Redundant domains contribute to the transcriptional activity of the thyroid transcription factor 1.

The thyroid transcription factor 1 (TTF-1) is a homeodomain-containing protein implicated in the activation of thyroid-specific gene expression. Here we report that TTF-1 is capable of activating transcription from thyroglobulin and, to a lesser extent, thyroperoxidase gene promoters in nonthyroid cells. Full transcriptional activation of the thyroglobulin promoter by TTF-1 requires the presence of at least two TTF-1 binding sites. TTF-1 activates transcription via two functionally redundant transcriptional activation domains that as suggested by competition experiments, could use a common intermediary factor

Formulation, pilot-scale preparation, physicochemical characterization and digestibility of a lentil protein-based model infant formula powder

Background: Infant formula is a human milk substitute for consumption during the first months of life. The protein component of such products is generally of dairy origin. Alternative sources of protein, such as those of plant origin, are of interest due to dairy allergies, intolerances, and ethical and environmental considerations. Lentils have high levels of protein (20–30%) with a good amino acid profile and functional properties. In this study, a model lentil protein-based formula (LF), in powder format, was produced and compared to two commercial plant-based infant formulae (i.e., soy; SF and rice; RF) in terms of physicochemical properties and digestibility. Results: The macronutrient composition was similar between all the samples; however, RF and SF had larger volume-weighted mean particle diameters (D[4,3] of 121–134 ∼m) than LF (31.9 ∼m), which was confirmed using scanning electron and confocal laser microscopy. The larger particle sizes of the commercial powders were attributed to their agglomeration during the drying process. Regarding functional properties, the LF showed higher D[4,3] values (17.8 ∼m) after 18 h reconstitution in water, compared with the SF and RF (5.82 and 4.55 ∼m, respectively), which could be partially attributed to hydrophobic protein–protein interactions. Regarding viscosity at 95 °C and physical stability, LF was more stable than RF. The digestibility analysis showed LF to have similar values (P <0.05) to the standard SF. Conclusion: These results demonstrated that, from the nutritional and physicochemical perspectives, lentil proteins represent a good alternative to other sources of plant proteins (e.g., soy and rice) in infant nutritional products

Hybrid photonic-bandgap accelerating cavities

In a recent investigation, we studied two-dimensional point-defected photonic bandgap cavities composed of dielectric rods arranged according to various representative periodic and aperiodic lattices, with special emphasis on possible applications to particle acceleration (along the longitudinal axis). In this paper, we present a new study aimed at highlighting the possible advantages of using hybrid structures based on the above dielectric configurations, but featuring metallic rods in the outermost regions, for the design of extremely-high quality factor, bandgap-based, accelerating resonators. In this framework, we consider diverse configurations, with different (periodic and aperiodic) lattice geometries, sizes, and dielectric/metal fractions. Moreover, we also explore possible improvements attainable via the use of superconducting plates to confine the electromagnetic field in the longitudinal direction. Results from our comparative studies, based on numerical full-wave simulations backed by experimental validations (at room and cryogenic temperatures) in the microwave region, identify the candidate parametric configurations capable of yielding the highest quality factor.Comment: 13 pages, 5 figures, 3 tables. One figure and one reference added; minor changes in the tex

CCAR2/DBC1 is required for Chk2-dependent KAP1 phosphorylation and repair of DNA damage

Cell cycle and apoptosis regulator 2 (CCAR2, formerly known as DBC1) is a nuclear protein largely involved in DNA damage response, apoptosis, metabolism, chromatin structure and transcription regulation. Upon DNA lesions, CCAR2 is phosphorylated by the apical kinases ATM/ATR and this phosphorylation enhances CCAR2 binding to SIRT1, leading to SIRT1 inhibition, p53 acetylation and p53-dependent apoptosis. Recently, we found that also the checkpoint kinase Chk2 and the proteasome activator REG\u3b3 are required for efficient CCAR2-mediated inhibition of SIRT1 and induction of p53-dependent apoptosis. Here, we report that CCAR2 is required for the repair of heterochromatic DNA lesions, as cells knock-out for CCAR2 retain, at late time-points after genotoxic treatment, abnormal levels of DNA damage-associated nuclear foci, whose timely resolution is reinstated by HP1\u3b2 depletion. Conversely, repair of DNA damages in euchromatin are not affected by CCAR2 absence. We also report that the impairment in heterochromatic DNA repair is caused by defective Chk2 activation, detectable in CCAR2 ablated cells, which finally impacts on the phosphorylation of the Chk2 substrate KAP1 that is required for the induction of heterochromatin relaxation and DNA repair. These studies further extend and confirm the role of CCAR2 in the DNA damage response and DNA repair and illustrate a new mechanism of Chk2 activity regulation. Moreover, the involvement of CCAR2 in the repair of heterochromatic DNA breaks suggests a new role for this protein in the maintenance of chromosomal stability, which is necessary to prevent cancer formation

Evaluating online games/activities by a group of elderly in a robotic experience aimed at supporting their independent living = Valutazione di giochi/attività online da parte di un gruppo di anziani, in un progetto di robotica a supporto del loro vivere indipendente

Le Tecnologie dell\u2019Informazione e della Comunicazione (TIC), in particolare robotica e domotica, si stanno progressivamente diffondendo nella societ\ue0 contemporanea e il loro utilizzo sta aumentando anche in ambito geriatrico. Anche se lo sviluppo di tecnologie dedicate agli anziani \ue8 principalmente finalizzato all\u2019assistenza e al monitoraggio della loro salute, le TIC possono anche favorire l\u2019apprendimento continuo e nuove forme di socializzazione. Il presente contributo espone i risultati di un\u2019indagine esplorativa basata su questionari, condotta con un campione persone di anziane, con familiarit\ue0 con le tecnologie, per raccogliere la percezione di usabilit\ue0 e il gradimento di alcuni giochi/attivit\ue0 online, analizzando il potenziale percepito di questi dispositivi per la socializzazione.Information and Communication Technologies (ICT), particularly robotics and domotics, are progressively spreading in the contemporary society and their use is increasing in the field of geriatrics too. Even if the implementation of new technologies dedicated to older people is mainly aimed at caring for them and monitor their health, ICT can also sustain continuing learning and develop new practices of socialization. This paper reports the results of an explorative questionnaire survey conducted with a sample of older people who had some familiarity with technologies. Our aim was to investigate their perception about usability and their enjoyment of some online digital games/activities, analyzing the perceived potentialities of those devices for elders\u2019 socialization

Coupling Impedance of the CERN SPS beam position monitors

A detailed knowledge of the beam coupling impedance of the CERN Super Proton Synchrotron (SPS) is required in order to operate this machine with a higher intensity for the foreseen Large Hadron Collider (LHC) luminosity upgrade. A large number of Beam Position Monitors (BPMs) is currently installed in the SPS, and this is why their contribution to the SPS impedance has to be assessed. This paper focuses on electromagnetic (EM) simulations and bench measurements of the longitudinal and transverse impedance generated by the horizontal and vertical BPMs installed in the SPS machine

SILAC-based phosphoproteomics reveals an inhibitory role of KSR1 in p53 transcriptional activity via modulation of DBC1

BACKGROUND We have previously identified kinase suppressor of ras-1 (KSR1) as a potential regulatory gene in breast cancer. KSR1, originally described as a novel protein kinase, has a role in activation of mitogen-activated protein kinases. Emerging evidence has shown that KSR1 may have dual functions as an active kinase as well as a scaffold facilitating multiprotein complex assembly. Although efforts have been made to study the role of KSR1 in certain tumour types, its involvement in breast cancer remains unknown. METHODS A quantitative mass spectrometry analysis using stable isotope labelling of amino acids in cell culture (SILAC) was implemented to identify KSR1-regulated phosphoproteins in breast cancer. In vitro luciferase assays, co-immunoprecipitation as well as western blotting experiments were performed to further study the function of KSR1 in breast cancer. RESULTS Of significance, proteomic analysis reveals that KSR1 overexpression decreases deleted in breast cancer-1 (DBC1) phosphorylation. Furthermore, we show that KSR1 decreases the transcriptional activity of p53 by reducing the phosphorylation of DBC1, which leads to a reduced interaction of DBC1 with sirtuin-1 (SIRT1); this in turn enables SIRT1 to deacetylate p53. CONCLUSION Our findings integrate KSR1 into a network involving DBC1 and SIRT1, which results in the regulation of p53 acetylation and its transcriptional activity

Chk2 and REGγ-dependent DBC1 regulation in DNA damage induced apoptosis

Human DBC1 (Deleted in Breast Cancer 1; KIAA1967; CCAR2) is a protein implicated in the regulation of apoptosis, transcription and histone modifications. Upon DNA damage, DBC1 is phosphorylated by ATM/ATR on Thr454 and this modification increases its inhibitory interaction with SIRT1, leading to p53 acetylation and p53-dependent apoptosis. Here, we report that the inhibition of SIRT1 by DBC1 in the DNA damage response (DDR) also depends on Chk2, the transducer kinase that is activated by ATM upon DNA lesions and contributes to the spreading of DNA damage signal. Indeed we found that inactivation of Chk2 reduces DBC1-SIRT1 binding, thus preventing p53 acetylation and DBC1-induced apoptosis. These events are mediated by Chk2 phosphorylation of the 11S proteasome activator REG\u3b3 on Ser247, which increases REG\u3b3-DBC1 interaction and SIRT1 inhibition. Overall our results clarify the mechanisms underlying the DBC1-dependent SIRT1 inhibition and link, for the first time, Chk2 and REG\u3b3 to the ATM-DBC1-SIRT1 axis

Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth

: Reprogramming of amino acid metabolism, sustained by oncogenic signaling, is crucial for cancer cell survival under nutrient limitation. Here we discovered that missense mutant p53 oncoproteins stimulate de novo serine/glycine synthesis and essential amino acids intake, promoting breast cancer growth. Mechanistically, mutant p53, unlike the wild-type counterpart, induces the expression of serine-synthesis-pathway enzymes and L-type amino acid transporter 1 (LAT1)/CD98 heavy chain heterodimer. This effect is exacerbated by amino acid shortage, representing a mutant p53-dependent metabolic adaptive response. When cells suffer amino acids scarcity, mutant p53 protein is stabilized and induces metabolic alterations and an amino acid transcriptional program that sustain cancer cell proliferation. In patient-derived tumor organoids, pharmacological targeting of either serine-synthesis-pathway and LAT1-mediated transport synergizes with amino acid shortage in blunting mutant p53-dependent growth. These findings reveal vulnerabilities potentially exploitable for tackling breast tumors bearing missense TP53 mutations