FAS/FASL are dysregulated in chordoma and their loss-of-function impairs zebrafish notochord formation

Chordoma is a rare malignant tumor that recapitulates the notochord phenotype and is thought to derive from notochord remnants not correctly regressed during development. Apoptosis is necessary for the proper notochord development in vertebrates, and the apoptotic pathway mediated by Fas and Fasl has been demonstrated to be involved in notochord cells regression. This study was conducted to investigate the expression of FAS/FASL pathway in a cohort of skull base chordomas and to analyze the role of fas/fasl homologs in zebrafish notochord formation. FAS/FASL expression was found to be dysregulated in chordoma leading to inactivation of the downstream Caspases in the samples analyzed. Both fas and fasl were specifically expressed in zebrafish notochord sorted cells. fas and fasl loss-of-function mainly resulted in larvae with notochord multi-cell-layer jumps organization, larger vacuolated notochord cells, defects in the peri-notochordal sheath structure and in vertebral mineralization. Interestingly, we observed the persistent expression of ntla and col2a1a, the zebrafish homologs of the human T gene and COL2A1 respectively, which are specifically up-regulated in chordoma. These results demonstrate for the first time the dysregulation of FAS/FASL in chordoma and their role in notochord formation in the zebrafish model, suggesting their possible implication in chordoma onset

Zebrafish Tmem230a cooperates with the Delta/Notch signaling pathway to modulate endothelial cell number in angiogenic vessels

During embryonic development, new arteries, and veins form from preexisting vessels in response to specific angiogenic signals. Angiogenic signaling is complex since not all endothelial cells exposed to angiogenic signals respond equally. Some cells will be selected to become tip cells and acquire migration and proliferation capacity necessary for vessel growth while others, the stalk cells become trailer cells that stay connected with pre-existing vessels and act as a linkage to new forming vessels. Additionally, stalk and tip cells have the capacity to interchange their roles. Stalk and tip cellular responses are mediated in part by the interactions of components of the Delta/Notch and Vegf signaling pathways. We have identified in zebrafish, that the transmembrane protein Tmem230a is a novel regulator of angiogenesis by its capacity to regulate the number of the endothelial cells in intersegmental vessels by co-operating with the Delta/Notch signaling pathway. Modulation of Tmem230a expression by itself is sufficient to rescue improper number of endothelial cells induced by aberrant expression or inhibition of the activity of genes associated with the Dll4/Notch pathway in zebrafish. Therefore, Tmem230a may have a modulatory role in vessel-network formation and growth. As the Tmem230 sequence is conserved in human, Tmem230 may represent a promising novel target for drug discovery and for disease therapy and regenerative medicine in promoting or restricting angiogenesis

GSK-3 Activity Is Critical for the Orientation of the Cortical Microtubules and the Dorsoventral Axis Determination in Zebrafish Embryos

The formation of dorsal-ventral (D–V) axis is the earliest event that breaks the radial symmetry and determines the bilateral body plan of a vertebrate embryo, however, the maternal control of this process is not fully understood. Here, we discovered a new dorsalizing window of acute lithium treatment, which covers only less than 10 minutes after fertilization. Lithium treatment in this window was not able to reverse the ventralized phenotype in tokkeabi (tkk) mutant embryos, and its dorsalizing activity on wild-type embryos was inhibited by nocodazole co-treatment. These evidences indicate that the underlying mechanism is independent of a direct activation of Wnt/β-catenin signaling, but depends on the upstream level of the microtubule mediated dorsal determinant transport. In order to identify the target of lithium in this newly discovered sensitive window, GSK-3 inhibitor IX as well as the IMPase inhibitor L690, 330 treatments were performed. We found that only GSK-3 inhibitor IX treatment mimicked the lithium treatment in the dorsalizing activity. Further study showed that the parallel pattern of cortical microtubules in the vegetal pole region and the directed migration of the Wnt8a mRNA were randomized by either lithium or GSK-3 inhibitor IX treatment. These results thus revealed an early and critical role of GSK-3 activity that regulates the orientation of the cortical microtubules and the directed transport of the dorsal determinants in zebrafish embryos

Molecular psychiatry of zebrafish

Due to their well-characterized neural development and high genetic homology to mammals, zebrafish (Danio rerio) have emerged as a powerful model organism in the field of biological psychiatry. Here, we discuss the molecular psychiatry of zebrafish, and its implications for translational neuroscience research and modeling central nervous system (CNS) disorders. In particular, we outline recent genetic and technological developments allowing for in vivo examinations, high-throughput screening and whole-brain analyses in larval and adult zebrafish. We also summarize the application of these molecular techniques to the understanding of neuropsychiatric disease, outlining the potential of zebrafish for modeling complex brain disorders, including attention-deficit/hyperactivity disorder (ADHD), aggression, post-traumatic stress and substance abuse. Critically evaluating the advantages and limitations of larval and adult fish tests, we suggest that zebrafish models become a rapidly emerging new field in modern molecular psychiatry research

Effects of melatonin in perimenopausal and menopausal women: a randomized and placebo controlled study.

ABSTRACT: The purpose of this clinical trial on possible effects of nocturnal MEL administration in perimenopausal women was to find if MEL by itself modifies levels of hormones and produces changes of any kind, independently of age (42-62 years of age) and the stage of the menstrual cycle. It is accepted that a close link exists between the pineal gland, MEL, and human reproduction and that a relationship exists between adenohypophyseal and steroid hormones and MEL during the ovarian cycle, perimenopause, and menopause. Subjects took a daily dose of 3 mg synthetic melatonin or a placebo for 6 months. Levels of melatonin were determined from five daily saliva samples taken at fixed times. Hormone levels were determined from blood samples three times over the 6-month period. Our results indicate that a cause-effect relationship between the decline of nocturnal levels of MEL and onset of menopause may exist. The follow up controls show that MEL abrogates hormonal, menopause-related neurovegetative disturbances and restores menstrual cyclicity and fertility in perimenopausal or menopausal women. At present we assert that the six-month treatment with MEL produced a remarkable and highly significant improvement of thyroid function, positive changes of gonadotropins towards more juvenile levels, and abrogation of menopause-related depression. KEYWORDS: melatonin; menopause; aging A progressive reduction of nocturnal serum melatonin (MEL) concentration is observed in aging healthy humans. 1 It has been demonstrated that the pineal gland is responsible for the development and maintenance of neuroendocrine and sexual functions. In fact, the identification of the key role of the pineal gland in the control of reproductive biology emerged from the observation of precocious puberty in children carrying pineal tumors

All satellites in view: GNSS-based synchronization for wide area multilateration

Wide Area Multilateration is a form of Cooperative Independent Surveillance, used in Air Traffic Control Systems, based on the principle of hyperbolic localization of targets that emit SSR Mode S signals that is received from a group of ground based stations. The accuracy of WAM systems is strongly dependent by the Time Stamp assigned by each receiving stations to the received signal. Hence a fundamental requirement is the complete and accurate synchronization of all the stations of the systems to a common reference clock time. In the paper a particular Satellite Common View technique (All Sat in View) is proposed and implemented for WAM synchronization also to overcome this limit; after an introduction of the WAM peculiarity to be taken into account for GNSS Common View and All in view techniques an analysis of a real case study is reported and some trials with real data are presented. Moreover, the implementation of a prediction and estimation Kalman filtering for the clock bias is discussed and analyzed with the use of real data

All satellites in view: GNSS-based synchronization for wide area multilateration

Wide Area Multilateration is a form of Cooperative Independent Surveillance, used in Air Traffic Control Systems, based on the principle of hyperbolic localization of targets that emit SSR Mode S signals that is received from a group of ground based stations. The accuracy of WAM systems is strongly dependent by the Time Stamp assigned by each receiving stations to the received signal. Hence a fundamental requirement is the complete and accurate synchronization of all the stations of the systems to a common reference clock time. In the paper a particular Satellite Common View technique (All Sat in View) is proposed and implemented for WAM synchronization also to overcome this limit; after an introduction of the WAM peculiarity to be taken into account for GNSS Common View and All in view techniques an analysis of a real case study is reported and some trials with real data are presented. Moreover, the implementation of a prediction and estimation Kalman filtering for the clock bias is discussed and analyzed with the use of real data

The zebrafish as a model for nociception studies.

Nociception is the sensory mechanism used to detect cues that can harm an organism. The understanding of the neural networks and molecular controls of the reception of pain remains an ongoing challenge for biologists. While we have made significant progress in identifying a number of molecules and pathways that are involved in transduction of noxious stimuli, from the skin through the sensory receptor cell and from this to the spinal cord on into the central nervous system, we still lack a clear understanding of the perceptual processes, the responses to pain and the regulation of pain perception. Mice and rat animal models have been extensively used for nociception studies. However, the study of pain and noiception in these organisms can be rather laborious, costly and time consuming. Conversely, the use of Drosophila and Caenorhabditis elegans may be affected by the large evolutionary distance between these animals and humans. We outline here the reasons why zebrafish presents a new and attractive model for studying pain reception and responses and the most interesting findings in the study of nociception that have been obtained using the zebrafish model