Expression and functional role of the prorenin receptor in the human adrenocortical zona glomerulosa and in primary aldosteronism.

OBJECTIVES: Prorenin can be detected in plasma of hypertensive patients. If detected in patients with primary aldosteronism could implicate prorenin in the development of primary aldosteronism. To address this issue, we measured the plasma prorenin levels in primary aldosteronism patients, the expression of the prorenin receptor (PRR) in the normal human adrenocortical zona glomerulosa and aldosterone-producing adenoma (APA), and we investigated the functional effects of PRR activation in human adrenocortical cells. METHOD: Plasma renin activity, aldosterone, and active and total trypsin-activated renin were measured in primary aldosteronism patients, essential hypertensive patients, and healthy individuals, and then prorenin levels were calculated. Localization and functional role of PRR were investigated in human and rat tissues, and aldosterone-producing cells. RESULTS: Primary aldosteronism patients had detectable plasma levels of prorenin. Using digital-droplet real-time PCR, we found a high PRR-to-porphobilinogen deaminase ratio in both the normal adrenal cortex and APAs. Marked expression of the PRR gene and protein was also found in HAC15 cells. Immunoblotting, confocal, and immunogold electron microscopy demonstrated PRR at the cell membrane and intracellularly. Renin and prorenin significantly triggered both CYP11B2 expression (aldosterone synthase) and ERK1/2 phosphorylation, but only CYP11B2 transcription was prevented by aliskiren. CONCLUSION: The presence of detectable plasma prorenin in primary aldosteronism patients, and the high expression of PRR in the normal human adrenal cortex, APA tissue, CD56+ aldosterone-producing cells, along with activation of CYP11B2 synthesis and ERK1/2 phosphorylation, suggest that the circulating and locally produced prorenin may contribute to the development or maintenance of human primary aldosteronism.

Hepatocyte nuclear factor-4 alpha regulates the human apolipoprotein AV gene: Identification of a novel response element and involvement in the control by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, AMP-activated protein kinase, and mitogen-activated protein kinase pathway

The recently discovered apolipoprotein AV (apoAV) gene has been reported to be a key player in modulating plasma triglyceride levels. Here we identify the hepatocyte nuclear factor-4 (HNF-4 ) as a novel regulator of human apoAV gene. Inhibition of HNF-4 expression by small interfering RNA resulted in down-regulation of apoAV. Deletion, mutagenesis, and binding assays revealed that HNF-4 directly regulates human apoAV promoter through DR1 [a direct repeat separated by one nucleotide (nt)], and via a novel element for HNF-4 consisting of an inverted repeat separated by 8 nt (IR8). In addition, we show that the coactivator peroxisome proliferator-activated receptor- coactivator-1 was capable of stimulating the HNF-4 -dependent transactivation of apoAV promoter. Furthermore, analyses in human hepatic cells demonstrated that AMP-activated protein kinase (AMPK) and the MAPK signaling pathway regulate human apoAV expression and suggested that this regulation may be mediated, at least in part, by changes in HNF-4 . Intriguingly, EMSAs and mice with a liver-specific disruption of the HNF-4 gene revealed a species-distinct regulation of apoAV by HNF-4 , which resembles that of a subset of HNF-4 target genes. Taken together, our data provide new insights into the binding properties and the modulation of HNF-4 and underscore the role of HNF-4 in regulating triglyceride metabolism.

Action Dominates Valence in Anticipatory Representations in the Human Striatum and Dopaminergic Midbrain

The acquisition of reward and the avoidance of punishment could logically be contingent on either emitting or withholding particular actions. However,the separate pathways inthe striatumfor go and no-go appearto violatethis independence, instead coupling affect and effect. Respect for this interdependence has biased many studies of reward and punishment, so potential action- outcome valence interactions during anticipatory phases remain unexplored. In a functional magnetic resonance imaging study with healthy human volunteers, we manipulated subjects" requirement to emit or withhold an action independent from subsequent receipt of reward or avoidance of punishment. During anticipation, in the striatum and a lateral region within the substantia nigra/ventral tegmental area (SN/VTA), action representations dominated over valence representations. Moreover, we did not observe any representation associated with different state values through accumulation of outcomes, challenging a conventional and dominant association between these areas and state value representations. In contrast, a more medial sector of the SN/VTA responded preferentially to valence, with opposite signs depending on whether action was anticipatedto be emitted or withheld. This dominant influence of action requires an enriched notion of opponency between reward and punishment.

Cooperative and Competitive Spreading Dynamics on the Human Connectome.

Increasingly detailed data on the network topology of neural circuits create a need for theoretical principles that explain how these networks shape neural communication. Here we use a model of cascade spreading to reveal architectural features of human brain networks that facilitate spreading. Using an anatomical brain network derived from high-resolution diffusion spectrum imaging (DSI), we investigate scenarios where perturbations initiated at seed nodes result in global cascades that interact either cooperatively or competitively. We find that hub regions and a backbone of pathways facilitate early spreading, while the shortest path structure of the connectome enables cooperative effects, accelerating the spread of cascades. Finally, competing cascades become integrated by converging on polysensory associative areas. These findings show that the organizational principles of brain networks shape global communication and facilitate integrative function.

An Advocacy for the Use of 3D Stem Cell Culture Systems for the Development of Regenerative Medicine: An Emphasis on Photoreceptor Generation

The availability of stem cells is of great promise to study early developmental stages and to generate adequate cells for cell transfer therapies. Although many researchers using stem cells were successful in dissecting intrinsic and extrinsic mechanisms and in generating specific cell phenotypes, few of the stem cells or the differentiated cells show the capacity to repair a tissue. Advances in cell and stem cell cultivation during the last years made tremendous progress in the generation of bona fide differentiated cells able to integrate into a tissue after transplantation, opening new perspectives for developmental biology studies and for regenerative medicine. In this review, we focus on the main works attempting to create in vitro conditions mimicking the natural environment of CNS structures such as the neural tube and its development in different brain region areas including the optic cup. The use of protocols growing cells in 3D organoids is a key strategy to produce cells resembling endogenous ones. An emphasis on the generation of retina tissue and photoreceptor cells is provided to highlight the promising developments in this field. Other examples are presented and discussed, such as the formation of cortical tissue, the epithelial gut or the kidney organoids. The generation of differentiated tissues and well-defined cell phenotypes from embryonic stem (ES) cells or induced pluripotent cells (iPSCs) opens several new strategies in the field of biology and regenerative medicine. A 3D organ/tissue development in vitro derived from human cells brings a unique tool to study human cell biology and pathophysiology of an organ or a specific cell population. The perspective of tissue repair is discussed as well as the necessity of cell banking to accelerate the progress of this promising field.

Individual differences in gene expression : insights from transcriptional control of the CSL gene and from human population studies

CSL is a key transcription factor, mostly acting as a repressor, which has been shown to have a highly context-dependent function. While known as the main effector of Notch signaling, it can also exert Notch-independent functions. The downstream effects of the Notch/CSL signaling pathway and its involvement in several biological processes have been intensively studied. We recently showed that CSL is important to maintain skin homeostasis, as its specific deletion in mouse dermal fibroblasts -or downmodulation in human stromal fibroblasts- creates an inducing environment for squamous cell carcinoma (SCC) development, possibly due to the conversion of stromal fibroblasts into cancer associated fibroblasts (CAFs). Despite the wide interest in CSL as a transcriptional regulator, the mechanism of its own regulation has so far been neglected. We show here that CSL expression levels differ between individuals, and correlate among others with genes involved in DNA damage response. Starting from this finding we show that in dermal fibroblasts CSL is under transcriptional control of stress inducers such as UVA irradiation and Reactive Oxygen Species (ROS) induction, and that a main player in CSL transcriptional regulation is the transcription factor p53. In a separate line of work, we focused on individual variability, studying the differences in gene expression between human populations in various cancer types, particularly focusing on the Caucasian and African populations. It is indeed widely known that these populations have different incidences and mortalities for various cancers, and response to cancer treatment may also vary between them. We show here several genes that are differentially expressed and could be of interest in the study of population differences in cancer. -- CSL est un facteur de transcription agissant essentiellement comme répresseur, et qui a une fonction hautement dépendant du contexte. C'est l'effecteur principal de la voie de signalisation de Notch, mais il peut également exercer ses fonctions dans une façon Notch- indépendante. Nous avons récemment montré que CSL est important pour maintenir l'homéostasie de la peau. Sa suppression spécifique dans les fibroblastes dermiques de la souris ou dans les fibroblastes stromales humaines crée un environnement favorable pour le développement du carcinome épidermoïde (SCC), probablement en raison de la conversion des fibroblastes en fibroblastes associé au cancer (CAF). Malgré le grand intérêt de CSL comme régulateur transcriptionnel, le mécanisme de sa propre régulation a été jusqu'ici négligée. Nous montrons ici que dans les fibroblastes dermiques CSL est sous le contrôle transcriptionnel de facteurs de stress tels que l'irradiation UVA et l'induction des ROS dont p53 est l'acteur principal de cette régulation. Nous montrons aussi que les niveaux d'expression de CSL varient selon les individus, en corrélation avec d'autres gènes impliqués dans la réponse aux dommages de l'ADN. Dans une autre axe de recherche, concernant la variabilité individuelle, nous avons étudié les différences dans l'expression des gènes dans différents types de cancer entre les populations humaines, en se concentrant particulièrement sur les populations africaines et caucasiennes. Il est en effet bien connu que ces populations montrent des variations dans l'incidence des cancers, la mortalité, ainsi que pour les réponses au traitement. Nous montrons ici plusieurs gènes qui sont exprimés différemment et pourraient être digne d'intérêt dans l'étude du cancer au sein de différentes populations.

Maladie des griffes du chat et autres bartonelloses [Cat scratch disease and other human infections caused by Bartonella species].

The different Bartonella species can cause various human infections such as cat scratch disease, chronic bacteremia (homeless patient with nonspecific symptom), endocarditis, bacillary angiomatosis, peliosis, and Carrion's disease. Diagnostic approaches include serology, culture and molecular approaches. PCR is especially useful on lymph nodes biopsies from patients with cat-scratch disease and on valvular samples taken from culture-negative endocarditis. Serology exhibits a very high sensitivity in the latter situation. The treatment should be chosen according to the clinical presentation.

Condition-dependence, pleiotropy and the handicap principle of sexual selection in melanin-based colouration.

The signalling function of melanin-based colouration is debated. Sexual selection theory states that ornaments should be costly to produce, maintain, wear or display to signal quality honestly to potential mates or competitors. An increasing number of studies supports the hypothesis that the degree of melanism covaries with aspects of body condition (e.g. body mass or immunity), which has contributed to change the initial perception that melanin-based colour ornaments entail no costs. Indeed, the expression of many (but not all) melanin-based colour traits is weakly sensitive to the environment but strongly heritable suggesting that these colour traits are relatively cheap to produce and maintain, thus raising the question of how such colour traits could signal quality honestly. Here I review the production, maintenance and wearing/displaying costs that can generate a correlation between melanin-based colouration and body condition, and consider other evolutionary mechanisms that can also lead to covariation between colour and body condition. Because genes controlling melanic traits can affect numerous phenotypic traits, pleiotropy could also explain a linkage between body condition and colouration. Pleiotropy may result in differently coloured individuals signalling different aspects of quality that are maintained by frequency-dependent selection or local adaptation. Colouration may therefore not signal absolute quality to potential mates or competitors (e.g. dark males may not achieve a higher fitness than pale males); otherwise genetic variation would be rapidly depleted by directional selection. As a consequence, selection on heritable melanin-based colouration may not always be directional, but mate choice may be conditional to environmental conditions (i.e. context-dependent sexual selection). Despite the interest of evolutionary biologists in the adaptive value of melanin-based colouration, its actual role in sexual selection is still poorly understood.

Transforming Maritime Safety Culture. Evaluation of the impacts of the ISM Code on maritime safety culture in Finland

The purpose of the METKU Project (Development of Maritime Safety Culture) is to study how the ISM Code has influenced the safety culture in the maritime industry. This literature review is written as a part of the Work Package 2 which is conducted by the University of Turku, Centre for Maritime Studies. The maritime traffic is rapidly growing in the Baltic Sea which leads to a growing risk of maritime accidents. Particularly in the Gulf of Finland, the high volume of traffic causes a high risk of maritime accidents. The growing risks give us good reasons for implementing the research project concerning maritime safety and the effectiveness of the safety measures, such as the safety management systems. In order to reduce maritime safety risks, the safety management systems should be further developed. The METKU Project has been launched to examine the improvements which can be done to the safety management systems. Human errors are considered as the most important reason for maritime accidents. The international safety management code (the ISM Code) has been established to cut down the occurrence of human errors by creating a safety-oriented organizational culture for the maritime industry. The ISM Code requires that a company should <i>provide safe practices in ship operation and a safe working environment and establish safeguards against all identified risk.</i> The fundamental idea of the ISM Code is that companies should continuously improve safety. The commitment of the top management is essential for implementing a safety-oriented culture in a company. The ISM Code has brought a significant contribution to the progress of maritime safety in recent years. Shipping companies and ships’ crews are more environmentally friendly and more safety-oriented than 12 years ago. This has been showed by several studies which have been analysed for this literature research. Nevertheless, the direct effect and influence of the ISM Code on maritime safety could not be isolated very well. No quantitative measurement (statistics/hard data) could be found in order to present the impacts of the ISM Code on maritime safety. In this study it has been discovered that safety culture has emerged and it is developing in the maritime industry. Even though the roots of the safety culture have been established there are still serious barriers to the breakthrough of the safety management. These barriers could be envisaged as cultural factors preventing the safety process. Even though the ISM Code has been effective over a decade, the old-established behaviour which is based on the old day’s maritime culture still occurs. In the next phase of this research project, these cultural factors shall be analysed in regard to the present safety culture of the maritime industry in Finland.

Protestant Churches and the making of the Universal Declaration of Human Rights

Kirjallisuusarvostelu