Sleep in normal and pathological aging

Cellular and Molecular Life Sciences -     

Mechanisms involved in normal and pathological osteoclastogenesis

Osteoclasts are bone-resorbing cells that play an essential role in bone remodeling. Defects in osteoclasts result in unbalanced bone remodeling and are linked to many bone diseases including osteoporosis, rheumatoid arthritis, primary bone cancer, and skeletal metastases. Receptor activator of NF-kappaB ligand (RANKL) is a classical inducer of osteoclast formation. In the presence of macrophage-colony-stimulating factor, RANKL and co-stimulatory signals synergistically regulate osteoclastogenesis. However, recent discoveries of alternative pathways for RANKL-independent osteoclastogenesis have led to a reassessment of the traditional mechanisms that regulate osteoclast formation. In this review, we provide an overview of signaling pathways and other regulatory elements governing osteoclastogenesis. We also identify how osteoclastogenesis is altered in pathological conditions and discuss therapeutic targets in osteoclasts for the treatment of skeletal diseases.     

CAS proteins in normal and pathological cell growth control

Proteins of the CAS (Crk-associated substrate) family (BCAR1/p130Cas, NEDD9/HEF1/Cas-L, EFS/SIN and CASS4/HEPL) are integral players in normal and pathological cell biology. CAS proteins act as scaffolds to regulate protein complexes controlling migration and chemotaxis, apoptosis, cell cycle, and differentiation, and have more recently been linked to a role in progenitor cell function. Reflecting these complex functions, over-expression of CAS proteins has now been strongly linked to poor prognosis and increased metastasis in cancer, as well as resistance to first-line chemotherapeutics in multiple tumor types including breast and lung cancers, glioblastoma, and melanoma. Further, CAS proteins have also been linked to additional pathological conditions including inflammatory disorders, Alzheimer’s and Parkinson’s disease, as well as developmental defects. This review will explore the roles of the CAS proteins in normal and pathological states in the context of the many mechanistic insights into CAS protein function that have emerged in the past decade.     

Aurora A kinase (AURKA) in normal and pathological cell division

Temporally and spatially controlled activation of the Aurora A kinase (AURKA) regulates centrosome maturation, entry into mitosis, formation and function of the bipolar spindle, and cytokinesis. Genetic amplification and mRNA and protein overexpression of Aurora A are common in many types of solid tumor, and associated with aneuploidy, supernumerary centrosomes, defective mitotic spindles, and resistance to apoptosis. These properties have led Aurora A to be considered a high-value target for development of cancer therapeutics, with multiple agents currently in early-phase clinical trials. More recently, identification of additional, non-mitotic functions and means of activation of Aurora A during interphase neurite elongation and ciliary resorption have significantly expanded our understanding of its function, and may offer insights into the clinical performance of Aurora A inhibitors. Here we review the mitotic and non-mitotic functions of Aurora A, discuss Aurora A regulation in the context of protein structural information, and evaluate progress in understanding and inhibiting Aurora A in cancer.     

Paper electrophoresis of cytoplasmic proteins from normal and pathological liver cells

Riassunto Viene studiato il comportamento elettroforetico su carta delle proteine cellulari di fegato normale ed in degenerazione vacuolare e grassa. Nei ferogrammi di fegati in degenerazione vacuolare si ha la comparsa di una banda di tipo albuminico, che non compare nei ferogrammi normali. I ferogrammi di fegati in degenerazione grassa si rivelano più semplici di quelli normali per la mancanza di una banda di tipo globulinico. Questi risultati vengono brevemente discussi.

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This investigation was aided by a grant from the Consiglio Nazionale delle Ricerche.     

Histochemical demonstration of 1,4-amylophosphorylase in the human testis under normal and pathological conditions

Riassunto La 1–4 amilofosforilasi è presente nel testicolo umano normale ove è localizzata nell'epitelio tubulare e in alcuni elementi peritubulari. Nella aplasia germinale la reazione è intensamente positiva solo in sede peritubulare, nell'arresto maturativo solo nel tubulo. L'enzima è probabilmente in rapporto con l'energia necessaria per la spermatogenesi e con la funzione contrattile delle cellule peritubulari.

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Supported by grant No. 1247 of Consiglio Nazionale delle Ricerche Roma, Italia.     

Sequential changes in serum glucose,triglycerides and cholesterol in aging of normal and alloxan-diabetic rats

Summary 16-week-old Wistar, alloxan diabetic rats exhibited progressive elevations in levels of serum glucose, total triglycerides, cholesterol and creatinine over a period of 8 weeks; hyperglycemia preceeded hyperlipidemia and hypercreatininemia and hypertriglyceridemia preceeded hypercholesteremia. Age-matched control rats failed to develop any signs of hyperglycemia or hypercreatininemia, but did develop both hypercholesterolemia and hypertriglyceridemia at 24 weeks of age. This suggests that the progressive cardiovascular derangements (e.g., atherosclerosis, hypertension) noted in experimental diabetes mellitus and in the normal aging (and maturation) process may be brought about by distinctly different biochemical processes.Supported by NIH grant nos. HL-18002 and HL-18015 and NIDA grant No. DA-02339.     

Sleep in parabiosis

Résumé Le taux de la synchronization de la phase de sommeil chez le rat parabiotique est plus élevé que chez le rat de controle, particulièrement en cas de sommeil paradoxal (P<0.001). Ces resultats indiquent que le facteur humoral joue un grand rôle dans le déclenchement et l'anticipation du sommeil paradoxal.     

EG-VEGF controls placental growth and survival in normal and pathological pregnancies: case of fetal growth restriction (FGR)

Identifiable causes of fetal growth restriction (FGR) account for 30 % of cases, but the remainders are idiopathic and are frequently associated with placental dysfunction. We have shown that the angiogenic factor endocrine gland-derived VEGF (EG-VEGF) and its receptors, prokineticin receptor 1 (PROKR1) and 2, (1) are abundantly expressed in human placenta, (2) are up-regulated by hypoxia, (3) control trophoblast invasion, and that EG-VEGF circulating levels are the highest during the first trimester of pregnancy, the period of important placental growth. These findings suggest that EG-VEGF/PROKR1 and 2 might be involved in normal and FGR placental development. To test this hypothesis, we used placental explants, primary trophoblast cultures, and placental and serum samples collected from FGR and age-matched control women. Our results show that (1) EG-VEGF increases trophoblast proliferation ([³H]-thymidine incorporation and Ki67-staining) via the homeobox-gene, HLX (2) the proliferative effect involves PROKR1 but not PROKR2, (3) EG-VEGF does not affect syncytium formation (measurement of syncytin 1 and 2 and β hCG production) (4) EG-VEGF increases the vascularization of the placental villi and insures their survival, (5) EG-VEGF, PROKR1, and PROKR2 mRNA and protein levels are significantly elevated in FGR placentas, and (6) EG-VEGF circulating levels are significantly higher in FGR patients. Altogether, our results identify EG-VEGF as a new placental growth factor acting during the first trimester of pregnancy, established its mechanism of action, and provide evidence for its deregulation in FGR. We propose that EG-VEGF/PROKR1 and 2 increases occur in FGR as a compensatory mechanism to insure proper pregnancy progress.     

Sleep and body restitution

Summary Although human non-REM sleep is usually associated with body restitution, such an hypothesis is debatable. This sleep, like REM sleep, may have a beneficial role for the brain. Because man demonstrates relaxed wakefulness, body restitution may not be confined to human sleep. However, for active mammals, sleep may be an enforced immobiliser facilitating this restitution.     

Immune aging and autoimmunity

Age is an important risk for autoimmunity, and many autoimmune diseases preferentially occur in the second half of adulthood when immune competence has declined and thymic T cell generation has ceased. Many tolerance checkpoints have to fail for an autoimmune disease to develop, and several of those are susceptible to the immune aging process. Homeostatic T cell proliferation which is mainly responsible for T cell replenishment during adulthood can lead to the selection of T cells with increased affinity to self- or neoantigens and enhanced growth and survival properties. These cells can acquire a memory-like phenotype, in particular under lymphopenic conditions. Accumulation of end-differentiated effector T cells, either specific for self-antigen or for latent viruses, have a low activation threshold due to the expression of signaling and regulatory molecules and generate an inflammatory environment with their ability to be cytotoxic and to produce excessive amounts of cytokines and thereby inducing or amplifying autoimmune responses.     

Sleep in the tortoiseKinosternon sp.

Summary Individuals ofKinosternon sp., previously confined to laboratory conditions, were chronically implanted with electrodes for electroencephalogram, electro-oculogram and electrocardiogram recording. Behavioral states of waking and sleep were clearly observed. Two sleep stages were present: quiet sleep and REM or active sleep. Electrical cerebral activity was polymorphic and irregular. EEG frequencies declined and amplitudes diminished with sleep. Arrhythmic spikes occurred during behavioral sleep and declined with waking. Heart rate decreased when passing from wakefulness to quiet sleep. It was slightly but consistently higher during active sleep compared with quiet sleep.