The role of NFI-C liver regeneration and its potential function as a general regulator of regenerative processes

Collectively, research aimed to understand the regeneration of certain tissues has unveiled the existence of common key regulators. Knockout studies of the murine Nuclear Factor I-C (NFI-C) transcription factor revealed a misregulation of growth factor signaling, in particular that of transforming growth factor ß-1 (TGF-ßl), which led to alterations of skin wound healing and the growth of its appendages, suggesting it may be a general regulator of regenerative processes. We sought to investigate this further by determining whether NFI-C played a role in liver regeneration. Liver regeneration following two-thirds removal of the liver by partial hepatectomy (PH) is a well-established regenerative model whereby changes elicited in hepatocytes following injury lead to a rapid, phased proliferation. However, mechanisms controlling the action of liver proliferative factors such as transforming growth factor-ßl (TGF-ß1) and plasminogen activator inhibitor-1 (PAI-1) remain largely unknown. We show that the absence of NFI-C impaired hepatocyte proliferation due to an overexpression of PAI-1 and the subsequent suppression of urokinase plasminogen (uPA) activity and hepatocyte growth factor (HGF) signaling, a potent hepatocyte mitogen. This indicated that NFI-C first acts to promote hepatocyte proliferation at the onset of liver regeneration in wildtype mice. The subsequent transient down regulation of NFI-C, as can be explained by a self- regulatory feedback loop with TGF-ßl, may limit the number of hepatocytes entering the first wave of cell division and/or prevent late initiations of mitosis. Overall, we conclude that NFI-C acts as a regulator of the phased hepatocyte proliferation during liver regeneration. Taken together with NFI-C's actions in other in vivo models of (re)generation, it is plausible that NFI-C may be a general regulator of regenerative processes. - L'ensemble des recherches visant à comprendre la régénération de certains tissus a permis de mettre en évidence l'existence de régulateurs-clés communs. L'étude des souris, dépourvues du gène codant pour le facteur de transcription NFI-C (Nuclear Factor I-C), a montré des dérèglements dans la signalisation de certains facteurs croissance, en particulier du TGF-ßl (transforming growth factor-ßl), ce qui conduit à des altérations de la cicatrisation de la peau et de la croissance des poils et des dents chez ces souris, suggérant que NFI-C pourrait être un régulateur général du processus de régénération. Nous avons cherché à approfondir cette question en déterminant si NFI-C joue un rôle dans la régénération du foie. La régénération du foie, induite par une hépatectomie partielle correspondant à l'ablation des deux-tiers du foie, constitue un modèle de régénération bien établi dans lequel la lésion induite conduit à la prolifération rapide des hépatocytes de façon synchronisée. Cependant, les mécanismes contrôlant l'action de facteurs de prolifération du foie, comme le facteur de croissance TGF-ßl et l'inhibiteur de l'activateur du plasminogène PAI-1 (plasminogen activator inhibitor-1), restent encore très méconnus. Nous avons pu montrer que l'absence de NFI-C affecte la prolifération des hépatocytes, occasionnée par la surexpression de PAI-1 et par la subséquente suppression de l'activité de la protéine uPA (urokinase plasminogen) et de la signalisation du facteur de croissance des hépatocytes HGF (hepatocyte growth factor), un mitogène puissant des hépatocytes. Cela indique que NFI-C agit en premier lieu pour promouvoir la prolifération des hépatocytes au début de la régénération du foie chez les souris de type sauvage. La subséquente baisse transitoire de NFI-C, pouvant s'expliquer par une boucle rétroactive d'autorégulation avec le facteur TGF-ßl, pourrait limiter le nombre d'hépatocytes qui entrent dans la première vague de division cellulaire et/ou inhiber l'initiation de la mitose tardive. L'ensemble de ces résultats nous a permis de conclure que NFI-C agit comme un régulateur de la prolifération des hépatocytes synchrones au cours de la régénération du foie.

Individual prediction of cognitive decline in mild cognitive impairment using support vector machine-based analysis of diffusion tensor imaging data.

Although cross-sectional diffusion tensor imaging (DTI) studies revealed significant white matter changes in mild cognitive impairment (MCI), the utility of this technique in predicting further cognitive decline is debated. Thirty-five healthy controls (HC) and 67 MCI subjects with DTI baseline data were neuropsychologically assessed at one year. Among them, there were 40 stable (sMCI; 9 single domain amnestic, 7 single domain frontal, 24 multiple domain) and 27 were progressive (pMCI; 7 single domain amnestic, 4 single domain frontal, 16 multiple domain). Fractional anisotropy (FA) and longitudinal, radial, and mean diffusivity were measured using Tract-Based Spatial Statistics. Statistics included group comparisons and individual classification of MCI cases using support vector machines (SVM). FA was significantly higher in HC compared to MCI in a distributed network including the ventral part of the corpus callosum, right temporal and frontal pathways. There were no significant group-level differences between sMCI versus pMCI or between MCI subtypes after correction for multiple comparisons. However, SVM analysis allowed for an individual classification with accuracies up to 91.4% (HC versus MCI) and 98.4% (sMCI versus pMCI). When considering the MCI subgroups separately, the minimum SVM classification accuracy for stable versus progressive cognitive decline was 97.5% in the multiple domain MCI group. SVM analysis of DTI data provided highly accurate individual classification of stable versus progressive MCI regardless of MCI subtype, indicating that this method may become an easily applicable tool for early individual detection of MCI subjects evolving to dementia.

Understanding mutational and selective processes that govern gene duplication in mammals

Abstract : Gene duplication is an essential source of material for the origin of genetic novelties. The reverse transcription of source gene mRNA followed by the genomic insertion of the resulting cDNA - retroposition - has provided the human genome with at least ~3600 detectable retrocopies. We find that ~30% of these retrocopies are transcribed, generally in testes. Their transcription often relies on preexisting regulatory elements (or open chromatin) close to their insertion site, which is illustrated by mRNA molecules containing retrocopies fused to their neighboring genes. Retrocopies appear to have been profoundly shaped by selection. Consistently, human retrocopies with an intact open reading (ORF) are more often transcribed than retropseudogenes, which leads to a minimal estimate of 120 functional retrogenes present in our genome. We also performed an analysis of Ka/Ks for human retrocopies. This analysis demonstrates that several intact retrocopies evolved under purifying selection and yields an estimated formation rate of ~1 retrogene per million year in the primate lineage. Using DNA sequencing and evolutionary simulations, we have identified 7 such primate-specific retrogenes that emerged on the lineage leading to humans In therian genomes, we found an excess of retrogenes with X-linked parents. Expression analyses support the idea that this "out of X" movement was driven by natural selection to produce autosomal functional counterparts for X-linked genes, which are silenced during male meiosis. Phylogenetic dating of this "out of X" movement suggests that our sex chromosomes arose about 180 MYA ago and are thus much younger than previously thought. Finally, we have also analyzed young gene duplications (and deletions) that arose by non allelic-homologous recombination and are not fixed in species. Using wild-caught and laboratory animals, we detected thousands of DNA segments that are polymorphic in copy number in mice. These copy number variants were found to profoundly alter the transcriptome of several mouse tissues. Strikingly, their influence on gene expression is not limited to the gene they contain but seems to extend to genes located up to 1.5 million bases away.

Shear thinning and thixotropy of HMHEC and HEC water solutions

Steady state viscosity and thixotropy of hydrophobically modified hydroxyethyl cellulose HMHEC and nonassociative cellulose water solutions are studied. Although all the samples are shear thinning, only the HMHEC is thixotropic, since the migration of hydrophobes to micelles is controlled by diffusion. The Cross model fits steady state curves. The Mewis model, a phenomenological model that proposes that the rate of change of viscosity when the shear rate is suddenly changed is related to the difference between the steady state and current values of viscosity raised to an exponent, fits structure construction experiments when the exponent, n, is estimated to be around 2. The Newtonian assumption used by Mewis cannot be used here, however. This seems to be related to the fact that the thickening is due to bridged micelle formation, which is a slow process, and also to topological constraints and entanglements, which are rapid processes. The kinetic parameter was redefined to kn in order to make it independent of initial conditions. So, kn depends only on how the shear affects the structure. kn reaches a plateau at shear rates too low to produce structure destruction and decreases at higher shear rates.

Astrocytic αVβ3 integrin inhibits neurite outgrowth and promotes retraction of neuronal processes by clustering Thy-1.

Thy-1 is a membrane glycoprotein suggested to stabilize or inhibit growth of neuronal processes. However, its precise function has remained obscure, because its endogenous ligand is unknown. We previously showed that Thy-1 binds directly to α(V)β(3) integrin in trans eliciting responses in astrocytes. Nonetheless, whether α(V)β(3) integrin might also serve as a Thy-1-ligand triggering a neuronal response has not been explored. Thus, utilizing primary neurons and a neuron-derived cell line CAD, Thy-1-mediated effects of α(V)β(3) integrin on growth and retraction of neuronal processes were tested. In astrocyte-neuron co-cultures, endogenous α(V)β(3) integrin restricted neurite outgrowth. Likewise, α(V)β(3)-Fc was sufficient to suppress neurite extension in Thy-1(+), but not in Thy-1(-) CAD cells. In differentiating primary neurons exposed to α(V)β(3)-Fc, fewer and shorter dendrites were detected. This effect was abolished by cleavage of Thy-1 from the neuronal surface using phosphoinositide-specific phospholipase C (PI-PLC). Moreover, α(V)β(3)-Fc also induced retraction of already extended Thy-1(+)-axon-like neurites in differentiated CAD cells as well as of axonal terminals in differentiated primary neurons. Axonal retraction occurred when redistribution and clustering of Thy-1 molecules in the plasma membrane was induced by α(V)β(3) integrin. Binding of α(V)β(3)-Fc was detected in Thy-1 clusters during axon retraction of primary neurons. Moreover, α(V)β(3)-Fc-induced Thy-1 clustering correlated in time and space with redistribution and inactivation of Src kinase. Thus, our data indicates that α(V)β(3) integrin is a ligand for Thy-1 that upon binding not only restricts the growth of neurites, but also induces retraction of already existing processes by inducing Thy-1 clustering. We propose that these events participate in bi-directional astrocyte-neuron communication relevant to axonal repair after neuronal damage.

High b-value Diffusion-weighted Imaging: A Sensitive Method to Reveal White Matter Changes in Schizophrenia

Background: b-value is the parameter characterizing the intensity of the diffusion weighting during image acquisition. Data acquisition is usually performed with low b value (b~1000 s/mm2). Evidence shows that high b-values (b>2000 s/mm2) are more sensitive to the slow diffusion compartment (SDC) and maybe more sensitive in detecting white matter (WM) anomalies in schizophrenia.Methods: 12 male patients with schizophrenia (mean age 35 +/-3 years) and 16 healthy male controls matched for age were scanned with a low b-value (1000 s/mm2) and a high b-value (4000 s/mm2) protocol. Apparent diffusion coefficient (ADC) is a measure of the average diffusion distance of water molecules per time unit (mm2/s). ADC maps were generated for all individuals. 8 region of interests (frontal and parietal region bilaterally, centrum semi-ovale bilaterally and anterior and posterior corpus callosum) were manually traced blind to diagnosis.Results: ADC measures acquired with high b-value imaging were more sensitive in detecting differences between schizophrenia patients and healthy controls than low b-value imaging with a gain in significance by a factor of 20- 100 times despite the lower image Signal-to-noise ratio (SNR). Increased ADC was identified in patient's WM (p=0.00015) with major contributions from left and right centrum semi-ovale and to a lesser extent right parietal region.Conclusions: Our results may be related to the sensitivity of high b-value imaging to the SDC believed to reflect mainly the intra-axonal and myelin bound water pool. High b-value imaging might be more sensitive and specific to WM anomalies in schizophrenia than low b-value imaging

Psychosocial analysis of the collective processes in the United States after September 11

This article studies alterations in the values, attitudes, and behaviors that emerged among U.S. citizens as a consequence of, and as a response to, the attacks of September 11, 2001. The study briefly examines the immediate reaction to the attack, before focusing on the collective reactions that characterized the behavior of the majority of the population between the events of 9/11 and the response to it in the form of intervention in Afghanistan. In studying this period an eight-phase sequential model (Botcharova, 2001) is used, where the initial phases center on the nation as the ingroup and the latter focus on the enemy who carried out the attack as the outgroup. The study is conducted from a psychosocial perspective and uses "social identity theory" (Tajfel & Turner, 1979, 1986) as the basic framework for interpreting and accounting for the collective reactions recorded. The main purpose of this paper is to show that the interpretation of these collective reactions is consistent with the postulates of social identity theory. The application of this theory provides a different and specific analysis of events. The study is based on data obtained from a variety of rigorous academic studies and opinion polls conducted in relation to the events of 9/11. In line with social identity theory, 9/11 had a marked impact on the importance attached by the majority of U.S. citizens to their identity as members of a nation. This in turn accentuated group differentiation and activated ingroup favoritism and outgroup discrimination (Tajfel & Turner, 1979, 1986). Ingroup favoritism strengthened group cohesion, feelings of solidarity, and identification with the most emblematic values of the U.S. nation, while outgroup discrimination induced U.S. citizens to conceive the enemy (al-Qaeda and its protectors) as the incarnation of evil, depersonalizing the group and venting their anger on it, and to give their backing to a military response, the eventual intervention in Afghanistan. Finally, and also in line with the postulates of social identity theory, as an alternative to the virtual bipolarization of the conflict (U.S. vs al-Qaeda), the activation of a higher level of identity in the ingroup is proposed, a group that includes the United States and the largest possible number of countries¿ including Islamic states¿in the search for a common, more legitimate and effective solution.

Effect of orthographic processes on letter identity and letter-position encoding in dyslexic children.

The ability to identify letters and encode their position is a crucial step of the word recognition process. However and despite their word identification problem, the ability of dyslexic children to encode letter identity and letter-position within strings was not systematically investigated. This study aimed at filling this gap and further explored how letter identity and letter-position encoding is modulated by letter context in developmental dyslexia. For this purpose, a letter-string comparison task was administered to French dyslexic children and two chronological age (CA) and reading age (RA)-matched control groups. Children had to judge whether two successively and briefly presented four-letter strings were identical or different. Letter-position and letter identity were manipulated through the transposition (e.g., RTGM vs. RMGT) or substitution of two letters (e.g., TSHF vs. TGHD). Non-words, pseudo-words, and words were used as stimuli to investigate sub-lexical and lexical effects on letter encoding. Dyslexic children showed both substitution and transposition detection problems relative to CA-controls. A substitution advantage over transpositions was only found for words in dyslexic children whereas it extended to pseudo-words in RA-controls and to all type of items in CA-controls. Letters were better identified in the dyslexic group when belonging to orthographically familiar strings. Letter-position encoding was very impaired in dyslexic children who did not show any word context effect in contrast to CA-controls. Overall, the current findings point to a strong letter identity and letter-position encoding disorder in developmental dyslexia.

Prospective and retrospective motion correction in diffusion magnetic resonance imaging of the human brain.

Diffusion-weighting in magnetic resonance imaging (MRI) increases the sensitivity to molecular Brownian motion, providing insight in the micro-environment of the underlying tissue types and structures. At the same time, the diffusion weighting renders the scans sensitive to other motion, including bulk patient motion. Typically, several image volumes are needed to extract diffusion information, inducing also inter-volume motion susceptibility. Bulk motion is more likely during long acquisitions, as they appear in diffusion tensor, diffusion spectrum and q-ball imaging. Image registration methods are successfully used to correct for bulk motion in other MRI time series, but their performance in diffusion-weighted MRI is limited since diffusion weighting introduces strong signal and contrast changes between serial image volumes. In this work, we combine the capability of free induction decay (FID) navigators, providing information on object motion, with image registration methodology to prospectively--or optionally retrospectively--correct for motion in diffusion imaging of the human brain. Eight healthy subjects were instructed to perform small-scale voluntary head motion during clinical diffusion tensor imaging acquisitions. The implemented motion detection based on FID navigator signals is processed in real-time and provided an excellent detection performance of voluntary motion patterns even at a sub-millimetre scale (sensitivity≥92%, specificity>98%). Motion detection triggered an additional image volume acquisition with b=0 s/mm2 which was subsequently co-registered to a reference volume. In the prospective correction scenario, the calculated motion-parameters were applied to perform a real-time update of the gradient coordinate system to correct for the head movement. Quantitative analysis revealed that the motion correction implementation is capable to correct head motion in diffusion-weighted MRI to a level comparable to scans without voluntary head motion. The results indicate the potential of this method to improve image quality in diffusion-weighted MRI, a concept that can also be applied when highest diffusion weightings are performed.

Contrasting diffusion of Quaternary gene pools across Europe: the case of the arctic-alpine Gentiana nivalis L. (Gentianaceae).

The fate of European arctic-alpine species during Pleistocene climatic oscillations still remains debated. Did these cold-adapted species invade much of the continental steppe or did they remain restricted to warmer slopes of inner mountain massifs? To examine this question, we investigated the phylogeography of Gentiana nivalis, a typical European arctic-alpine plant species. Genome fingerprinting analyses revealed that four genetic pools are actually unevenly distributed across the continent. One cluster covers almost all mountain massifs as well as northern areas, and thus coincides with a scenario of past distribution covering a large part of the European glacial steppe. In contrast, the three other lineages are strongly restricted spatially to western, central, and eastern Alps, respectively, thus arguing towards a scenario of in situ glacial survival. The coexistence of lineages with such contrasting demographic histories in Europe challenges our classical view of refugia and corroborates several hypotheses of biogeographers from the twentieth century.

Psychosocial analysis of the collective processes in the United States after September 11

This article studies alterations in the values, attitudes, and behaviors that emerged among U.S. citizens as a consequence of, and as a response to, the attacks of September 11, 2001. The study briefly examines the immediate reaction to the attack, before focusing on the collective reactions that characterized the behavior of the majority of the population between the events of 9/11 and the response to it in the form of intervention in Afghanistan. In studying this period an eight-phase sequential model (Botcharova, 2001) is used, where the initial phases center on the nation as the ingroup and the latter focus on the enemy who carried out the attack as the outgroup. The study is conducted from a psychosocial perspective and uses "social identity theory" (Tajfel & Turner, 1979, 1986) as the basic framework for interpreting and accounting for the collective reactions recorded. The main purpose of this paper is to show that the interpretation of these collective reactions is consistent with the postulates of social identity theory. The application of this theory provides a different and specific analysis of events. The study is based on data obtained from a variety of rigorous academic studies and opinion polls conducted in relation to the events of 9/11. In line with social identity theory, 9/11 had a marked impact on the importance attached by the majority of U.S. citizens to their identity as members of a nation. This in turn accentuated group differentiation and activated ingroup favoritism and outgroup discrimination (Tajfel & Turner, 1979, 1986). Ingroup favoritism strengthened group cohesion, feelings of solidarity, and identification with the most emblematic values of the U.S. nation, while outgroup discrimination induced U.S. citizens to conceive the enemy (al-Qaeda and its protectors) as the incarnation of evil, depersonalizing the group and venting their anger on it, and to give their backing to a military response, the eventual intervention in Afghanistan. Finally, and also in line with the postulates of social identity theory, as an alternative to the virtual bipolarization of the conflict (U.S. vs al-Qaeda), the activation of a higher level of identity in the ingroup is proposed, a group that includes the United States and the largest possible number of countries¿ including Islamic states¿in the search for a common, more legitimate and effective solution.

Chemodiversity and molecular plasticity: recognition processes as explored by property spaces.

In the last few years, a need to account for molecular flexibility in drug-design methodologies has emerged, even if the dynamic behavior of molecular properties is seldom made explicit. For a flexible molecule, it is indeed possible to compute different values for a given conformation-dependent property and the ensemble of such values defines a property space that can be used to describe its molecular variability; a most representative case is the lipophilicity space. In this review, a number of applications of lipophilicity space and other property spaces are presented, showing that this concept can be fruitfully exploited: to investigate the constraints exerted by media of different levels of structural organization, to examine processes of molecular recognition and binding at an atomic level, to derive informative descriptors to be included in quantitative structure--activity relationships and to analyze protein simulations extracting the relevant information. Much molecular information is neglected in the descriptors used by medicinal chemists, while the concept of property space can fill this gap by accounting for the often-disregarded dynamic behavior of both small ligands and biomacromolecules. Property space also introduces some innovative concepts such as molecular sensitivity and plasticity, which appear best suited to explore the ability of a molecule to adapt itself to the environment variously modulating its property and conformational profiles. Globally, such concepts can enhance our understanding of biological phenomena providing fruitful descriptors in drug-design and pharmaceutical sciences.

Hepatic hemangiomas : factors associated with T2 shine-through effect on diffusion-weighted MR sequences

Objectifs: Déterminer la fréquence et les facteurs prédictifs de l'effet T2 shine-through dans l'hémangiome hépatique. Matériels et méthodes: Entre janvier 2010 et novembre 2011, l'imagerie par résonance magnétique du foie de 149 patients avec 388 hémangiomes hépatiques a été revue rétrospectivement. Les caractéristiques lésionnelles: la taille, la localisation, le signal et l'aspect en T1, T2 et en diffusion, l'effet T2 shine-through, le coefficient apparent de diffusion des hémangiomes hépatiques et du foie et type de rehaussement ont été évalués. Résultats: L'effet T2 shine-through était observé dans 204/388 (52.6%) des hémangiomes hépatiques et 100 (67.1%) patients. L'ADC moyen des hémangiomas avec T2 shine-through effect était significativement plus bas que les hémangiomas sans T2 shine-through effect (2.0 +/- 0.48 vs 2.38 +/- 0.45 10"3 mm2/s, P < .0001). L'analyse multivariée retrouvait comme facteurs indépendants de la présence d'un effet T2 shine-through un hypersignal sur les images fat- suppressed T2-weighted fast spin-echo, les hémangiomes avec un rehaussement classique et retardé, et l'ADC du foie. Conclusion: Le T2 shine-through effect est fréquemment observé dans les hémangiomes hépatiques et dépend des caractéristiques lésionnelles. Sa présence ne remet pas en question le diagnostic lorsque les signes IRM typiques sont présents.