Ret is essential to mediate GDNF’s neuroprotective and neuroregenerative effect in a Parkinson disease mouse model

Glial cell line-derived neurotrophic factor (GDNF) is a potent survival and regeneration-promoting factor for dopaminergic neurons in cell and animal models of Parkinson disease (PD). GDNF is currently tested in clinical trials on PD patients with so far inconclusive results. The receptor tyrosine kinase Ret is the canonical GDNF receptor, but several alternative GDNF receptors have been proposed, raising the question of which signaling receptor mediates here the beneficial GDNF effects. To address this question we overexpressed GDNF in the striatum of mice deficient for Ret in dopaminergic neurons and subsequently challenged these mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Strikingly, in this established PD mouse model, the absence of Ret completely abolished GDNF’s neuroprotective and regenerative effect on the midbrain dopaminergic system. This establishes Ret signaling as absolutely required for GDNF’s effects to prevent and compensate dopaminergic system degeneration and suggests Ret activation as the primary target of GDNF therapy in PD

α-Synuclein in central nervous system and from erythrocytes, mammalian cells, and Escherichia coli exists predominantly as disordered monomer

Since the discovery and isolation of α-synuclein (α-syn) from human brains, it has been widely accepted that it exists as an intrinsically disordered monomeric protein. Two recent studies suggested that α-syn produced in Escherichia coli or isolated from mammalian cells and red blood cells exists predominantly as a tetramer that is rich in α-helical structure (Bartels, T., Choi, J. G., and Selkoe, D. J. (2011) Nature 477, 107-110; Wang, W., Perovic, I., Chittuluru, J., Kaganovich, A., Nguyen, L. T. T., Liao, J., Auclair, J. R., Johnson, D., Landeru, A., Simorellis, A. K., Ju, S., Cookson, M. R., Asturias, F. J., Agar, J. N., Webb, B. N., Kang, C., Ringe, D., Petsko, G. A., Pochapsky, T. C., and Hoang, Q. Q. (2011) Proc. Natl. Acad. Sci. 108, 17797-17802). However, it remains unknown whether or not this putative tetramer is the main physiological form of α-syn in the brain. In this study, we investigated the oligomeric state of α-syn in mouse, rat, and human brains. To assess the conformational and oligomeric state of native α-syn in complex mixtures, we generated α-syn standards of known quaternary structure and conformational properties and compared the behavior of endogenously expressed α-syn to these standards using native and denaturing gel electrophoresis techniques, size-exclusion chromatography, and an oligomer-specific ELISA. Our findings demonstrate that both human and rodent α-syn expressed in the central nervous system exist predominantly as an unfolded monomer. Similar results were observed when human α-syn was expressed in mouse and rat brains as well as mammalian cell lines (HEK293, HeLa, and SH-SY5Y). Furthermore, we show that α-syn expressed in E. coli and purified under denaturing or nondenaturing conditions, whether as a free protein or as a fusion construct with GST, is monomeric and adopts a disordered conformation after GST removal. These results do not rule out the possibility that α-syn becomes structured upon interaction with other proteins and/or biological membranes

High serum acid phosphatase values in a case of lymphoblastic leukaemia.

In a patient with acute lymphoblastic leukaemia and a greatly increased serum acid nitrophenylphosphatase activity, as measured with the Sigma procedure (Sigma Technical Bulletin No. 104, revised August 1961), disappearance of blast cells from the bone marrow and the blood after chemotherapy was followed by the return of serum acid phosphatase levels to normal. Relapse was again accompanied by a rise in enzyme levels. © 1970, British Medical Journal Publishing Group. All rights reserved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Contrôle de la qualité du béton en laboratoire et sur chantier.

info:eu-repo/semantics/publishe

Binding and activation properties of angiotensin II in dispersed rat anterior pituitary cells

The properties of angiotensin II receptors were studied in isolated rat anterior pituitary cells prepared by trypsin digestion. Angiotensin II bound in a time- and temperature-dependent manner to pituitary cells, with Kd of 4.1 x 10(-9) M. The heptapeptide, des-Asp1-angiotensin II, had only one-tenth of the affinity of the octapeptide (Ki = 5.5 x 10(-8) M). These two peptides displayed a similar potency ratio in their ability to stimulate ACTH release from pituitary cells. These results indicate that angiotensin II may play a regulatory role in controlling ACTH secretion from the pituitary gland

Corticotropin-releasing activity of the renin-angiotensin system peptides in rat and in man

In this study we investigated in the rat the binding and corticotropin-releasing factor (CRF) activity of various constituents of the renin-angiotensin system and the possible angiotensin II receptor changes following procedures known to alter plasma renin activity. We investigated also the CRF activity of angiotensin II in vitro and in vivo in humans. The CRF activity of peptides was studied by their ability to stimulate ACTH release from pituitary cells. Deleting amino acids from the N-terminus of angiotensin II resulted in decreased CRF activity; while the ED50 for angiotensin II was 2 nM, it increased to about 10 nM for the (2-8)-heptapeptide. Angiotensin I had a weak CRF activity, whereas the substrate angiotensinogen had no stimulatory effect even at a concentration of 100 nM. There was a strong correlation between the activation and binding properties of all peptides tested. Dietary salt load or depletion as well as dexamethasone treatment did not affect the number nor the affinity of pituitary angiotensin II receptors. Angiotensin II had a CRF activity on human pituitary cells in vitro. However, peripherally injected agiotensin II at a pressive dose of 7 ng/kg/min did not produce any ACTH release in normal male volunteers. These data suggest that angiotensin II may play a modulatory role in the physiological regulation of ACTH secretion, but this role might be attributed to the endogenous brain angiotensin II as it is not closely dependent on the angiotensin II plasma levels

Risk of COVID-19 and Psychological Impact of the Pandemic in Swiss Primary Care Physicians.

There is limited data on primary care physicians (PCPs) who suffered from COVID-19. We aimed to assess the proportion of PCPs with COVID-19, the proportion hospitalized with COVID-19, and the number of days off work. We also explored their psychological suffering due to the pandemic. We selected a random sample of 1,000 PCPs practicing in the seven cantons of Western Switzerland (November/December 2020). PCPs were invited by mail to complete a questionnaire. The participation rate was 51% (N=506). The burden of disease was high among PCPs: 13% suffered from COVID-19, 0.4% needed hospitalization, and 10 days off work were required on average. In addition, many PCPs reported experiencing heightened psychological symptoms, mainly fatigue (53%) and stress/anxiety (48%). These findings highlight the urgent need to implement preventive measures to reduce the risk of COVID-19 and psychological illness in PCPs