42,265 research outputs found
Pharmacological and biotechnological in vitro approaches unveil the role of GPR17 signaling in regulating the timing of oligodendroglial differentiation
No full textBackground and Purpose - In the adult central nervous system there are many oligodendrocyte precursor cells (OPCs) that serve as the primary source of remyelinating cells in demyelinated lesions. Knowledge of the mechanisms regulating OPC maturation is needed to unveil novel pharmacological targets in demyelinating diseases. The G-protein-coupled membrane receptor GPR17, activated by both uracil nucleotides and cysteinyl-leucotrienes [1], has recently emerged as an important player in oligodendrogliogenesis [2,3]. It has been previously reported that GPR17 presence is restricted to NG2+-OPCs at early differentiation stages and is completely segregated from that of myelin proteins [4]. Here, we used purified primary OPCs from rat cortical parenchyma to assess the functional consequences of GPR17 modulation by either pharmacological or biotechnological approaches on the differentiation program of these cells.
Methods and Results - OPCs were exposed to the GPR17 agonists UDP-glucose, UDP and LTE4 for 48 hours. The degree of OPC differentiation was assessed on fixed cultures by immunostaining with an antibody against Myelin basic protein (MBP), a marker of mature oligodendrocytes. Data show that all these agonists increase the proportion of MBP+ cells compared to controls, suggesting acceleration of cell maturation by promoting receptor activation. Secondly, transfection experiments with fluorescent plasmids, enabling either silencing or over-expression of GPR17 were performed to univocally correlate the expression of this receptor with cell shape changes and phenotype acquisition during oligodendroglial maturation. Preliminary results show that suppression of GPR17 expression at early differentiation stages reduces the number of MBP+cells in culture, indicating that its silencing impairs the normal program of OPC differentiation.
Conclusions - Globally, these data point at GPR17 as a key regulator of oligodendrogliogenesis and at GPR17 ligands as extrinsic local regulators of OPCs under physiological conditions and during myelin repair.
References
[1] P. Ciana, M. Fumagalli, M.L. Trincavelli, C. Verderio, P. Rosa, D. Lecca, S. Ferrario, C. Parravicini, V. Capra, P. Gelosa, U. Guerrini, S. Belcredito, M. Cimino, L. Sironi, E. Tremoli, G.E. Rovati, C. Martini, M.P. Abbracchio, The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinil-leukotrienes receptor. EMBO J, 19, 4615-2627, 2006.
[2] D. Lecca, M.L. Trincavelli, P. Gelosa, L. Sironi, P. Ciana, M. Fumagalli, G. Villa, C. Verderio, C. Grumelli, U. Guerrini, E. Tremoli, P. Rosa, S. Cuboni, C. Martini, A. Buffo, M Cimino, M.P. Abbracchio, The recently identified P2Y-like receptor GPR17 is a sensor of brain damage and a new target for brain repair. PloS One, 10, e3579, 2008.
[3] Y. Chen, H. Wu, S. Wang, H. Koito, J. Li, F. Ye, J. Hoang, S.S. Escobar, A. Gow, H.A. Arnett, B.D. Trapp, N.J. Karandikar, J. Hsieh, Q.R. Lu, The oligodendrocyte-specific G protein-coupled receptor GPR17 is a cell-intrinsic timer of myelination. Nature Neuroscience, 12, 1398-1406.
[4] M. Fumagalli, S. Daniele, D. Lecca, P.R. Lee, C. Parravicini, R.D. Fields,P. Rosa, F. Antonucci, C. Verderio, M.L Trincavelli, P. Bramanti, C. Martini, M.P. Abbracchio, Phenotypic changes, signaling pathway, and functional correlates of GPR17-expressing neural precursor cells during oligodendrocyte differentiation. The Journal of biology chemistry,12, 10593-10604
La seconda fase del Rift Sardo: vulcanismo ed evoluzione dei sub-bacini di Ardara-Chilivani e Bonorva (Sardegna settentrionale)
No full textThe second stage of the Sardinian Rift: volcanism and evolution of Ardara-Chilivani and Bonorva sub-basins (Northern Sardinia).
The Oligo-Miocene Sardinian Rift (27-15 Ma; CHERCHI & MONTADERT, 1982; LECCA et alii, 1997), is a typical intra arc-massif basin (sensu DICKINSON, 1974) made up of several sub-basins filled by thick orogenic volcanic sequences and marine sediments. This arc is linked to the subduction of the Neotethys oceanic plate under the European plate and to the Africa-Europe convergence. The displacement of the arc or, in other words, the drift of the Sardinia-Corsica Block, is related to the orogenesis of the northern Apennine and of the Maghrebid-Sicilian chain.
Despite the key-role played by the Sardinia Rift in the knowledge of the geodynamic evolution of the western Mediterranean basin, the stratigraphy of volcanic sequences is still incomplete
because large portions of this rift still require detailed mapping.
At the regional scale, the Sardinia Rift shows marked differences with regard to volcanic and tectonic style. In northern Sardinia, the rift is arranged into several half-graben type sub-basins,
related to tilted block and horst block systems. The basins are schematically attributable to the relative mobility of the main blocks with minor relative strike-slip to transtensional movements along NE-SW trending faults among the sub-blocks of eastern Sardinia.
The Chilivani-Ardara and Bonorva sub-basins contain a poorly known thick pyroclastic sequence buried by epicontinental marine sediments. On the basis of field, petrographic and volcanological criteria, the volcanic pile is constituted, from bottom to the top, by early volcanics of broadly andesitic composition (M. Cuguttada Unit: MC), densely welded and rheomorphic ignimbrites (WI) followed by ash and pumice pyroclastic flow deposits named throughout this paper Pianu Ladu (PL), Pianu de Puma (IC) and Chilivani Unit (CH). Epiclastic deposits (EVL) are observed locally at different stratigraphic levels (the so-called «lacustre», VARDABASSO & ATZENI, 1962; PECORINI, 1962). Marine deposits onlap the volcano-sedimentary sequence in the upper Burdigalian-Serravallian interval. Published K-Ar (LECCA et alii, 1997) and Ar-Ar (EDEL et alii, 2001) radiometric data obtained for the pyroclastic flow deposits indicate a
quite narrow time span in the range of 20-18 Ma.
With regard to the regional stratigraphic picture proposed by LECCA et alii (1997), MC andesites belong to the A1 andesites; WI are the densely welded reomorphic ignimbrites, whereas the PL, IC and CH ash and pumice flow-Units constitute the AP2 group.
In detail, pyroclastic units belonging to the latter group show the following: Pianu Ladu Unit (PL). The PL unit is a light grey-coloured ash and pumice pyroclastic flow deposit, outcropping with continuity at the northern edge of the Chilivani-Ardara sub-basin. It lies normally on WI ignimbrites or locally on reddish matrix-supported conglomerates made up of clasts of Palaezoic basement. Content of pumice and xenoliths (accidental and cognate), ranges from 20 to 10% moving from S. A. of Bisarcio towards M. Ladu, while size and degree of welding decrease.
Pianu de Puma Unit (IC). The IC Unit constitutes discontinuous outcrops in the Bonorva basin as well as in the southern part of Chilivani- Ardara. It lies with nonconformity on the Palaeozoic basement and/or on the WI. Locally (Pianu de Puma), it is preceded by greenish to yellow coloured epiclastic deposits at least 5 m thick, containing rare clasts of the Palaeozoic basement dispersed in an ashy matrix. In the field, it is a poorly porphyritic greyish coloured ashy pyroclastic flow deposit ranging in thickness from a few metres to 30 m the greater thickness being observed eastward of Pranu Mannu.
Epiclastic deposits (EVL). They constitute discontinuous interbeds among the PL, IC and CH Units; characterized essentially by ash, crystals and pumice-fragments and containing conglomerate beds formed at the expense of Palaeozoic basement and WI ignimbrites. In the field they commonly show a greenish colour and typical cross and parallel bedding structures.
Chilivani Unit (CH). This is an ash and pumice compound ignimbrite made up of at least three different flow units well exposed in the Chilivani-Ardara sub-basin. It represents the volumetrically most important volcanic unit of the investigated area constituting wide plateaux dismembered by post-depositional faulting. The thickness of the unit CH ranges from 10 m (M. Salattu and M. Filigosu sectors), up to 100 m in M. Cordianu-M. S. Bernardo and in the west of Pranu Mannu (sub-basin of Bonorva). Macroscopically, it is easily recognizable because of its high porphyritic index.
Petrographic characters suggest that the pyroclastic units recognized may be related to different magmatic reservoirs localized in the upper crust, along active fault zones. In a tectonic/volcanism feedback scenario, the progressive discharge of magmatic reservoirs gives rise to caldera-like structures favoured by a progressive extensional regime.
Several lines of evidence indicate that the PL, IC and CH units mark the early supply in the studied basins, predating the marine ingression. They were erupted along regional volcanogenic faults observable westward in Bosa sub-basin, as well as in the Chilivani- Ardara and Bonorva sub-basins.
The whole data set suggest that the volcanic products fill the inner regions of the subsiding sub-basins in the eastern Logudoro, prolonging the continental conditions that end with the volcanic activity.
The volcanic activity of the sub-basins described is tectonically related to NE-SW trending sinistral transtensive faults which show a more pronounced extensional character with time. The sub-basins’ evolution can be summarized as progressive fault blocking and tilting of a block system, easily recognizable by the through the WI cover that represents a lithostratigraphic marker for northern Sardinia.
Tectonic subsidence favoured the local deposition of fluvial conglomerates (Pianu Ladu) and finally ash and pumice flowdeposits (IC and PL) which mark the acme of sub-basin filling and assume a tectonic significance. In the general picture of the multiphase evolution of the Sardinian Rift, these sub-basins belong to the second rifting phase sensu LECCA et alii (1997), during which the transtensional-extensional faulting affects particularly north eastern Sardinia at about 18 Ma and predates the beginning of the extension in the north Tyrrhenian domain
GPR17-expressing oligodendrocyte precursor cells differentially react to damage in experimental autoimmune encephalomyelitis and cuprizone-induced demyelination
No full textIntroduction
In the central nervous system, oligodendrocytes provide support to axons thanks to the production of a myelin sheath. During their maturation oligodendroglial precursors (OPCs) follow a very precise differentiation program, finely orchestrated by transcription factors, epigenetic factors and microRNAs, a class of small non-coding RNAs involved in post-transcriptional regulation. Any alterations in this program can potentially contribute to dysregulated myelination, impaired remyelination and neurodegenerative conditions, as it happens in multiple sclerosis.
Methods
Eight-week-old age male C57BL/6 mice were fed with 0.2% cuprizone supplemented diet ad libitum for 5 weeks to induce de-myelination and were then switched to normal diet for further 3 weeks to allow spontaneous re- myelination.
Stereotaxic injection of the detergent lysolecithin was performed in the subcortical white matter of C57BL/6 adult mice to produces a focal demyelinating injury. Lentiviral infection was performed in the same site 9 days later, then animals were sacrificed at 21 days post-lesion.
Results
Recently, we identified miR-125a-3p as a new actor of oligodendroglial maturation, that could also be involved in the pathological consequences of multiple sclerosis, showing that its over-expression impairs, whereas its silencing promotes, oligodendrocyte maturation (Lecca et al., Sci Rep, 2016).
To shed light on the mechanism underlying this effect, we performed a microarray analysis on OPCs after miR- 125a-3p over-expression. This analysis suggested that miR-125a-3p is indeed involved in the regulation of biological processes important for OPC maturation, such as cell-cell interaction and morphological differentiation. Interestingly, we also found that miR-125a-3p levels were up-regulated in vivo in presence of de-myelinating conditions. To evaluate whether miR-125a-3p modulation may influence the progression of remyelination in vivo, we overexpressed the miR-125a-3p by lentiviral approach in a focal lysolecithin-mediated demyelinating lesion in the subcortical white matter of adult mice. Interestingly, also in this case, we found that miRNA-overexpressing OPCs persisted in an immature (i.e. PDGRα+/NG2+) state. Relevant to the human disease, we found that miR- 125a-3p levels are altered in the cerebrospinal fluid of multiple sclerosis patients in the active phase (relapsing), suggesting that it could be a potential biomarker of pathology.
Conclusion
The identification of new pathogenetic mechanisms regulated by miRNAs provides new means for treatments of diseases. Based on these results, we hypothesize that antago-miRNA for miR-125a-3p may help to promote oligodendrocyte maturation in demyelinating conditions. Sponsored by Fondazione Cariplo, grant n° 2014-1207 to DL
Reply to comment on Lecca, LI; Portoghese, I.; Mucci, N.; Galletta, M.; Meloni, F.; Pilia, I.; Marcias, G.; Fabbri, D.; Fostinelli, J.; Lucchini, RG; Cocco, P.; Campagna, M. association between work-related stress and qt prolongation in male workers
No full textWe appreciate the interest raised by our paper on the association between conditions linked to work-related stress and the prolongation of the QT interval on the electrocardiogram [...]
Erratum to: Effect of moderate red wine intake on cardiac prognosis after recent acute myocardial infarction of subjects with Type 2 diabetes mellitus (Diabetic Medicine, (2006), 23, 9, (974-981), 10.1111/j.1464-5491.2006.01886.x)
No full textIn an article by Marfella et al, the author name C. Saron is incorrect and should be listed as C. Sardu. Therefore the correct author list is: R. Marfella, F. Cacciapuoti, M. Siniscalchi, F. C. Sasso, F. Marchese, F. Cinone, E. Musacchio, M. A. Marfella, L. Ruggiero, G. Chiorazzo, D. Liberti, G. Chiorazzo, G. F. Nicoletti, C. Sardu, F. D'Andrea, C. Ammendola, M. Verza and L. Coppola.In an article by Marfella et al, the author name C. Saron is incorrect and should be listed as C. Sardu. Therefore the correct author list is: R. Marfella, F. Cacciapuoti, M. Siniscalchi, F. C. Sasso, F. Marchese, F. Cinone, E. Musacchio, M. A. Marfella, L. Ruggiero, G. Chiorazzo, D. Liberti, G. Chiorazzo, G. F. Nicoletti, C. Sardu, F. D'Andrea, C. Ammendola, M. Verza and L. Coppola
The mammalian target of rapamycin (mTOR) controls oligodendrocyte maturation by fine-tuning the activity of GPR17 receptor via G protein-coupled receptor kinases.
No full textBackground and Purpose - In the adult central nervous system (CNS), oligodendrocyte precursor cells (OPCs) dispersed throughout the parenchyma serve as a primary source of myelinating cells in demyelinated lesions. The Gi-protein-coupled receptor GPR17 is activated by both uracil nucleotides (e.g. UDP-glucose) and cysteinyl-leukotrienes (e.g. LTD4). We previously reported that GPR17 (i) is transiently expressed by early OPCs (ii) its activation by endogenous ligands promotes OPC differentiation1, and that, (iii) its forced over-expression at late differentiation stages inhibits cell maturation, suggesting that the receptor needs to be down-regulated to allow terminal OPC maturation. Physiologically, GPR17 down-regulation may occur through agonist-induced receptor phosphorylation via G-protein coupled receptor kinases (GRKs)2, and may, in turn, be controlled by the mTOR pathway, that indeed plays a pivotal role in oligodendrocyte maturation3. Here, we used primary OPC cultures to investigate the mechanisms underlying GPR17 down-regulation/desensitization. Their characterization is quite important, since alterations leading to prolonged GPR17 expression in OPCs may contribute to the limited remyelination observed in demyelinating diseases.
Methods and Results - To assess whether GPR17 desensitization occurs through agonist-induced receptor phosphorylation via G-protein coupled receptor kinases (GRKs), OPCs were pre-treated with GPR17 ligands for different time periods and GPR17 ability to inhibit forskolin-induced cAMP formation was measured with a cAMP assay. Through this assay, we demonstrated a loss of GPR17 responsiveness after prolonged exposure to both UDP-glucose and LTD4. Moreover, we also showed that the same agonists induce the direct physical association of GPR17 with GRK2, which in turn phosphorylates the receptor, suggesting a role for GRK2 in GPR17 regulation. Interestingly, we also demonstrated that inhibition of the mTOR pathway by rapamycin determines a significant reduction of GRK2 levels, with parallel increases in GPR17 expression and strong impairment of OPC maturation.
Conclusions - Globally, these data suggest that dysregulation of the pathways controlling GPR17 desensitization leads to aberrant GPR17 overexpression, which, in turn, may prematurely block OPC differentiation at a pre-immature stage. New pharmacological or biotechnological strategies able to re-normalize GPR17 function in demyelinating diseases will help implementing the reparative potential of the OPCs that are still present in the adult CNS.
References
[1] M. Fumagalli, S. Daniele,D. Lecca, P.R. Lee, C. Parravicini, R.D. Fields, P. Rosa, F. Antonucci, C. Verderio, M.L. Trincavelli, P. Bramanti, C. Martini, M.P. Abbracchio, Phenotypic changes, signaling pathway, and functional correlates of GPR17-expressing neural precursor cells during oligodendrocyte differentiation. J Biol Chem. 286(12):10593-604, 2011.
[2] S. Daniele, M.L. Trincavelli, P. Gabelloni, D. Lecca, P. Rosa, M.P. Abbracchio, C. Martini, Agonist-induced desensitization/resensitization of human G protein-coupled receptor 17: a functional cross-talk between purinergic and cysteinyl-leukotriene ligands. J Pharmacol Exp Ther. 338(2):559-67, 2011.
[3] W.A. Tyler, N. Gangoli, P. Gokina, H.A. Kim, M. Covey, S.W. Levison, T.L. Wood, Activation of the mammalian target of rapamycin (mTOR) is essential for oligodendrocyte differentiation. J Neurosci. 29(19):6367-78, 2009
Misdiagnosed Hypomanic Symptoms in Patients with Treatment-Resistant Major Depressive Disorder in Italy: Results from the Improve Study
No full textBackground: Undiagnosed and therefore inadequately treated hypomanic symptoms may be a leading cause of drug resistance in depression diagnosed as unipolar (major depressive disorder, MDD). The purpose of the IMPROVE study was to identify the rate of misdiagnoses in patients with treatment-resistant MDD by screening for the presence of previous hypomanic episodes, and to study the characteristics of those patients with a positive history of hypomania. Methods: Patients attending 29 psychiatric units throughout Italy with a diagnosis of MDD who were resistant to antidepressant treatment were included in this multicentre, observational single visit study. The Hypomania Checklist 32 (HCL-32) was administered to detect underlying bipolarity. Results: Among the 466 enrolled patients, 256 (57.40%) were positive at screening for a previous hypomanic episode (HCL-32 ≥12), therefore suggesting a misdiagnosis. These patients scored higher than those with a negative history in both the "active/elated hypomania" (11.27±3.11 vs 3.57±3.05; P<0.0001) and "irritable/risk-taking hypomania" (2.87±2.03 vs 2.06±1.73; P<0.001) HCL-32 sub-scales. Patients with a positive history of hypomania were younger, had a higher number of previous depressive episodes and a higher frequency of comorbid conditions compared to those with a negative history. Conclusions: This study suggests that screening for hypomania in MDD-resistant patients facilitates identification of a notable proportion of undiagnosed cases of bipolar spectrum disorder. Patients with a positive history of hypomania at screening had a demographic/clinical bipolar-like profile that included young age, higher number of previous depressive episodes and higher frequency of comorbid conditions. They also had both higher active and irritable hypomania symptom scores
New Fossil Vertebrate remains from San Giovanni di Sinis (Late Pleistocene, Sardinia): the last Mauremys (Reptilia, Testudines) in the Central Mediterranean. Rivista Italiana di Paleontologia e Stratigrafia
No full textNew fossil vertebrates from the most representative Upper Pleistocene section (Tyrrhenian, MIS 5e) of the outcrop of San Giovanni di Sinis (Oristano, Sardinia) are here reported and described. The fossils, although scarce and fragmentary, document the occurrence of a terrapin (Mauremys sp.) and the endemic Sardinian deer (Praemegaceros cazioti). Significant is the occurrence of the terrapin because it is the youngest representative of the genus in the central Mediterranean area where it is extinct at present. The Late Pleistocene extinction of Mauremys in Italy follows the same pattern of other Mediterranean reptiles, in being in some cases delayed on the islands. A comparison of the modern range of Mauremys and that of the pond turtle, Emys, as well as of their past ranges as evidenced by the fossil record, might suggest that some sort of thermophily (at least during pre-hatching stages) characterized the former taxon and is responsible for its past and present distribution
[Memo from Lieutenant Colonel M. F. Hass, Civil Affairs Division, with amendments to an evacuation proposal]
No full textA memorandum sent form Lieutenant General M. F. Hass, Civil Affairs Division, which has two corrections from a an evacuation proposal originally sent on May 13, 1942. The correction changes the destination to the Merced Assembly Center.The War Relocation Authority (WRA), together with the Wartime Civil Control Administration (WCCA), the Civil Affairs Division (CAD) and the Office of the Commanding General (OFG) of the Western Defense Command (WDC) operated together to segregate and house some 110,000 men women and children from 1942 to 1945. The collection contains documents and photographs relating to the establishment and administrative workings of the (WDC), the (WRA) and the (WCCA) for the year 1942
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