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At least 109 records · Page 6Linked to original sources
PubMed2004

A novel triple-modality reporter gene for whole-body fluorescent, bioluminescent, and nuclear noninvasive imaging.

Two genetic reporter systems were developed for multimodality reporter gene imaging of different molecular-genetic processes using fluorescence, bioluminescence (BLI), and nuclear imaging techniques. The eGFP cDNA was fused at the N-terminus with HSV1-tk cDNA bearing a nuclear export signal from MAPKK (NES-HSV1-tk) or with truncation at the N-terminus of the first 45 amino acids (Delta45HSV1-tk) and with firefly luciferase at the C-terminus. A single fusion protein with three functional subunits is formed following transcription and translation from a single open reading frame. The NES-TGL (NES-TGL) or Delta45HSV1-tk/GFP/luciferase (Delta45-TGL) triple-fusion gene cDNAs were cloned into a MoMLV-based retrovirus, which was used for transduction of U87 human glioma cells. The integrity, fluorescence, bioluminescence, and enzymatic activity of the TGL reporter proteins were assessed in vitro. The predicted molecular weight of the fusion proteins (~130 kDa) was confirmed by western blot. The U87-NES-TGL and U87-Delta45-TGL cells had cytoplasmic green fluorescence. The in vitro BLI was 7- and 13-fold higher in U87-NES-TGL and U87-Delta45-TGL cells compared to nontransduced control cells. The Ki of (14)C-FIAU was 0.49+/-0.02, 0.51+/-0.03, and 0.003+/-0.001 ml/min/g in U87-NES-TGL, U87-Delta45-TGL, and wild-type U87 cells, respectively. Multimodality in vivo imaging studies were performed in nu/ nu mice bearing multiple s.c. xenografts established from U87-NES-TGL, U87-Delta45-TGL, and wild-type U87 cells. BLI was performed after administration of d-luciferin (150 mg/kg i.v.). Gamma camera or PET imaging was conducted at 2 h after i.v. administration of [(131)I]FIAU (7.4 MBq/animal) or [(124)I]FIAU (7.4 MBq/animal), respectively. Whole-body fluorescence imaging was performed in parallel with the BLI and radiotracer imaging studies. In vivo BLI and gamma camera imaging showed specific localization of luminescence and radioactivity to the TGL transduced xenografts with background levels of activity in the wild-type xenografts. Tissue sampling yielded values of 0.47%+/-0.08%, 0.86%+/-0.06%, and 0.03%+/-0.01%dose/g [(131)I]FIAU in U87-NES-TGL, U87-Delta45-TGL, and U87 xenografts, respectively. The TGL triple-fusion reporter gene preserves the functional activity of its subunits and is very effective for multimodality imaging. It provides for the seamless transition from fluorescence microscopy and FACS to whole-body bioluminescence imaging, to nuclear (PET, SPET, gamma camera) imaging, and back to in situ fluorescence image analysis.

Animals↗
PubMed2003

Bio-array images processing and genetic networks modelling.

The new tools available for gene expression studies are essentially the bio-array methods using a large variety of physical detectors (isotopes, fluorescent markers, ultrasounds...). Here we present first rapidly an image-processing method independent of the detector type, dealing with the noise and with the peaks overlapping, the peaks revealing the detector activity (isotopic in the presented example), correlated with the gene expression. After this primary step of bio-array image processing, we can extract information about causal influence (activation or inhibition) a gene can exert on other genes, leading to clusters of genes co-expression in which we extract an interaction matrix M and an associated interaction graph G explaining the genetic regulatory dynamics correlated to the studied tissue function. We give two examples of such interaction matrices and graphs (the flowering genetic regulatory network of Arabidopsis thaliana and the lytic/lysogenic operon of the phage Mu) and after some theoretical rigorous results recently obtained concerning the asymptotic states generated by the genetic networks having a given interaction matrix and reciprocally concerning the minimal (in the sense of having a minimal number of non-zero coefficients) matrices having given stationary stable states.

Arabidopsis↗
PubMed1991

Application of D'Arcy Thompson's coordinate transformation approach to clinical genetics photographs using image processing techniques.

The coordinate transformation approach outlined by D'Arcy Thompson for analysing biological shape was extended using modern computerised image processing techniques so that it could be applied to photographs for the study of patients with syndromes of altered facial morphogenesis. Photographs digitised at a resolution of 512 by 480 pixels were subjected to 'rubbersheeting' transformations using a fast microcomputer. Starting with a photograph of a normal child, a single application of the rubbersheeting algorithm produced features such as an upturned nose quite simply. Other facial anomalies may also be recreated with multiple applications. Preliminary results suggest that this technique may be a useful tool in attempts to understand and analyse the changes in facial configuration in a variety of syndromes with facial anomalies.

Analog-Digital Conversion↗
PubMed2002

Hemimegalencephaly: part 1. Genetic, clinical, and imaging aspects.

Hemimegalencephaly is a rare hamartomatous malformation of the brain, remarkable for its extreme asymmetry. It can be isolated or associated with several neurocutaneous syndromes; less frequently, it also involves the brain stem and cerebellum. Traditionally, hemimegalencephaly has been considered a primary neuroblast migratory disturbance. At present, genetic theories of pathogenesis and modern histopathology provide a basis for this complex malformation as a primary disturbance in cellular lineage, differentiation, and proliferation, interacting with a disturbance in gene expression of body symmetry, with earlier onset than radial neuroblast migration. From my personal experience with 10 patients with hemimegalencephaly and review of the literature, I have found the same clinical neurologic, neuroimaging, and neuropathologic features in isolated and syndromic hemimegalencephaly. Magnetic resonance imaging (MRI) reveals abnormal gyration, ventriculomegaly, colpocephaly, an "occipital sign" (displacement of the occipital lobe across the midline), and increased volume and T2 signal of white matter, in addition to the overall increased size of the involved hemisphere. Mild, moderate, and severe grades of severity can be recognized, providing a functional neurologic prognosis and therapeutic plan. Early diagnosis is crucial because despite neuroimaging and pathologic evidence, hemimegalencephaly sometimes still is unrecognized. Also, misdiagnosis of obstructive hydrocephalus or cerebral neoplasm can lead to unnecessary surgical procedures. Although hemispherectomy has a high morbidity, it is recommended early for patients with severe, intractable epilepsy. The mildest forms of hemimegalencephaly are infrequent and the least recognized.

Brain↗
PubMed2002

Clinical, imaging, lesion, and genetic approaches toward a model of cognitive control.

The ability to suppress or override competing attentional and behavioral responses is a key component of cognitive processes. This ability continues to develop throughout childhood and appears to be disrupted in a number of childhood disorders (e.g., attention deficit/hyperactivity disorder and Tourette syndrome). At least two brain regions have been implicated repeatedly in these disorders--the frontal lobes and the basal ganglia. The common problem in cognitive control and overlap in implicated brain regions across disorders suggest a single underlying biological mechanism. At the same time, the distinct symptomatology observed across these disorders suggests multiple mechanisms are at play. This article presents converging evidence from clinical, neuroimaging, lesion, and genetic studies to provide a mechanistic model of cognitive control whereby the basal ganglia are involved in inhibition of competing actions and the frontal cortex is involved in representing the relevant thoughts and guiding the appropriate behaviors.

Adolescent↗
PubMed1995

Bilateral simultaneous optic neuropathy in adults: clinical, imaging, serological, and genetic studies.

To elucidate the cause(s) of acute or subacute bilateral simultaneous optic neuropathy (BSON) in adult life, a follow up study of 23 patients was performed with clinical assessment, brain MRI, HLA typing, and mitochondrial DNA analysis. The results of CSF electrophoresis were available from previous investigations in 11 patients. At follow up, five (22%) had developed clinically definite multiple sclerosis, four (17%) had mitochondrial DNA point mutations indicating a diagnosis of Leber's hereditary optic neuropathy (LHON). The remaining 14 patients (61%) still had clinically isolated BSON a mean of 50 months after the onset of visual symptoms: three of 14 (21%) had multiple MRI white matter lesions compatible with multiple sclerosis, three of 14 (21%) had the multiple sclerosis associated HLA-DR15/DQw6 haplotype, and one of seven tested had CSF oligoclonal IgG bands; in total only five (36%) had one or more of these risk factors. The low frequency of risk factors for the development of multiple sclerosis in these 14 patients suggests that few will develop multiple sclerosis with more prolonged follow up. It is concluded that: (a) about 20% of cases of BSON without affected relatives are due to LHON; (b) multiple sclerosis develops after BSON in at least 20% of cases, but the long term conversion rate is likely to be considerably less than the rate of over 70% seen after an episode of acute unilateral optic neuritis in adult life.

Adolescent↗
PubMed2002

Mapping genetic influences on human brain structure.

Recent advances in brain imaging and genetics have empowered the mapping of genetic and environmental influences on the human brain. These techniques shed light on the 'nature/nurture' debate, revealing how genes determine individual differences in intelligence quotient (IQ) or risk for disease. They visualize which aspects of brain structure and function are heritable, and to what degree, linking these features with behavioral or cognitive traits or disease phenotypes. In genetically transmitted disorders such as schizophrenia, patterns of brain structure can be associated with increased disease liability, and sites can be mapped where non-genetic triggers may initiate disease. We recently developed a large-scale computational brain atlas, including data components from the Finnish Twin registry, to store information on individual variations in brain structure and their heritability. Algorithms from random field theory, anatomical modeling, and population genetics were combined to detect a genetic continuum in which brain structure is heavily genetically determined in some areas but not others. These algorithmic advances motivate studies of disease in which the normative atlas acts as a quantitative reference for the heritability of structural differences and deficits in patient populations. The resulting genetic brain maps isolate biological markers for inherited traits and disease susceptibility, which may serve as targets for genetic linkage and association studies. Computational methods from brain imaging and genetics can be fruitfully merged, to shed light on the inheritance of personality differences and behavioral traits, and the genetic transmission of diseases that affect the human brain.

Algorithms↗
PubMed2003

The genetic epidemiology of body attitudes, the attitudinal component of body image in women.

BACKGROUND: There were four purposes of the current study, including the investigation of the: (i) adequacy of a multidimensional measure of body image; (ii) genetic and environmental epidemiology of this measure; (iii) shared variance between genetic and environmental risk factors for body mass index (BMI) and body image; and (iv) Equal Environment Assumption (EEA) as it related to body attitudes. METHOD: Six types of body attitudes, as measured by the Body Attitudes Questionnaire (BAQ) and reported by 894 complete female-female twin pairs (mean age 32.35 years, S.D. = 41.8) from the Australian Twin Registry, were analysed. RESULTS: Confirmatory factor analysis of the BAQ supported the adequacy of the measure. Additive genetic and unique environmental influences best accounted for the variance of all six of the BAQ subscales. The relationship between BMI and body attitudes was primarily due to shared genes rather than environment but the majority of genetic and environmental effects on body attitudes were independent of BMI, with the exception of the Feeling Fat subscale, which shared 53% of its genetic risk factors with BMI. One violation of the EEA was suggested, namely similarity of childhood treatment influenced similarity on Lower Body Fatness subscale. CONCLUSIONS: Findings support the notion that: (i) body image is a multidimensional concept; (ii) it is relatively independent of BMI; and (iii) both genetic and non-shared environment are influential determinants of body attitudes.

Adult↗
PubMed1996

A classification scheme for malformations of cortical development.

Malformations of the cerebral cortex are being recognized more frequently as a cause of epilepsy, developmental delay, neurological deficits, and mental retardation. Nonetheless, a standard nomenclature and classification system of these malformations, based upon state-of-the art knowledge derived from genetics, embryology, imaging, and pathology, has not been devised. In this manuscript, we propose such a classification system. Moreover, we have constructed the system such that both the framework and the classifications themselves are flexible and can be adapted as our knowledge of the embryology, genetics, imaging, and pathology of these disorders advances. We believe that the use of this classification system will help both clinicians and researchers to understand and think about these disorders and their causes better. In turn, we hope that this improved understanding will lead to further refinements in classification, to advances in our knowledge and, ultimately, to improvements in therapy.

Brain Damage, Chronic↗
PubMed1994

Mirror-image tumors in mirror-image twins.

Genetic factors are known to play a role in causing lung cancer. Twin cases of bronchioloalveolar, squamous, and anaplastic bronchogenic carcinoma have been previously reported. We describe mirror-image twins with adenocarcinoma of the lung occurring in mirror-image locations. They shared smoking and an occupational risk, carpentry, in addition to identical genetic backgrounds.

Adenocarcinoma↗
PubMed2005

Optical imaging and control of genetically designated neurons in functioning circuits.

Proteins with engineered sensitivities to light are infiltrating the biological mechanisms by which neurons generate and detect electrochemical signals. Encoded in DNA and active only in genetically specified target cells, these proteins provide selective optical interfaces for observing and controlling signaling by defined groups of neurons in functioning circuits, in vitro and in vivo. Light-emitting sensors of neuronal activity (reporting calcium increase, neurotransmitter release, or membrane depolarization) have begun to reveal how information is represented by neuronal assemblies, and how these representations are transformed during the computations that inform behavior. Light-driven actuators control the electrical activities of central neurons in freely moving animals and establish causal connections between the activation of specific neurons and the expression of particular behaviors. Anchored within mathematical systems and control theory, the combination of finely resolved optical field sensing and finely resolved optical field actuation will open new dimensions for the analysis of the connectivity, dynamics, and plasticity of neuronal circuits, and perhaps even for replacing lost--or designing novel--functionalities.

Animals↗
PubMed2005

Cerebral small vessel diseases: cerebral microangiopathies.

PURPOSE OF REVIEW: Small vessel diseases of the brain are still clinically underrecognized whereas their burden is increasing steeply. The most frequent is acquired degenerative small vessel disease. Many hereditary or idiopathic small vessel diseases have also been identified, of which cerebral autosomal-dominant arteriopathy with stroke and ischaemic leukoencephalopathy (CADASIL) is the most prominent. In this review, we will highlight current evidence on pathophysiology and genetics, new imaging tools, and treatment options. RECENT FINDINGS: Recent imaging studies have stressed the disruption of white matter connections in the pathogenesis of cognitive impairment in acquired small vessel disease. Clinical trials suggest a therapeutic benefit of acetylcholinesterase inhibitors. CADASIL is caused by mutations in the Notch3 gene. Current basic research has identified Notch genes to be important for endothelial and smooth muscle cells to form arteries and veins. Diagnosis can now be made reliably by magnetic resonance brain imaging, skin biopsy, or genetic testing. The so-called retinocerebral vasculopathies share the involvement of both retinal, cerebral and cochlear arterioles (e.g. Susac's syndrome). Cerebral amyloid angiopathy, occurring either sporadically or as a cause of various gene mutations, predisposes to lobar haemorrhages caused by rupture of affected small cortical vessels. Other rare cerebral microangiopathies, such as mitochondrial cytopathies, Fabry's disease and toxemic vasculopathy, offer established or new therapeutic options. SUMMARY: Cerebral small vessel diseases are highly variable in their aetiopathogenesis and clinical course. Current pathophysiological insights will help develop better treatment modalities; new imaging tools will provide surrogate markers for monitoring disease progression and treatment effects.

CADASIL↗
PubMed1996

Image feature selection by a genetic algorithm: application to classification of mass and normal breast tissue.

We investigated a new approach to feature selection, and demonstrated its application in the task of differentiating regions of interest (ROIs) on mammograms as either mass or normal tissue. The classifier included a genetic algorithm (GA) for image feature selection, and a linear discriminant classifier or a backpropagation neural network (BPN) for formulation of the classifier outputs. The GA-based feature selection was guided by higher probabilities of survival for fitter combinations of features, where the fitness measure was the area Az under the receiver operating characteristic (ROC) curve. We studied the effect of different GA parameters on classification accuracy, and compared the results to those obtained with stepwise feature selection. The data set used in this study consisted of 168 ROIs containing biopsy-proven masses and 504 ROIs containing normal tissue. From each ROI, a total of 587 features were extracted, of which 572 were texture features and 15 were morphological features. The GA was trained and tested with several different partitionings of the ROIs into training and testing sets. With the best combination of the GA parameters, the average test Az value using a linear discriminant classifier reached 0.90, as compared to 0.89 for stepwise feature selection. Test Az values with a BPN classifier and a more limited feature pool were 0.90 with GA-based feature selection, and 0.89 for stepwise feature selection. The use of a GA in tailoring classifiers with specific design characteristics was also discussed. This study indicates that a GA can provide versatility in the design of linear or nonlinear classifiers without a trade-off in the effectiveness of the selected features.

Algorithms↗
PubMed2001

Genetic analysis of brain imaging abnormalities.

A number of child psychiatric disorders have recently been associated with specific structural brain abnormalities. This article discusses the advantages of neuroimaging for genetic studies, such as clarifying etiologic heterogeneity and establishing pathophysiology. The advantages of twin or family designs for neuroimaging investigations are also discussed.

Adolescent↗
PubMed2026

Genetic Correlation Between Brain Imaging Phenotypes and Externalizing Behavior: A Large-Scale LDSC Analysis of UK Biobank IDPs.

Externalizing has been associated with differences in brain structure and function; however, it remains unclear whether these associations reflect shared common-variant genetic influences. Cross-trait linkage disequilibrium score regression was used to estimate genome-wide genetic correlations between externalizing genome-wide association study (GWAS) results and 3,935 brain imaging-derived phenotypes from the UK Biobank BIG40 resource. The imaging phenotypes covered structural magnetic resonance imaging (MRI), diffusion MRI, susceptibility-weighted imaging, resting-state functional MRI, and task-based functional MRI. Results were included in the primary analysis when the imaging phenotype had positive single-nucleotide polymorphism (SNP) heritability, a heritability Z statistic of at least 1.96, a mean GWAS chi-square statistic of at least 1.02, at least 200,000 regression SNPs, and a complete LDSC result without a fatal error. Technical imaging quality-control phenotypes were excluded from biological inference. Individual results were corrected using the Benjamini-Hochberg false discovery rate procedure. Aggregated Cauchy association tests (ACATs) were used to evaluate evidence across all imaging phenotypes and within predefined imaging categories. Statistical power, simultaneous confidence bounds, and alternative quality-control definitions were examined in sensitivity analyses. Of the 3,935 imaging phenotypes, 3,716 produced estimable genetic correlations, 2,980 met the primary LDSC quality-control criteria, and 2,967 were classified as biological imaging phenotypes. No individual phenotype survived false discovery rate correction. The smallest unadjusted P value was 0.0005, and the minimum adjusted q value was 0.486. The distribution of genetic correlations was centered near zero, with a median genetic correlation of 0.0014 and a median absolute genetic correlation of 0.0338. ACAT provided no evidence of an aggregate association across all biological imaging phenotypes (P = 0.302), and no predefined imaging category survived multiple-testing correction. The median minimum detectable genetic correlation at 80% power was 0.216. Bonferroni-adjusted simultaneous confidence intervals were fully contained within the interval [-0.30, 0.30] for 80.0% of phenotypes in the primary analysis and 88.0% under the stringent heritability quality-control definition. Broad and stringent sensitivity analyses produced the same overall conclusions. In this study, no statistically robust evidence of genome-wide genetic correlations between externalizing and individual UK Biobank brain imaging phenotypes was found. Nevertheless, small, localized, mixed-direction, or developmentally specific genetic effects remain possible.

Journal Article↗