved. Membrane lipid has not been implicated as a receptor for merozoites, but may instead non-specifically modify binding, as may electrostatic and hydrophobic interactions. The results of data using monoclonal antibodies and lectins, although possibly helpful in identifying specific determinants, must be interpreted with caution. Overall the data suggest that the red cell receptors for all strains of P. falciparum tested to date are located on the glycophorins. Accordingly these putative receptors have been used to affinity-purify complementary parasite components which may yet prove to be of protective immunological significance in a vaccine.

Animals↗
PubMed2006

[Advances in neurobiological understanding of schizophrenia. Perspectives for new therapeutic concepts].

Causal treatment options for schizophrenia are lacking due to our restricted knowledge of its etiology and pathogenesis. However, recently three postulated disposition genes for schizophrenia have been increasingly better confirmed: dysbindin, neuregulin-1, and G(72)/DAOA genes. These genes code proteins involved in processes ranging from brain development to the maintenance of glutamatergic transmission in the mature brain. Current interpretation of neuroanatomical findings points at reminiscences of disturbed brain development and a loss of nonneuronal elements, the so-called neuropil, as a correlate of brain atrophy. This reduction in neuropil is mainly caused by synaptic elements. Biochemical findings supporting this show that besides the dopaminergic and serotonergic system, glutamatergic transmission is also disturbed in schizophrenia. All these findings fit very well with the presumed functions of the disposition genes. Hypothesis-free approaches in structural brain imaging and the combination of functional imaging with relevant gene variants open new avenues for using markers from brain imaging to improve the diagnosis of schizophrenia and judge the response to neuroleptic treatment. Despite the enormous increase in knowledge for example in genetic research, the risk variants known until now provide no contribution to early diagnosis of schizophrenia. Furthermore, pharmacogenetics is currently unable to give a clear answer as to whether a single patient is responding to treatment or not.

Animals↗