34 research outputs found
A transcriptomic study of Williams-Beuren syndrome associated genes in mouse embryonic stem cells
No full textWilliams-Beuren syndrome (WBS) is a relatively rare disease caused by the deletion of 1.5 to 1.8 Mb on chromosome 7 which contains approximately 28 genes. This multisystem disorder is mainly characterized by supravalvular aortic stenosis, mental retardation, and distinctive facial features. We generated mouse embryonic stem (ES) cells clones expressing each of the 4 human WBS genes (WBSCR1, GTF2I, GTF2IRD1 and GTF2IRD2) found in the specific delated region 7q11.23 causative of the WBS. We generated at least three stable clones for each gene with stable integration in the ROSA26 locus of a tetracycline-inducible upstream of the coding sequence of the genet tagged with a 3xFLAG epitope. Three clones for each gene were transcriptionally profiled in inducing versus non-inducing conditions for a total of 24 profiles. This small collection of human WBS-ES cell clones represents a resource to facilitate the study of the function of these genes during differentiation
Positivity conditions for generalized Schwarzschild space-times
No full textWe analyze the impact of positivity conditions on static spherically symmetric deformations of the Schwarzschild space-time. The metric is taken to satisfy, at least asymptotically, the Einstein equation in the presence of a nontrivial stress-energy tensor, on which we impose various physicality conditions. We systematically study and compare the impact of these conditions on the space-time deformations. The universal nature of our findings applies to both classical and quantum metric deformations with and without event horizons. We further discuss minimal realizations of the asymptotic stress energy tensor in terms of physical fields. Finally, we illustrate our results by discussing concrete models of quantum black holes
Structural cerebellar correlates of cognitive functions in spinocerebellar Ataxia type 2
No full textSpinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease involving the cerebellum and characterized by a typical motor syndrome. In addition, the presence of cognitive impairment is now widely acknowledged as a feature of SCA2. Given the extensive connections between the cerebellum and associative cerebral areas, it is reasonable to hypothesize that cerebellar neurodegeneration associated with SCA2 may impact on the cerebellar modulation of the cerebral cortex, thus resulting in functional impairment.
The aim of the present study was to investigate and quantitatively map the pattern of cerebellar gray matter (GM) atrophy due to SCA2 neurodegeneration and to correlate that with patients’ cognitive performances.
Cerebellar GM maps were extracted and compared between SCA2 patients (n=9) and controls (n=33) by using voxel-based morphometry. Furthermore, the relationship between cerebellar GM atrophy and neuropsychological scores of the patients was assessed. Specific cerebellar GM regions were found to be affected in patients. Additionally, GM loss in cognitive posterior lobules (VI, Crus I, Crus II, VIIB, IX) correlated with visuospatial, verbal memory and executive tasks, while additional correlations with motor anterior (V) and posterior (VIIIA, VIIIB) lobules were found for the tasks engaging motor and planning components.
Our results provide evidence that the SCA2 neurodegenerative process affects the cerebellar cortex and that MRI indices of atrophy in different cerebellar subregions may account for the specificity of cognitive symptomatology observed in patients, as result of a cerebello-cerebral dysregulation
New physics pathways from B processes
No full textWe re-consider recent measures of RK and RKjavax.xml.bind.JAXBElement@26c6f3c, now compatible with the Standard Model expectations, as well as the results for the process BR(Bs→μ+μ−) alongside earlier determinations of RDjavax.xml.bind.JAXBElement@5a764aa4 and BR(Bc→τν). We provide analytic constraints on the associated Wilson coefficients in both the b→s and the b→c sectors. These allow us to estimate the scale of potential New Physics for generic extensions of the Standard Model. We then use the results to constrain the leptoquark landscape
The cerebellar topography of attention sub-components in spinocerebellar ataxia type 2
No full textSpinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease characterized by a progressive cerebellar syndrome and multiple-domain cognitive impairments. The cerebellum is known to contribute to distinct functional networks related to higher-level functions. The aims of the present study were to investigate the different sub-components of attention and to analyse possible correlations between attention deficits and specific cerebellar regions in SCA2 patients.
To this purpose, 11 SCA2 patients underwent an exhaustive attention battery that evaluated several attention sub-components. The SCA2 group performed below the normal range in tasks assessing selective attention, divided attention, and sustained attention, obtaining negative Z-scores. These results were confirmed by non-parametric Mann-Whitney U tests that showed significant differences between SCA2 and control subjects in the same sub-components of the attention battery, allowing us to speculate on cerebellar involvement when a high cognitive demand is required (i.e., multisensory integration, sequencing, prediction of events, and inhibition of inappropriate response behaviours).
The voxel-based morphometry analysis showed a pattern of significantly reduced grey matter volume in specific cerebellar lobules. In particular, the SCA2 patients showed significant grey matter loss in bilateral regions of the anterior cerebellar hemisphere (I-V) and in the posterior lobe (VI-IX) and posterior vermis (VI-IX).
Statistical analysis found significant correlations between grey matter reductions in the VIIb/VIIIa cerebellar lobules and impairments in Sustained and Divided Attention tasks and between grey matter reduction in the vermal VI lobule and impairment in the Go/NoGo task.
For the first time, the study demonstrated the involvement of specific cerebellar lobules in different sub-components of the attention domain, giving further support to the inclusion of the cerebellum within the attention network
Reverse engineering a mouse embryonic stem cell-specific transcriptional network reveals a new modulator of neuronal differentiation
No full textGene expression profiles can be used to infer previously unknown transcriptional regulatory interaction among thousands of genes, via systems biology ‘reverse engineering’ approaches. We ‘reverse engineered’ an embryonic stem (ES)-specific transcriptional network from 171 gene expression profiles, measured in ES cells, to identify master regulators of gene expression (‘hubs’). We discovered that E130012A19Rik (E13), highly expressed in mouse ES cells as compared with differentiated cells, was a central ‘hub’ of the network. We demonstrated that E13 is a protein-coding gene implicated in regulating the commitment towards the different neuronal subtypes and glia cells. The overexpression and knock-down of E13 in ES cell lines, undergoing differentiation into neurons and glia cells, caused a strong up-regulation of the glutamatergic neurons marker Vglut2 and a strong down-regulation of the GABAergic neurons marker GAD65 and of the radial glia marker Blbp. We confirmed E13 expression in the cerebral cortex of adult mice and during development. By immuno-based affinity purification, we characterized protein partners of E13, involved in the Polycomb complex. Our results suggest a role of E13 in
regulating the division between glutamatergic projection neurons and GABAergic interneurons and glia cells possibly by epigenetic-mediated transcriptional regulation
Adaptive modification of the cat’s vestibulospinal reflex during sustained and combined roll tilt of the whole animal and forepaw rotation: cerebellar mechanisms.
No full textAbstract—In decerebrate cats, the electromyogram (EMG)
activity of the forelimb extensor triceps brachii (TB) increases
during side-down roll tilt of the whole animal (vestibulospinal
reflex, VSR) at about 0.15 Hz. (10°), while decreases
during side up tilt. On the other hand, the TB activity
increases during dorsal flexion of the ipsilateral forepaw
(0.15 Hz, 5°–10°), but decreases during ventral flexion. In six
experiments, these stimuli were synergistically associated
(side-down tilt coincided with dorsal flexion of the forepaw),
so that the EMG modulation of the TB activity was greater
than that induced by the individual stimuli. During a 3-h
period of this sustained stimulation, the amplitude of the pure
VSR progressively increased to reach the maximum value at
the end of the third hour and persisted unmodified during the
post-adaptation period (1 h). In three experiments, animal tilt
and forepaw rotation were antagonistically associated (sidedown tilt coincided with ventral flexion of the forepaw). In these instances the VSR gain remained on the average stable, but, at the end of the 3-h period of combined stimulation, a proportion of TB responses to animal tilt howed a phase reversal. In a digitigrade animal like the cat, a dorsal flexion of the wrist is associated with a decrease in limb length and would occur when the extensor tone is not appropriate to support body weight; we propose, therefore, that somatosensory volleys elicited by wrist rotation modify the gain of VSR so as to maintain postural stability. Inactivation, on the side of muscle recording, of the corticocerebellar region which projects to the lateral vestibular nucleus of Deiters, by local microinjection of the GABA-A agonist muscimol (0.5 l at 16 g/l), decreased the already adapted gain of VSR. In conclusion, the results of this study suggest that somatosensory reafferent inputs to the cerebellar vermis are used to plastically modify the gain of VSR, when external forces produce changes in the final posture of the foot during animal tilt
Reverse engineering a mouse embryonic stem cell-specific transcriptional network reveals a new modulator of neuronal differentiation
No full textGene expression profiles can be used to infer previously unknown transcriptional regulatory interaction among thousands of genes, via systems biology 'reverse engineering' approaches. We 'reverse engineered' an embryonic stem (ES)-specific transcriptional network from 171 gene expression profiles, measured in ES cells, to identify master regulators of gene expression ('hubs'). We discovered that E130012A19Rik (E13), highly expressed in mouse ES cells as compared with differentiated cells, was a central 'hub' of the network. We demonstrated that E13 is a protein-coding gene implicated in regulating the commitment towards the different neuronal subtypes and glia cells. The overexpression and knock-down of E13 in ES cell lines, undergoing differentiation into neurons and glia cells, caused a strong up-regulation of the glutamatergic neurons marker Vglut2 and a strong down-regulation of the GABAergic neurons marker GAD65 and of the radial glia marker Blbp. We confirmed E13 expression in the cerebral cortex of adult mice and during development. By immuno-based affinity purification, we characterized protein partners of E13, involved in the Polycomb complex. Our results suggest a role of E13 in regulating the division between glutamatergic projection neurons and GABAergic interneurons and glia cells possibly by epigenetic-mediated transcriptional regulation
Reverse engineering a mouse embryonic stem cell-specific transcriptional network reveals a new modulator of neuronal differentiation
No full textGene expression profiles can be used to infer previously unknown transcriptional regulatory interaction among thousands of genes, via systems biology 'reverse engineering' approaches. We 'reverse engineered' an embryonic stem (ES)-specific transcriptional network from 171 gene expression profiles, measured in ES cells, to identify master regulators of gene expression ('hubs'). We discovered that E130012A19Rik (E13), highly expressed in mouse ES cells as compared with differentiated cells, was a central 'hub' of the network. We demonstrated that E13 is a protein-coding gene implicated in regulating the commitment towards the different neuronal subtypes and glia cells. The overexpression and knock-down of E13 in ES cell lines, undergoing differentiation into neurons and glia cells, caused a strong up-regulation of the glutamatergic neurons marker Vglut2 and a strong down-regulation of the GABAergic neurons marker GAD65 and of the radial glia marker Blbp. We confirmed E13 expression in the cerebral cortex of adult mice and during development. By immuno-based affinity purification, we characterized protein partners of E13, involved in the Polycomb complex. Our results suggest a role of E13 in regulating the division between glutamatergic projection neurons and GABAergic interneurons and glia cells possibly by epigenetic-mediated transcriptional regulation
