How do gravity alterations affect animal and human systems at a cellular/tissue level?

The present white paper concerns the indications and recommendations of the SciSpacE Science Community to make progress in filling the gaps of knowledge that prevent us from answering the question: "How Do Gravity Alterations Affect Animal and Human Systems at a Cellular/Tissue Level?" This is one of the five major scientific issues of the ESA roadmap "Biology in Space and Analogue Environments". Despite the many studies conducted so far on spaceflight adaptation mechanisms and related pathophysiological alterations observed in astronauts, we are not yet able to elaborate a synthetic integrated model of the many changes occurring at different system and functional levels. Consequently, it is difficult to develop credible models for predicting long-term consequences of human adaptation to the space environment, as well as to implement medical support plans for long-term missions and a strategy for preventing the possible health risks due to prolonged exposure to spaceflight beyond the low Earth orbit (LEO). The research activities suggested by the scientific community have the aim to overcome these problems by striving to connect biological and physiological aspects in a more holistic view of space adaptation effects.

Physiological and pharmacological overview of the gonadotropin releasing hormone.

Gonadotropin-Releasing Hormone (GnRH) is a decapeptide responsible for the control of the reproductive functions. It shows C- and N-terminal aminoacid modifications and two other distinct isoforms have been so far identified. The biological effects of GnRH are mediated by binding to high-affinity G-protein couple receptors (GnRHR), showing characteristic very short C tail. In mammals, including humans, GnRH-producing neurons originate in the embryonic nasal compartment and during early embryogenesis they undergo rapid migration towards the hypothalamus; the increasing knowledge of such mechanisms improved diagnostic and therapeutic approaches to infertility. The pharmacological use of GnRH, or its synthetic peptide and non-peptide agonists or antagonists, provides a valid tool for reproductive disorders and assisted reproduction technology (ART). The presence of GnRHR in several organs and tissues indicates additional functions of the peptide. The identification of a GnRH/GnRHR system in the human endometrium, ovary, and prostate has extended the functions of the peptide to the physiology and tumor transformation of such tissues. Likely, the activity of a GnRH/GnRHR system at the level of the hippocampus, as well as its decreased expression in mice brain aging, raised interest in its possible involvement in neurogenesis and neuronal functions. In conclusion, GnRH/GnRHR appears to be a fascinating biological system that exerts several possibly integrated pleiotropic actions in the complex control of reproductive functions, tumor growth, neurogenesis, and neuroprotection. This review aims to provide an overview of the physiology of GnRH and the pharmacological applications of its synthetic analogs in the management of reproductive and non-reproductive diseases.

Lithium as a possible therapeutic strategy for Cornelia de Lange syndrome.

Cornelia de Lange Syndrome (CdLS) is a rare developmental disorder affecting a multitude of organs including the central nervous system, inducing a variable neurodevelopmental delay. CdLS malformations derive from the deregulation of developmental pathways, inclusive of the canonical WNT pathway. We have evaluated MRI anomalies and behavioral and neurological clinical manifestations in CdLS patients. Importantly, we observed in our cohort a significant association between behavioral disturbance and structural abnormalities in brain structures of hindbrain embryonic origin. Considering the cumulative evidence on the cohesin-WNT-hindbrain shaping cascade, we have explored possible ameliorative effects of chemical activation of the canonical WNT pathway with lithium chloride in different models: (I) Drosophila melanogaster CdLS model showing a significant rescue of mushroom bodies morphology in the adult flies; (II) mouse neural stem cells restoring physiological levels in proliferation rate and differentiation capabilities toward the neuronal lineage; (III) lymphoblastoid cell lines from CdLS patients and healthy donors restoring cellular proliferation rate and inducing the expression of CyclinD1. This work supports a role for WNT-pathway regulation of CdLS brain and behavioral abnormalities and a consistent phenotype rescue by lithium in experimental models.