2,937 research outputs found
The Influence of Technology on Long-Term Care Systems
New technologies may have a beneficial impact on long-term care (LTC) systems by improving
the quality, effectiveness and efficiency of LTC provision, and even by decreasing the need for LTC in the
first place. Given the great uncertainty about the diffusion and implementation of available technology, there
is little point in trying to make quantitative forecasts about the impact of technology. A more useful approach
is to study the mechanisms through which technology can have an impact on LTC. This is the subject of
Work Package 4 of the ANCIEN project. Both generally and via a number of case studies, it develops a
framework to analyse the impact of technology on LTC. The functioning of this framework is illustrated by
considering a number of specific long-term conditions, such as dementia, obesity and diabetes
Sempervirine inhibits RNA polymerase I transcription independently from p53 in tumor cells
In the search of small molecules that can target MDM2/p53 pathway in testicular germ cell tumors (TGCTs), we identified sempervirine (2,3,4,13-tetrahydro-1H-benz[g]indolo[2,3-a]quinolizin-6-ium), an alkaloid of Gelsemium sempervirens, that has been previously proposed as an inhibitor of MDM2 that targets p53-wildtype (wt) tumor cells. We found that sempervirine not only affects cell growth of p53-wt cancer cells, but it is also active in p53-mutated and p53-null cells by triggering p53-dependent and independent pathways without affecting non-transformed cells. To understand which mechanism/s could be activated both in p53-wt and -null cells, we found that sempervirine induced nucleolar remodeling and nucleolar stress by reducing protein stability of RPA194, the catalytic subunit of RNA polymerase I, that led to rRNA synthesis inhibition and to MDM2 block. As shown for other cancer cell models, MDM2 inhibition by nucleolar stress downregulated E2F1 protein levels both in p53-wt and p53-null TGCT cells with the concomitant upregulation of unphosphorylated pRb. Finally, we show that sempervirine is able to enter the nucleus and accumulates within the nucleolus where it binds rRNA without causing DNA damage. Our results identify semperivirine as a novel rRNA synthesis inhibitor and indicate this drug as a non-genotoxic anticancer small molecule
Osteogenic differentiation of mesenchymal stem cells from dental bud: Role of integrins and cadherins
Several studies have reported the beneficial effects of mesenchymal stem cells (MSCs) in tissue repair and regeneration. New sources of stem cells in adult organisms are continuously emerging; dental tissues have been identified as a source of postnatal MSCs. Dental bud is the immature precursor of the tooth, is easy to access and we show in this study that it can yield a high number of cells with â„ 95% expression of mesenchymal stemness makers and osteogenic capacity. Thus, these cells can be defined as Dental Bud Stem Cells (DBSCs) representing a promising source for bone regeneration of stomatognathic as well as other systems. Cell interactions with the extracellular matrix (ECM) and neighboring cells are critical for tissue morphogenesis and architecture; such interactions are mediated by integrins and cadherins respectively. We characterized DBSCs for the expression of these adhesion receptors and examined their pattern during osteogenic differentiation. Our data indicate that N-cadherin and cadherin-11 were expressed in undifferentiated DBSCs and their expression underwent changes during the osteogenic process (decreasing and increasing respectively), while expression of E-cadherin and P-cadherin was very low in DBSCs and did not change during the differentiation steps. Such expression pattern reflected the mesenchymal origin of DBSCs and confirmed their osteoblast-like features. On the other hand, osteogenic stimulation induced the upregulation of single subunits, αV, ÎČ3, α5, and the formation of integrin receptors α5ÎČ1 and αVÎČ3. DBSCs differentiation toward osteoblastic lineage was enhanced when cells were grown on fibronectin (FN), vitronectin (VTN), and osteopontin (OPN), ECM glycoproteins which contain an integrin-binding sequence, the RGD motif. In addition we established that integrin αVÎČ3 plays a crucial role during the commitment of MSCs to osteoblast lineage, whereas integrin α5ÎČ1 seems to be dispensable. These data suggest that functionalization of biomaterials with such ECM proteins would improve bone reconstruction therapies starting from dental stem cells
Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection
Hepatitis C virus infection (HCV) represents a unique model to characterize, from early to late stages of infection, the T cell differentiation process leading to exhaustion of human CD8+ T cells. Here we show that in early HCV infection, exhaustion-committed virus-specific CD8+ T cells display a marked upregulation of transcription associated with impaired glycolytic and mitochondrial functions, that are linked to enhanced ataxia-telangiectasia mutated (ATM) and p53 signaling. After evolution to chronic infection, exhaustion of HCV-specific T cell responses is instead characterized by a broad gene downregulation associated with a wide metabolic and anti-viral function impairment, which can be rescued by histone methyltransferase inhibitors. These results have implications not only for treatment of HCV-positive patients not responding to last-generation antivirals, but also for other chronic pathologies associated with T cell dysfunction, including cancer
Agenesis of the putamen and globus pallidus caused by recessive mutations in the homeobox gene GSX2
Basal ganglia are subcortical grey nuclei that play essential roles in controlling voluntary movements, cognition and emotion. While basal ganglia dysfunction is observed in many neurodegenerative or metabolic disorders, congenital malformations are rare. In particular, dysplastic basal ganglia are part of the malformative spectrum of tubulinopathies and X-linked lissencephaly with abnormal genitalia, but neurodevelopmental syndromes characterized by basal ganglia agenesis are not known to date. We ascertained two unrelated children (both female) presenting with spastic tetraparesis, severe generalized dystonia and intellectual impairment, sharing a unique brain malformation characterized by agenesis of putamina and globi pallidi, dysgenesis of the caudate nuclei, olfactory bulbs hypoplasia, and anomaly of the diencephalic-mesencephalic junction with abnormal corticospinal tract course. Whole-exome sequencing identified two novel homozygous variants, c.26C>A; p.(S9*) and c.752A>G; p.(Q251R) in the GSX2 gene, a member of the family of homeobox transcription factors, which are key regulators of embryonic development. GSX2 is highly expressed in neural progenitors of the lateral and median ganglionic eminences, two protrusions of the ventral telencephalon from which the basal ganglia and olfactory tubercles originate, where it promotes neurogenesis while negatively regulating oligodendrogenesis. The truncating variant resulted in complete loss of protein expression, while the missense variant affected a highly conserved residue of the homeobox domain, was consistently predicted as pathogenic by bioinformatic tools, resulted in reduced protein expression and caused impaired structural stability of the homeobox domain and weaker interaction with DNA according to molecular dynamic simulations. Moreover, the nuclear localization of the mutant protein in transfected cells was significantly reduced compared to the wild-type protein. Expression studies on both patients' fibroblasts demonstrated reduced expression of GSX2 itself, likely due to altered transcriptional self-regulation, as well as significant expression changes of related genes such as ASCL1 and PAX6. Whole transcriptome analysis revealed a global deregulation in genes implicated in apoptosis and immunity, two broad pathways known to be involved in brain development. This is the first report of the clinical phenotype and molecular basis associated to basal ganglia agenesis in humans
Tricritical directed percolation
We consider a modification of the contact process incorporating higher-order
reaction terms. The original contact process exhibits a non-equilibrium phase
transition belonging to the universality class of directed percolation. The
incorporated higher-order reaction terms lead to a non-trivial phase diagram.
In particular, a line of continuous phase transitions is separated by a
tricritical point from a line of discontinuous phase transitions. The
corresponding tricritical scaling behavior is analyzed in detail, i.e., we
determine the critical exponents, various universal scaling functions as well
as universal amplitude combinations
Colour reconnection in e+e- -> W+W- at sqrt(s) = 189 - 209 GeV
The effects of the final state interaction phenomenon known as colour
reconnection are investigated at centre-of-mass energies in the range sqrt(s) ~
189-209 GeV using the OPAL detector at LEP. Colour reconnection is expected to
affect observables based on charged particles in hadronic decays of W+W-.
Measurements of inclusive charged particle multiplicities, and of their angular
distribution with respect to the four jet axes of the events, are used to test
models of colour reconnection. The data are found to exclude extreme scenarios
of the Sjostrand-Khoze Type I (SK-I) model and are compatible with other
models, both with and without colour reconnection effects. In the context of
the SK-I model, the best agreement with data is obtained for a reconnection
probability of 37%. Assuming no colour reconnection, the charged particle
multiplicity in hadronically decaying W bosons is measured to be (nqqch) =
19.38+-0.05(stat.)+-0.08 (syst.).Comment: 30 pages, 9 figures, Submitted to Euro. Phys. J.
Determination of alpha_s using Jet Rates at LEP with the OPAL detector
Hadronic events produced in e+e- collisions by the LEP collider and recorded
by the OPAL detector were used to form distributions based on the number of
reconstructed jets. The data were collected between 1995 and 2000 and
correspond to energies of 91 GeV, 130-136 GeV and 161-209 GeV. The jet rates
were determined using four different jet-finding algorithms (Cone, JADE, Durham
and Cambridge). The differential two-jet rate and the average jet rate with the
Durham and Cambridge algorithms were used to measure alpha(s) in the LEP energy
range by fitting an expression in which order alpah_2s calculations were
matched to a NLLA prediction and fitted to the data. Combining the measurements
at different centre-of-mass energies, the value of alpha_s (Mz) was determined
to be
alpha(s)(Mz)=0.1177+-0.0006(stat.)+-0.0012$(expt.)+-0.0010(had.)+-0.0032(theo.)
\.Comment: 40 pages, 17 figures, Submitted to Euro. Phys. J.
Ultrafast relaxation of photoexcited carriers in semiconductor quantum wires: A Monte Carlo approach
A detailed analysis of the cooling and thermalization process for photogenerated carriers in semiconductor quantum wires is presented. The energy relaxation of the nonequilibrium carrier distribution is investigated for the âârealistic'' case of a rectangular multisubband quantum-wire structure. By means of a direct ensemble Monte Carlo simulation of both the carrier and the phonon dynamics, all the nonlinear phenomena relevant for the relaxation process, such as carrier-carrier interaction, hot-phonon effects, and degeneracy, are investigated. The results of these simulated experiments show a significant reduction of the carrier-relaxation process compared to the bulk case, which is mainly due to the reduced efficiency of carrier-carrier scattering; on the contrary, the role of hot-phonon effects and degeneracy seems to be not so different from that played in bulk semiconductors
Measurements of Flavour Dependent Fragmentation Functions in Z^0 -> qq(bar) Events
Fragmentation functions for charged particles in Z -> qq(bar) events have
been measured for bottom (b), charm (c) and light (uds) quarks as well as for
all flavours together. The results are based on data recorded between 1990 and
1995 using the OPAL detector at LEP. Event samples with different flavour
compositions were formed using reconstructed D* mesons and secondary vertices.
The \xi_p = ln(1/x_E) distributions and the position of their maxima \xi_max
are also presented separately for uds, c and b quark events. The fragmentation
function for b quarks is significantly softer than for uds quarks.Comment: 29 pages, LaTeX, 5 eps figures (and colour figs) included, submitted
to Eur. Phys. J.
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