Genomic organization, fine-mapping, and expression of the human islet-brain 1 (IB1)/c-Jun-amino-terminal kinase interacting protein-1 (JIP-1) gene.

Islet-brain 1 (IB1), a regulator of the pancreatic beta-cell function in the rat, is homologous to JIP-1, a murine inhibitor of c-Jun amino-terminal kinase (JNK). Whether IB1 and JIP-1 are present in humans was not known. We report the sequence of the 2133-bp human IB1 cDNA, the expression, structure, and fine-mapping of the human IB1 gene, and the characterization of an IB1 pseudogene. Human IB1 is 94% identical to rat IB1. The tissue-specific expression of IB1 in human is similar to that observed in rodent. The IB1 gene contains 12 exons and maps to chromosome 11 (11p11.2-p12), a region that is deleted in DEFECT-11 syndrome. Apart from an IB1 pseudogene on chromosome 17 (17q21), no additional IB1-related gene was found in the human genome. Our data indicate that the sequence and expression pattern of IB1 are highly conserved between rodent and human and provide the necessary tools to investigate whether IB1 is involved in human diseases.

Free-breathing 3 T magnetic resonance t(2)-mapping of the heart.

OBJECTIVES: This study sought to establish an accurate and reproducible T(2)-mapping cardiac magnetic resonance (CMR) methodology at 3 T and to evaluate it in healthy volunteers and patients with myocardial infarct. BACKGROUND: Myocardial edema affects the T(2) relaxation time on CMR. Therefore, T(2)-mapping has been established to characterize edema at 1.5 T. A 3 T implementation designed for longitudinal studies and aimed at guiding and monitoring therapy remains to be implemented, thoroughly characterized, and evaluated in vivo. METHODS: A free-breathing navigator-gated radial CMR pulse sequence with an adiabatic T(2) preparation module and an empirical fitting equation for T(2) quantification was optimized using numerical simulations and was validated at 3 T in a phantom study. Its reproducibility for myocardial T(2) quantification was then ascertained in healthy volunteers and improved using an external reference phantom with known T(2). In a small cohort of patients with established myocardial infarction, the local T(2) value and extent of the edematous region were determined and compared with conventional T(2)-weighted CMR and x-ray coronary angiography, where available. RESULTS: The numerical simulations and phantom study demonstrated that the empirical fitting equation is significantly more accurate for T(2) quantification than that for the more conventional exponential decay. The volunteer study consistently demonstrated a reproducibility error as low as 2 ± 1% using the external reference phantom and an average myocardial T(2) of 38.5 ± 4.5 ms. Intraobserver and interobserver variability in the volunteers were -0.04 ± 0.89 ms (p = 0.86) and -0.23 ± 0.91 ms (p = 0.87), respectively. In the infarction patients, the T(2) in edema was 62.4 ± 9.2 ms and was consistent with the x-ray angiographic findings. Simultaneously, the extent of the edematous region by T(2)-mapping correlated well with that from the T(2)-weighted images (r = 0.91). CONCLUSIONS: The new, well-characterized 3 T methodology enables robust and accurate cardiac T(2)-mapping at 3 T with high spatial resolution, while the addition of a reference phantom improves reproducibility. This technique may be well suited for longitudinal studies in patients with suspected or established heart disease.

Disparate activation of the coronary sinus and inferior left atrium during atrial tachycardia after persistent atrial fibrillation ablation: prevalence, pitfalls, and impact on mapping.

INTRODUCTION: Persistent atrial fibrillation (AF) ablation may lead to partial disconnection of the coronary sinus (CS). As a result, disparate activation sequences of the local CS versus contiguous left atrium (LA) may be observed during atrial tachycardia (AT). We aimed to evaluate the prevalence of this phenomenon and its impact on activation mapping. METHODS: AT occurring after persistent AF ablation were investigated in 74 consecutive patients. Partial CS disconnection during AT was suspected when double potentials with disparate activation sequences were observed on the CS catheter. Endocardial mapping facing CS bipoles was performed to differentiate LA far-field from local CS potentials. RESULTS: A total of 149 ATs were observed. Disparate LA-CS activations were apparent in 20 ATs after magnifying the recording scale (13%). The most common pattern (90%) was distal to proximal endocardial LA activation against proximal to distal CS activation, the latter involving the whole CS or its distal part. Perimitral macroreentry was more common when disparate LA-CS activations were observed (67% vs 29%; P = 0.002). Partial CS disconnection also resulted in "pseudo" mitral isthmus (MI) block during LA appendage pacing in 20% of patients as local CS activation was proximal to distal despite distal to proximal activation of the contiguous LA. CONCLUSION: Careful analysis of CS recordings during AT following persistent AF ablation often reveals disparate patterns of activation. Recognizing when endocardial LA activation occurs in the opposite direction to the more obvious local CS signals is critical to avoid misleading interpretations during mapping of AT and evaluation of MI block.

Positive contrast visualization of nitinol devices using susceptibility gradient mapping.

MRI visualization of devices is traditionally based on signal loss due to T(2)* effects originating from local susceptibility differences. To visualize nitinol devices with positive contrast, a recently introduced postprocessing method is adapted to map the induced susceptibility gradients. This method operates on regular gradient-echo MR images and maps the shift in k-space in a (small) neighborhood of every voxel by Fourier analysis followed by a center-of-mass calculation. The quantitative map of the local shifts generates the positive contrast image of the devices, while areas without susceptibility gradients render a background with noise only. The positive signal response of this method depends only on the choice of the voxel neighborhood size. The properties of the method are explained and the visualizations of a nitinol wire and two stents are shown for illustration.

Mapping the proteome of Leishmania Viannia parasites using two-dimensional polyacrylamide gel electrophoresis and associated technologies.

In this study we have demonstrated the potential of two-dimensional electrophoresis (2DE)-based technologies as tools for characterization of the Leishmania proteome (the expressed protein complement of the genome). Standardized neutral range (pH 5-7) proteome maps of Leishmania (Viannia) guyanensis and Leishmania (Viannia) panamensis promastigotes were reproducibly generated by 2DE of soluble parasite extracts, which were prepared using lysis buffer containing urea and nonidet P-40 detergent. The Coomassie blue and silver nitrate staining systems both yielded good resolution and representation of protein spots, enabling the detection of approximately 800 and 1,500 distinct proteins, respectively. Several reference protein spots common to the proteomes of all parasite species/strains studied were isolated and identified by peptide mass spectrometry (LC-ES-MS/MS), and bioinformatics approaches as members of the heat shock protein family, ribosomal protein S12, kinetoplast membrane protein 11 and a hypothetical Leishmania-specific 13 kDa protein of unknown function. Immunoblotting of Leishmania protein maps using a monoclonal antibody resulted in the specific detection of the 81.4 kDa and 77.5 kDa subunits of paraflagellar rod proteins 1 and 2, respectively. Moreover, differences in protein expression profiles between distinct parasite clones were reproducibly detected through comparative proteome analyses of paired maps using image analysis software. These data illustrate the resolving power of 2DE-based proteome analysis. The production and basic characterization of good quality Leishmania proteome maps provides an essential first step towards comparative protein expression studies aimed at identifying the molecular determinants of parasite drug resistance and virulence, as well as discovering new drug and vaccine targets.

Discovery and fine mapping of serum protein loci through transethnic meta-analysis.

Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p < 5 × 10(-8)) for serum albumin (HPN-SCN1B, GCKR-FNDC4, SERPINF2-WDR81, TNFRSF11A-ZCCHC2, FRMD5-WDR76, and RPS11-FCGRT, in up to 53,190 European-ancestry and 9,380 Japanese individuals) and three loci for total protein (TNFRS13B, 6q21.3, and ELL2, in up to 25,539 European-ancestry and 10,168 Japanese individuals). We observed little evidence of heterogeneity in allelic effects at these loci between groups of European and Japanese ancestry but obtained substantial improvements in the resolution of fine mapping of potential causal variants by leveraging transethnic differences in the distribution of linkage disequilibrium. We demonstrated a functional role for the most strongly associated serum albumin locus, HPN, for which Hpn knockout mice manifest low plasma albumin concentrations. Other loci associated with serum albumin harbor genes related to ribosome function, protein translation, and proteasomal degradation, whereas those associated with serum total protein include genes related to immune function. Our results highlight the advantages of transethnic meta-analysis for the discovery and fine mapping of complex trait loci and have provided initial insights into the underlying genetic architecture of serum protein concentrations and their association with human disease.

Mapping complex tissue architecture with diffusion spectrum magnetic resonance imaging.

Methods are presented to map complex fiber architectures in tissues by imaging the 3D spectra of tissue water diffusion with MR. First, theoretical considerations show why and under what conditions diffusion contrast is positive. Using this result, spin displacement spectra that are conventionally phase-encoded can be accurately reconstructed by a Fourier transform of the measured signal's modulus. Second, studies of in vitro and in vivo samples demonstrate correspondence between the orientational maxima of the diffusion spectrum and those of the fiber orientation density at each location. In specimens with complex muscular tissue, such as the tongue, diffusion spectrum images show characteristic local heterogeneities of fiber architectures, including angular dispersion and intersection. Cerebral diffusion spectra acquired in normal human subjects resolve known white matter tracts and tract intersections. Finally, the relation between the presented model-free imaging technique and other available diffusion MRI schemes is discussed.

Functional MRI Mapping of the Human Auditory Cortex

Mapping the human auditory cortex with standard functional imaging techniques is difficult because of its small size and angular position along the Sylvian fissure. As a result, the exact number and location of auditory cortex areas in the human remains unknown. In a first experiment, we measured the two largest tonotopic areas of primary auditory cortex (PAC, Al and R) using high-resolution functional MRI at 7 Tesla relative to the underlying anatomy of Heschl's gyrus (HG). The data reveals a clear anatomical- functional relationship that indicates the location of PAC across the range of common morphological variants of HG (single gyri, partial duplication and complete duplication). Human PAC tonotopic areas are oriented along an oblique posterior-to-anterior axis with mirror-symmetric frequency gradients perpendicular to HG, as in the macaque. In a second experiment, we tested whether these primary frequency-tuned units were modulated by selective attention to preferred vs. non-preferred sound frequencies in the dynamic manner needed to account for human listening abilities in noisy environments, such as cocktail parties or busy streets. We used a dual-stream selective attention experiment where subjects attended to one of two competing tonal streams presented simultaneously to different ears. Attention to low-frequency tones (250 Hz) enhanced neural responses within low-frequency-tuned voxels relative to high (4000 Hz), and vice versa when at-tention switched from high to low. Human PAC is able to tune into attended frequency channels and can switch frequencies on demand, like a radio. In a third experiment, we investigated repetition suppression effects to environmental sounds within primary and non-primary early-stage auditory areas, identified with the tonotopic mapping design. Repeated presentations of sounds from the same sources, as compared to different sources, gave repetition suppression effects within posterior and medial non-primary areas of the right hemisphere, reflecting their potential involvement in semantic representations. These three studies were conducted at 7 Tesla with high-resolution imaging. However, 7 Tesla scanners are, for the moment, not yet used for clinical diagnosis and mostly reside in institutions external to hospitals. Thus, hospital-based clinical functional and structural studies are mainly performed using lower field systems (1.5 or 3 Tesla). In a fourth experiment, we acquired tonotopic maps at 3 and 7 Tesla and evaluated the consistency of a tonotopic mapping paradigm between scanners. Mirror-symmetric gradients within PAC were highly similar at 7 and 3 Tesla across renderings at different spatial resolutions. We concluded that the tonotopic mapping paradigm is robust and suitable for definition of primary tonotopic areas, also at 3 Tesla. Finally, in a fifth study, we considered whether focal brain lesions alter tonotopic representations in the intact ipsi- and contralesional primary auditory cortex in three patients with hemispheric or cerebellar lesions, without and with auditory complaints. We found evidence for tonotopic reorganisation at the level of the primary auditory cortex in cases of brain lesions independently of auditory complaints. Overall, these results reflect a certain degree of plasticity within primary auditory cortex in different populations of subjects, assessed at different field strengths. - La cartographie du cortex auditif chez l'humain est difficile à réaliser avec des techniques d'imagerie fonctionnelle standard, étant donné sa petite taille et position angulaire le long de la fissure sylvienne. En conséquence, le nombre et l'emplacement exacts des différentes aires du cortex auditif restent inconnus chez l'homme. Lors d'une première expérience, nous avons mesuré, avec de l'imagerie par résonance magnétique à haute intensité (IRMf à 7 Tesla) chez des sujets humains sains, deux larges aires au sein du cortex auditif primaire (PAC; Al et R) avec une représentation spécifique des fréquences pures préférées - ou tonotopie. Nos résultats ont démontré une relation anatomico- fonctionnelle qui définit clairement la position du PAC à travers toutes les variantes du gyrus d'Heschl's (HG). Les aires tonotopiques du PAC humain sont orientées le long d'un axe postéro-antérieur oblique avec des gradients de fréquences spécifiques perpendiculaires à HG, d'une manière similaire à celles mesurées chez le singe. Dans une deuxième expérience, nous avons testé si ces aires primaires pouvaient être modulées, de façon dynamique, par une attention sélective pour des fréquences préférées par rapport à celles non-préférées. Cette modulation est primordiale lors d'interactions sociales chez l'humain en présence de bruits distracteurs tels que d'autres discussions ou un environnement sonore nuisible (comme par exemple, dans la circulation routière). Dans cette étude, nous avons utilisé une expérience d'attention sélective où le sujet devait être attentif à une des deux voies sonores présentées simultanément à chaque oreille. Lorsque le sujet portait était attentif aux sons de basses fréquences (250 Hz), la réponse neuronale relative à ces fréquences augmentait par rapport à celle des hautes fréquences (4000 Hz), et vice versa lorsque l'attention passait des hautes aux basses fréquences. De ce fait, nous pouvons dire que PAC est capable de focaliser sur la fréquence attendue et de changer de canal selon la demande, comme une radio. Lors d'une troisième expérience, nous avons étudié les effets de suppression due à la répétition de sons environnementaux dans les aires auditives primaires et non-primaires, d'abord identifiées via le protocole de la première étude. La présentation répétée de sons provenant de la même source sonore, par rapport à de sons de différentes sources sonores, a induit un effet de suppression dans les aires postérieures et médiales auditives non-primaires de l'hémisphère droite, reflétant une implication de ces aires dans la représentation de la catégorie sémantique. Ces trois études ont été réalisées avec de l'imagerie à haute résolution à 7 Tesla. Cependant, les scanners 7 Tesla ne sont pour le moment utilisés que pour de la recherche fondamentale, principalement dans des institutions externes, parfois proches du patient mais pas directement à son chevet. L'imagerie fonctionnelle et structurelle clinique se fait actuellement principalement avec des infrastructures cliniques à 1.5 ou 3 Tesla. Dans le cadre dune quatrième expérience, nous avons avons évalués la cohérence du paradigme de cartographie tonotopique à travers différents scanners (3 et 7 Tesla) chez les mêmes sujets. Nos résultats démontrent des gradients de fréquences définissant PAC très similaires à 3 et 7 Tesla. De ce fait, notre paradigme de définition des aires primaires auditives est robuste et applicable cliniquement. Finalement, nous avons évalués l'impact de lésions focales sur les représentations tonotopiques des aires auditives primaires des hémisphères intactes contralésionales et ipsilésionales chez trois patients avec des lésions hémisphériques ou cérébélleuses avec ou sans plaintes auditives. Nous avons trouvé l'évidence d'une certaine réorganisation des représentations topographiques au niveau de PAC dans le cas de lésions cérébrales indépendamment des plaintes auditives. En conclusion, nos résultats démontrent une certaine plasticité du cortex auditif primaire avec différentes populations de sujets et différents champs magnétiques.

Assessment of myocardial edema and area-at-risk in acute myocardial infarction by CMR: Evaluation of a novel T2-mapping method

Objectives. The goal of this study is to evaluate a T2-mapping sequence by: (i) measuring the reproducibility intra- and inter-observer variability in healthy volunteers in two separate scanning session with a T2 reference phantom; (2) measuring the mean T2 relaxation times by T2-mapping in infarcted myocardium in patients with subacute MI and compare it with patient's the gold standard X-ray coronary angiography and healthy volunteers results. Background. Myocardial edema is a consequence of an inflammation of the tissue, as seen in myocardial infarct (MI). It can be visualized by cardiovascular magnetic resonance (CMR) imaging using the T2 relaxation time. T2-mapping is a quantitative methodology that has the potential to address the limitation of the conventional T2-weighted (T2W) imaging. Methods. The T2-mapping protocol used for all MRI scans consisted in a radial gradient echo acquisition with a lung-liver navigator for free-breathing acquisition and affine image registration. Mid-basal short axis slices were acquired.T2-maps analyses: 2 observers semi- automatically segmented the left ventricle in 6 segments accordingly to the AHA standards. 8 healthy volunteers (age: 27 ± 4 years; 62.5% male) were scanned in 2 separate sessions. 17 patients (age : 61.9 ± 13.9 years; 82.4% male) with subacute STEMI (70.6%) and NSTEMI underwent a T2-mapping scanning session. Results. In healthy volunteers, the mean inter- and intra-observer variability over the entire short axis slice (segment 1 to 6) was 0.1 ms (95% confidence interval (CI): -0.4 to 0.5, p = 0.62) and 0.2 ms (95% CI: -2.8 to 3.2, p = 0.94, respectively. T2 relaxation time measurements with and without the correction of the phantom yielded an average difference of 3.0 ± 1.1 % and 3.1 ± 2.1 % (p = 0.828), respectively. In patients, the inter-observer variability in the entire short axis slice (S1-S6), was 0.3 ms (95% CI: -1.8 to 2.4, p = 0.85). Edema location as determined through the T2-mapping and the coronary artery occlusion as determined on X-ray coronary angiography correlated in 78.6%, but only in 60% in apical infarcts. All except one of the maximal T2 values in infarct patients were greater than the upper limit of the 95% confidence interval for normal myocardium. Conclusions. The T2-mapping methodology is accurate in detecting infarcted, i.e. edematous tissue in patients with subacute infarcts. This study further demonstrated that this T2-mapping technique is reproducible and robust enough to be used on a segmental basis for edema detection without the need of a phantom to yield a T2 correction factor. This new quantitative T2-mapping technique is promising and is likely to allow for serial follow-up studies in patients to improve our knowledge on infarct pathophysiology, on infarct healing, and for the assessment of novel treatment strategies for acute infarctions.

Debris flow susceptibility mapping at a regional scale along the National Road N7, Argentina

A first assessment of debris flow susceptibility at a large scale was performed along the National Road N7, Argentina. Numerous catchments are prone to debris flows and likely to endanger the road-users. A 1:50,000 susceptibility map was created. The use of a DEM (grid 30 m) associated to three complementary criteria (slope, contributing area, curvature) allowed the identification of potential source areas. The debris flow spreading was estimated using a process- and GISbased model (Flow-R) based on basic probabilistic and energy calculations. The best-fit values for the coefficient of friction and the mass-to-drag ratio of the PCM model were found to be ? = 0.02 and M/D = 180 and the resulting propagation on one of the calibration site was validated using the Coulomb friction model. The results are realistic and will be useful to determine which areas need to be prioritized for detailed studies.