Search

Metal-poor stars formed from a gas enriched by the ejecta of the explosion of one/few generations of first massive stars. With the Pristine photometry combined with the Gaia data, we selected a sample of bright giants metal-poor candidates to be observed at high resolution. Of the 43 stars observed, 36 were confirmed to be metal-poor, supporting the high success-rate of Pristine in selecting metal-poor stars. We centred the investigation on Cu and Zn, which are elements usually neglected, also because they are the ‘killing elements’ for identifying the Pair Instability Supernovae (PISN) descendants, the explosion of very massive first stars. We derived detailed chemical abundances of 22 species of 18 elements for 36 giant stars. The study of the kinematics of the stars in the sample revealed the presence of metal-poor stars on disc-like orbits (17 per cent of the sample) and even on thin disc orbits (8 per cent of the sample). Four stars are members of the Gaia–Sausage–Enceladus, one star is also likely a member of it. Three stars in the sample (TYC 1118−595−1, TYC 2207−992−1, and TYC 1194−507−1) show a chemical pattern compatible with the one theoretically derived for the PISN descendants, i.e. stars formed out from a gaseous environment enriched by PISN (>50 per cent level) and subsequent generations of normal stars evolving as core-collapse SNe.

The very massive first stars ($m>100\rm M_{\odot}$) were fundamental to the early phases of reionization, metal enrichment, and super-massive black hole formation. Among them, those with $140\leq\rm m/\rm M_{\odot}\leq260$ are predicted to evolve as Pair Instability Supernovae (PISN) leaving a unique chemical signature in their chemical yields. Still, despite long searches, the stellar descendants of PISN remain elusive. Here we propose a new methodology, the PISN-explorer, to identify candidates for stars with a dominant PISN enrichment. The PISN-explorer is based on a combination of physically driven models, and the FERRE code; and applied to data from large spectroscopic surveys (APOGEE, GALAH, GES, MINCE, and the JINA database). We looked into more than 1.4 million objects and built a catalogue with 166 candidates of PISN descendants. One of which, 2M13593064+3241036, was observed with UVES at VLT and full chemical signature was derived, including the killing elements, Cu and Zn. We find that our proposed methodology is efficient in selecting PISN candidates from both the Milky Way and dwarf satellite galaxies such as Sextans or Draco. Further high-resolution observations are highly required to confirm our best selected candidates, therefore allowing us to probe the existence and properties of the very massive First Stars., 13 pages, 7 figures Accepted for publication in MNRAS

The chemical fingerprints of the first stars are retained within the photospheres of ancient unevolved metal-poor stars. A significant fraction of these stellar fossils is represented by stars known as Carbon-Enhanced Metal-Poor (CEMP), $\mathrm{[C/Fe]} \gt +0.7$ and $\mathrm{[Fe/H]} \lt -2$, which are likely imprinted by low-energy primordial supernovae. These CEMP stars are largely observed in the Galactic halo and ultrafaint dwarf galaxies, with values reaching $\rm [C/Fe]=+4.5$. The Galactic bulge is predicted to host the oldest stars, but it shows a striking dearth of CEMP stars with $\rm [C/Fe]\gtrsim +2.0$. Here, we explore the possible reasons for this anomaly by performing a statistical analysis of the observations of metal-poor stars in combination with the predictions of Lambda cold dark matter models. We suggest that the dearth of CEMP stars with high $\mathrm{[C/Fe]}$ is not due to the low statistics of observed metal-poor stars but is the result of the different formation process of the bulge. N-body simulations show that the first star-forming haloes which end up in the bulge are characterized by the highest star formation rates. These rates enable the formation of rare massive first stars exploding as pair-instability supernovae (PISNe), which wash out the signature of primordial faint supernovae. We demonstrate that the mean $\mathrm{[C/Fe]}$ of first stars polluted environments decreases with the increasing contribution of PISNe. We conclude that the dearth of CEMP stars in the Galactic bulge indirectly probes the existence of elusive PISNe, and propose a novel method which exploits this lack to constrain the mass distribution of the first stars.

We present a new homogeneous survey of VLT/FLAMES LR8 line-of-sight radial velocities (vlos) for 1604 resolved red giant branch stars in the Sculptor dwarf spheroidal galaxy. In addition, we provide reliable Ca II triplet metallicities, [Fe/H], for 1339 of these stars. From this combination of new observations (2257 individual spectra) with ESO archival data (2389 spectra), we obtain the largest and most complete sample of vlos and [Fe/H] measurements for individual stars in any dwarf galaxy. Our sample includes VLT/FLAMES LR8 spectra for 55% of the red giant branch stars at G $70$% of the brightest stars, G $, A&A, in press

Background COVID-19 infection can lead to a constellation of long-lasting post-infectious sequelae, including myocardial dysfunction, whose outcome is strongly affected by a fine-tuned balance between pro- and anti-inflammatory systemic immune responses. Plasma cytokines are key mediators of this immunological balance. In this preliminary study we evaluated the cross-sectional association between the circulating levels of the main pro- and anti-inflammatory cytokines and cardiac magnetic resonance (CMR) abnormalities. Methods 71 subjects (59% female, mean age 52±14) with previous diagnosis of COVID-19 infection were enrolled at our institution for MULTICOVID protocol, comprehensive of CMR and biomarkers assessment performed >3 months and Results After a median of 9 (IQR 6–11) months following negative swab, CMR was normal in 48 subjects, while in 23 (32%) it revealed tissue characterization abnormalities (myocardial late enhancement and/or edema). By multivariate regression analysis (adjusted for age, sex, vaccination, severity degrees of the initial COVID disease, presence of comorbidities, smoke, time interval between COVID diagnosis and CMR assessment) the cytokine ratio TNF-α/(IL-10+IL-13) was independently associated (OR=2.89, 95% CI 1.19–7.04, p=0.02) with CMR abnormalities. Interestingly, the cumulative pro-/anti-inflammatory cytokine ratio (IL-1β+TNF-α+IFN-α2+IL-6+IL-17A+IL-8)/(IL-10+IL-13) showed a positive (OR=1.70, 95% CI: 1.04–2.75) and significant (p=0.03) association with CMR imaging aspects. Also, the ratio IFN-α2/(IL-10+IL-13), although without achieving a complete statistical significance (p=0.09), was associated positively with CMR findings. Conclusions The preliminary results of this cross-sectional study suggest that the systemic inflammatory environment, long-lasting unbalanced towards a prevalent cytokine-driven pro-inflammatory condition following COVID infection, could affect the development of CMR-detectable myocardial edema and fibrosis in long-term post-COVID subjects. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Tuscany Region

We introduce SERRA, a suite of zoom-in high-resolution ($\sim 10\,\rm pc$) cosmological simulations including non-equilibrium chemistry and on-the-fly radiative transfer. The outputs are post-processed to derive galaxy UV+FIR continuum and emission line properties. Results are compared with available multi-wavelength data to constrain the physical properties (e.g., star formation rates, stellar/gas/dust mass, metallicity) of high-redshift $6 \lesssim z \lesssim 15$ galaxies. This flagship paper focuses on the $z=7.7$ sub-sample, including 202 galaxies with stellar mass $10^7 M_\odot \lesssim M_\star \lesssim 5\times 10^{10}M_\odot$, and specific star formation ranging from ${\rm sSFR} \sim 100\,{\rm Gyr}^{-1}$ in young, low-mass galaxies to $\sim 10\,{\rm Gyr}^{-1}$ for older, massive ones. At this redshift, SERRA galaxies are typically bursty, i.e. they are located above the Schmidt-Kennicutt relation by a factor $\kappa_s = 3.03^{+4.9}_{-1.8}$, consistent with recent findings for [OIII] and [CII] emitters at high-$z$. They also show relatively large ${\rm IRX} = L_{\rm FIR}/L_{\rm UV}$ values as a result of their compact/clumpy morphology effectively blocking the stellar UV luminosity. Note that this conclusion might be affected by insufficient spatial resolution at the molecular cloud level. We confirm that early galaxies lie on the standard $\rm [CII]-SFR$ relation; their observed $L_{\rm [OIII]}/L_{\rm [CII]} \simeq 1-10$ ratios can be reproduced by a part of the SERRA galaxies without the need of a top-heavy IMF and/or anomalous C/O abundances. [OI] line intensities are similar to local ones, making ALMA high-$z$ detections challenging but feasible ($\sim 6\,\rm hr$ for a SFR of $50\,M_\odot\,{\rm yr}^{-1}$)., Comment: 23 pages, 14 figures, accepted by MNRAS; part of the data used for this study is available at the website http://cosmology.sns.it/data_access.html

SMSS J160540.18$-$144323.1 is the carbon-enhanced metal-poor (CEMP) star with the lowest iron abundance ever measured, [Fe/H]=-6.2, which was first reported with the SkyMapper telescope. The carbon abundance is A(C)~6.1 in the low-C band, as the majority of the stars in this metallicity range. Yet, constraining the isotopic ratio of key species, such as carbon, sheds light on the properties and origin of these elusive stars. We performed high-resolution observations of SMSS1605$-$1443 with the ESPRESSO spectrograph to look for variations in the radial velocity ($v_{rad}$) with time. These data have been combined with older MIKE and UVES archival observations to enlarge the temporal baseline. The $^{12}$C/$^{13}$C isotopic ratio is also studied to explore the possibility of mass transfer from a binary companion. A cross-correlation function against a natural template was applied to detect $v_{rad}$ variability and a spectral synthesis technique was used to derive $^{12}$C/$^{13}$C in the stellar atmosphere. We confirm previous indications of binarity in SMSS1605$-$1443 and measured a lower limit $^{12}$C/$^{13}$C$>60$ at more than a 3$\sigma$ confidence level, proving that this system is chemically unmixed and that no mass transfer from the unseen companion has happened so far. Thus, we confirm the CEMP-no nature of SMSS1605$-$1443 and show that the pristine chemical composition of the cloud from which it formed is currently imprinted in its stellar atmosphere free of contamination., Comment: Published in A&A, 9 pages, 6 figures

The objective of this study was to evaluate possible influences of parenteral nutrition on growth and bone development in preterms and to search for markers of bone status.Metacarpus bone transmission time (mc-BTT) was performed at birth, 21 days and 36 weeks of gestational age (GA) in preterms, receiving two different nutritional regimens, together with biochemical analysis.A total of 234 patients were studied. Newborns with aggressive nutrition had significantly better growth rate and higher values of mc-BTT until discharge. Mc-BTT at day 21 correlates positively with nutritional intakes and phosphatemia; lower limb length positively correlated with mc-BTT (P0.01). Newborns with low energy intake in the first week of life (70 kcal kg(-1) per day) and low serum phosphate level (1.4 mmol l(-1)) at 21 days had lower mc-BTT at 36 weeks of GA (P0.01).Aggressive parenteral intakes in preterms improve growth and bone status in the short-medium term, suggesting that early nutrition could influence bone development.

Analysis of the bark beetle outbreak in the forest “Alta Val Parma” (Corniglio, Parma, Italy) and strategies for its regeneration. Norway spruce plantations located in the Foresta Demaniale Alta Val Parma (Corniglio, province of Parma - Italy) experienced since 2004 a massive outbreak of Norway spruce bark beetle (Ips typographus). This outbreak has been triggered by the exceptionally warm and dry summer of 2003. In the following years bark beetle attacks repeated and spread, raising concern about the future of this kind of stands. A survey program has been carried out to help local administration to chose the correct managements strategies. Monitoring of Ips typographus population, carried out between 2007 and 2013, confirmed the presence of two generations per year, with values above the risk threshold in 2007 and just below though very high in 2011. In the affected area, six survey plots have been realized to test different management options with the aim of favoring a fast regeneration of the forest cover. The tested options showed the great difficulty in the establishment of natural generation either for the lack of mother plants in such pure stands or for competition with tall grasses. Sowing brought no significative results, while direct plantation of indigenous broadleaves was more effective, with almost half of the individuals still alive after three years. Our results confirm the great difficulty to rebuild the forest cover after strong ecological disturbances in these artificial forests. Hybrid management strategies and ad hoc silvicultural choices seem to be the only way to manage such kind of situations in a National park, where the priority is biodiversity conservation.

Background Opioid tolerance is a limiting factor in chronic pain. Delta opioid peptide (DOP)(δ) receptor antagonism has been shown to reduce tolerance. Here, the common clinical mu opioid peptide (MOP)(µ) receptor agonist fentanyl has been linked to the DOP antagonist Dmt-Tic (2′,6′-dimethyl-L-tyrosyl-1,2,3,4-tetrahydrisoquinoline-3-carboxylic acid) to create new bivalent compounds. Methods Binding affinities of bivalents(#9, #10, #11, #12 and #13) were measured in Chinese hamster ovary (CHO) cells expressing recombinant human MOP, DOP, Kappa opioid peptide (KOP)(κ) and nociceptin/orphanin FQ opioid peptide (NOP) receptors. Functional studies, measuring GTPγ[35S] or β-arrestin recruitment, were performed in membranes or whole cells respectively expressing MOP and DOP. Results The new bivalents bound to MOP (pKi : #9:7.31; #10:7.58; #11:7.91; #12:7.94; #13:8.03) and DOP (#9:8.03; #10:8.16; #11:8.17; #12:9.67; #13:9.71). In GTPγ[35S] functional assays, compounds #9(pEC50:6.74; intrinsic activity:0.05) #10(7.13;0.34) and #11(7.52;0.27) showed weak partial agonist activity at MOP. Compounds #12 and #13, with longer linkers, showed no functional activity at MOP. In antagonist assays at MOP, compounds #9 (pKb:6.87), #10(7.55) #11(7.81) #12(6.91) and #13(7.05) all reversed the effects of fentanyl. At DOP, all compounds showed antagonist affinity (#9:6.85; #10:8.06; #11:8.11; #12:9.42; #13:9.00), reversing the effects of DPDPE ([D-Pen2,5]enkephalin). In β-arrestin assays, compared with fentanyl (with response at maximum concentration (RMC):13.62), all compounds showed reduced ability to activate β-arrestin (#9 RMC:1.58; #10:2.72; #11:2.40; #12:1.29; #13:1.58). Compared with fentanyl, the intrinsic activity was: #9:0.12; #10:0.20; #11:0.18; #12:0.09 and #13:0.12. Conclusions The addition of a linker between fentanyl and Dmt-Tic did not alter the ability to bind to MOP and DOP, however a substantial loss in MOP functional activity was apparent. This highlights the difficulty in multifunctional opioid development.

Objectives Preclinical diagnosis of Parkinson's disease (PD) is nowadays a topic of interest as the neuropathological process could begin years before the appearance of motor symptoms. Several symptoms, among them hyposmia, could precede motor features in PD. In the preclinical phase of PD, a subclinical reduction in motor skills is highly likely. In this pilot study, we investigate a step-by-step method to achieve preclinical PD diagnosis. Material and methods We used the IOIT (Italian Olfactory Identification Test) to screen a population of healthy subjects. We identified 20 subjects with idiopathic hyposmia. Hyposmic subjects underwent an evaluation of motor skills, at baseline and after 1 year, using motion analysis sensors previously created by us. Results One subject showed significant worsening in motor measurements. In this subject, we further conducted a dopaminergic challenge test monitored with the same sensors and, finally, he underwent [123I]-FP/CIT (DaTscan) SPECT brain imaging. The results show that he is probably affected by preclinical PD. Conclusions Our pilot study suggests that the combined use of an olfactory test and motor sensors for motion analysis could be useful for a screening of healthy subjects to identify those at a high risk of developing PD.

Hematopoietic cell transplant (HCT) recipients have a substantial risk of developing secondary solid cancers (SSCs). The aim of this retrospective study was to compare the incidence of SSC in a monocentric cohort of thalassemia major (TM) patients (n=122) who received HCT versus an hematopoietic cell donor monocentric cohort (n=122) and versus a large multicenter cohort of age- and sex-matched TM patients (n=244) who received conventional therapy. With a median follow-up of 24 years, 8 transplanted patients were diagnosed with SSC at a median of 18 years after HCT and at a median age of 33 years. Three patients died of cancer progression and 5 are living after a follow-up ranging from 10 months to 16 years after SSC diagnosis. The 30-year cumulative incidence of developing SSC was 13.24%. The occurrence of solid cancers in the hematopoietic cell donor cohort was limited to only one case for a significantly lower cumulative incidence (3.23%, P=0.02) and to 3 cases in the cohort of nontransplant patients for a significantly lower cumulative incidence (1.32%, P=0.005). This study shows that the magnitude of increased risk of SST is fourfold to sixfold for patients treated with HCT as compared with hematopoietic cell donors and nontransplant patients.

Background and Purpose An innovative chemical approach, named peptide welding technology (PWT), allows the synthesis of multibranched peptides with extraordinary high yield, purity and reproducibility. With this approach, three different tetrabranched derivatives of nociceptin/orphanin FQ (N/OFQ) have been synthesized and named PWT1-N/OFQ, PWT2-N/OFQ and PWT3-N/OFQ. In the present study we investigated the in vitro and in vivo pharmacological profile of PWT N/OFQ derivatives and compared their actions with those of the naturally occurring peptide. Experimental Approach The following in vitro assays were used: receptor and [35S]-GTPγS binding, calcium mobilization in cells expressing the human N/OFQ peptide (NOP) receptor, or classical opioid receptors and chimeric G proteins, electrically stimulated mouse vas deferens bioassay. In vivo experiments were performed; locomotor activity was measured in normal mice and in animals with the NOP receptor gene knocked out [NOP(−/−)]. Key Results In vitro PWT derivatives of N/OFQ behaved as high affinity potent and rather selective full agonists at human recombinant and animal native NOP receptors. In vivo PWT derivatives mimicked the inhibitory effects exerted by the natural peptide on locomotor activity showing 40-fold higher potency and extremely longer lasting action. The effects of PWT2-N/OFQ were no longer evident in NOP(−/−) mice. Conclusions and Implications The results showed that the PWT can be successfully applied to the peptide sequence of N/OFQ to generate tetrabranched derivatives characterized by a pharmacological profile similar to the native peptide and associated with a higher potency and marked prolongation of action in vivo.

Background and Purpose Intrathecally (i.t.) administered nociceptin/orphanin FQ (N/OFQ) evokes antinociceptive effects in rodents. Recent studies in monkeys demonstrated that i.t. co-application of N/OFQ and morphine elicits synergistic antinociceptive actions suggesting mixed N/OFQ peptide (NOP) and μ opioid receptor agonists as innovative spinal analgesics. Thus, novel N/OFQ related peptides were synthesized in order to identify and pharmacologically characterize a mixed NOP/ μ opioid receptor agonist. Experimental Approach The following in vitro assays were used: calcium mobilization in cells expressing the human NOP or classical opioid receptors and chimeric G proteins, receptor and [35S]-GTPγS binding, [35S]-GTPγS binding in rat spinal cord membranes, guinea pig ileum bioassay. In vivo experiments were performed in monkeys using the tail withdrawal assay. Key Results From calcium mobilization studies [Dmt1]N/OFQ(1–13)-NH2 was selected as the most potent and least selective compound. The mixed NOP/opioid full agonist activity and high affinity of [Dmt1]N/OFQ(1–13)-NH2 was confirmed at human recombinant receptors in receptor binding, calcium mobilization and/or [35S]-GTPγS binding studies, at rat spinal cord receptors in [35S]-GTPγS binding experiments, and at guinea pig receptors inhibiting neurogenic contractions in the ileum. In vivo in the tail withdrawal assay in monkeys i.t. [Dmt1]N/OFQ(1–13)-NH2 was able to elicit robust and long-lasting antinociceptive effects. Conclusions and Implications Collectively, these results demonstrate that [Dmt1]N/OFQ(1–13)-NH2 behaves as NOP/opioid receptor universal agonist and substantiate the suggestion that such mixed ligands are worthy of development as innovative spinal analgesics.

Riassunto Obiettivi Per ancoraggio si intende resistenza a un movimento dentale indesiderato. L’obiettivo di questo studio e quello di analizzare il background biologico per un corretto controllo dell’ancoraggio e di valutare le differenti possibilita di ancoraggio a seconda del tipo di movimento da ottenere. Materiali e metodi E stata effettuata una revisione critica della letteratura con un approccio di tipo sistematico. La ricerca degli articoli scientifici e stata effettuata sul database della US National Library of Medicine tramite il servizio PubMed ( www.ncbi.nim.nih.gov/pubmed ). Le parole chiave stabilite sono state “anchorage and orthodontics”. Sono stati selezionati solamente alcuni articoli di cui e stato ricercato e valutato il testo integrale. Risultati Un buon ancoraggio dipende dall’attivita cellulare del sistema parodontale. Da un punto di vista biologico il miglior ancoraggio prevede un parodonto privo di qualsiasi cambiamento nel turn over tissutale. Questo risulta possibile se le forze che agiscono sul legamento parodontale e sull’osso circostante rimangono al di sotto della soglia che promuove il movimento dentale. Conclusioni Lo scopo della biomeccanica e quello di minimizzare gli effetti collaterali indesiderati e quello di massimizzare gli spostamenti dentali desiderati.

Objectives A case of congenital macroglossia is reported. The most important sign of macroglossia is tongue protrusion through the lips. Tongue protrusion might influence skeletal growth and can cause anterior open bite, proclination of upper and lower incisors and development of diastemas. Materials and methods A 4 year-old female patient was diagnosed with congenital macroglossia. Parents referred an abnormal tongue dimension since birth and the development of a progressive anterior open bite. The treatment of macroglossia included tongue reduction by partial glossectomy. She was seen regularly and at the age of eight years old a lingual frenectomy was performed and an orthodontic treatment was planned. Results At the end of the orthodontic treatment a Class I occlusion was obtained with correct overbite and overjet values. Conclusions Early interception of macroglossia and surgical reduction in combination with orthodontic treatment can be seen as preventive measures to avoid the tongue influence on the development of malocclusions.

Background and purpose: Neuropeptide S (NPS) is a recently identified neurotransmitter/neuromodulator able to increase arousal and wakefulness while decreasing anxiety-like behaviour. As several classical transmitters play a role in arousal and anxiety, we here investigated the possible presynaptic regulation of transmitter release by NPS. Experimental approach: Synaptosomes purified from mouse frontal cortex were prelabelled with [3H]5-hydroxytryptamine (5-HT), noradrenaline, dopamine, choline, D-aspartate or GABA and depolarized in superfusion with 12–15 mmol·L−1 KCl to evoke [3H]neurotransmitter exocytosis. NPS was added at different concentrations (0.001 to 100 nmol·L−1). Key results: NPS behaved as an extremely potent inhibitor of the evoked overflow of [3H]5-HT and [3H]noradrenaline exhibiting EC50 values in the low picomolar range. The inhibitory action of NPS on [3H]5-HT release was mimicked by [Ala2]NPS that was, however, about 100-fold less potent than the natural peptide. NPS (up to 100 nmol·L−1) was unable to affect the depolarization-evoked overflow of [3H]D-aspartate and [3H]GABA. The neuropeptide only weakly reduced the overflow of [3H]dopamine and [3H]ACh when added at relatively high concentrations. Conclusions and implications: NPS, at low picomolar concentrations, can selectively inhibit the evoked release of 5-HT and noradrenaline in the frontal cortex by acting directly on 5-hydroxytryptaminergic and noradrenergic nerve terminals. These direct effects may explain only in part the unique behavioural activities of NPS, while an indirect involvement of other transmitters, especially of glutamate, must be considered.

Activation of delta-opioid receptors (DOR) attenuates anoxic K(+) leakage and protects cortical neurons from anoxic insults by inhibiting Na(+) influx. It is unknown, however, which pathway(s) that mediates the Na(+) influx is the target of DOR signal. In the present work, we found that, in the cortex, (1) DOR protection was largely dependent on the inhibition of anoxic Na(+) influxes mediated by voltage-gated Na(+) channels; (2) DOR activation inhibited Na(+) influx mediated by ionotropic glutamate N-methyl-D-aspartate (NMDA) receptors, but not that by non-NMDA receptors, although both played a role in anoxic K(+) derangement; and (3) DOR activation had little effect on Na(+)/Ca(2+) exchanger-based response to anoxia. We conclude that DOR activation attenuates anoxic K(+) derangement by restricting Na(+) influx mediated by Na(+) channels and NMDA receptors, and that non-NMDA receptors and Na(+)/Ca(2+) exchangers, although involved in anoxic K(+) derangement in certain degrees, are less likely the targets of DOR signal.

Turbine entry conditions are characterized by unsteady and strongly non-uniform velocity, temperature and pressure fields. The uncertainty and the lack of confidence associated with these conditions require the application of wide safety margins during the design of the turbine cooling systems, with a detrimental effect on engine efficiency. The adoption of lean-burn technology in modern aero-engines to reduce NOx emissions exacerbates the situation, as the absence of dilution holes keeps the strong swirl component generated by the burners up to the combustor outlet and prevents to control the pattern factor. Complexity and costs associated with the experimental investigation of combustor-turbine interaction, makes Computational Fluid Dynamics (CFD) paramount to understand the physical phenomena involved. Moreover, due to the well-known limitations of the Reynolds-Averaged Navier-Stokes (RANS) approach and the increase in computational resources, hybrid RANS-LES models, such as Scale Adaptive Simulation (SAS), are proving to be a viable approach to capture the main structures of the flow field. This paper reports the main findings of the numerical investigation on a test rig representative of a lean-burn, effusion cooled, annular combustor, developed in the context of the EU Project FACTOR (Full Aerothermal Combustor-Turbine interactiOns Research) with the aim of studying combustor-turbine interaction. Results obtained with RANS and unsteady SAS were critically compared to experimental data and analysed in order to better understand the flow physics within such a device, as well as to assess the improvements related to the use of hybrid models. The main discrepancies between RANS and SAS are highlighted in predicting the recirculating region, which has slight influence on the velocity field at the combustor outlet, but affects dramatically mixing and the resulting temperature distribution. Accuracy of the results achieved suggest a possible exploitation of SAS model with a view to the future inclusion of the nozzle guide vanes within the test rig.

Background and purpose: δ-Opioid receptors (DOP receptors) could represent a novel target in the treatment of depressive disorders. To explore this new field of interest, the development of highly selective DOP receptor agonists is essential. UFP-512 [H-Dmt-Tic-NH-CH(CH2-COOH)-Bid], was recently shown to behave in vitro as a selective and potent DOP receptor agonist and to promote antidepressant- and anxiolytic-like effects in vivo (Vergura et al., 2007). Here, we have characterized the pharmacological properties of UFP-512 and established a link between desensitization and tolerance. Experimental approach: Studies were performed in the human neuroblastoma SK-N-BE cells to establish i) binding parameters for UFP-512 ii) signalling pathways activated after acute and chronic treatment iii) regulation (phosphorylation and trafficking) of human DOP (hDOP) receptors after sustained activation by UFP-512. In vivo, we studied UFP-512-induced antidepressant-like effects after acute or chronic treatment in the mouse forced swimming test. Key results: In vitro, UFP-512 was a high affinity agonist for DOP receptors. While UFP-512 induced marked phosphorylation of DOP receptors on Ser363, we observed a low desensitization of the cAMP pathway, associated with receptor endocytosis and recycling without any reduction on extracellular signal-regulated protein kinase 1/2 activation. In vivo, acute administration of UFP-512 produced an antidepressant-like effect, without any sign of tolerance after chronic administration. Conclusions and implications: There was a correlation between weak desensitization, significant internalization and recycling of the human DOP receptors and lack of tolerance to UFP-512. This suggests that this compound would be a promising drug prototype for exploring innovative treatments for mood disorders. British Journal of Pharmacology (2007) 152, 1312–1324; doi:10.1038/sj.bjp.0707497; published online 5 November 2007

The δ selectivity and antagonism of peptides containing l -tetrahydro-3-isoquinoline carboxylic acid (Tic) in second position can be attributed mainly to the Tyr-Tic unit. These properties can be further enhanced by substituting Tyr 1 with 2,6-dimethyl- l -tyrosyl (Dmt). Dmt-Tic-NH 2 , Dmt-Tic-OH, Dmt-Tic-Ala-NH 2 and Dmt-Tic-Ala-OH are all more active and/or selective than the corresponding [Tyr 1 ]-parent peptides. In fact the selectivities of Dmt-Tic-OH and Dmt-Tic-Ala-OH are the highest ever recorded for opioid molecules. 1 H NMR spectra in a DMSO/water mixture at 278 K reveal the presence of two similar conformers, characterised by a cis or trans Dmt-Tic bond, in all four peptides. A detailed conformational analysis in solution of Dmt-Tic-NH 2 shows that these conformers have a shape very similar to that of the bioactive conformation of Tyr-Tic-NH 2 and to that of naltrindole.

1 The present study describes the labelling of the nociceptin (NC) receptor, ORL1, in mouse forebrain membranes with a new ligand partially protected from metabolic degradation at the C-terminal; the ligand, [3H]-NC-NH2, has a specific activity of 24.5 Ci mmol−1 2 Saturation experiments revealed a single class of binding sites with a KD value of 0.55 nm and Bmax of 94 fmol mg−1 of protein. Non specific binding was 30% of total binding. Kinetic binding studies yielded the following rate constants: Kobs=0.104 min−1; K1=0.034 min−1; T1/2=20 min; K+1=0.07 min nm−1. 3 Thermodynamic analyses indicated that [3H]-NC-NH2 binding to the mouse ORL1 is totally entropy driven, similar to what has been observed for the labelled agonists to the opioid receptors OP1(δ), OP2(κ) and OP3(μ). 4 Receptor affinities of several NC fragments and analogues, including the newly discovered ORL-1 receptor antagonist [Phe1ψ(CH2-NH)Gly2]NC(1–13)-NH2 ([F/G]NC(1–13)-NH2), were also evaluated in displacement experiments. The competition curves for these compounds were found to be parallel to that of NC and the following order of potency was determined for NC fragments: NC-OH=NC-NH2=NC(1–13)-NH2 >> NC(1–12)-NH2 > NC(1–13)-OH >> NC(1–11)-NH2, and for NC and NC(1–13)-NH2 analogues: [Tyr1]NC-NH2 [Leu1]NC(1–13)-NH2 [Tyr1]NC(1–13)-NH2 [F/G]NC(1–13)-NH2 >> [Phe3]NC(1–13)-NH2 > [DF/G]NC(1–13)-NH2. 5 Standard opioid receptor ligands (either agonists or antagonists) were unable to displace [3H]-NC-NH2 binding when applied at concentrations up to 10 μm indicating that this new radioligand interacts with a non opioid site, probably the ORL1 receptor. British Journal of Pharmacology (1998) 125, 1485–1490; doi:10.1038/sj.bjp.0702226

1 The newly discovered neuropeptide nociceptin (NC) has recently been reported to be the endogenous ligand of the opioid-like orphan receptor. Despite its structural similarity to opioids, when injected intracerebroventricularly (i.c.v.) in the mouse, NC exerts a direct hyperalgesic effect and reverses opioid-induced analgesia. In the present investigation, these two effects of NC were evaluated under the same experimental conditions; in addition, a pharmacological characterization of the receptor mediating these central effects of NC was attempted. 2 NC caused a dose dependent (0.1–10 nmol/mouse), naloxone-insensitive reduction of tail withdrawal latency with a maximal effect of about 50% of the reaction time observed in saline injected mice. In the same range of doses, NC inhibited morphine (1 nmol/mouse) induced analgesia. 3 The effects of the natural peptide were mimicked by NCNH2 and NC(1–13)NH2 (all tested at 1 nmol/mouse) while 1 nmol NC(1–9)NH2 was found to be inactive either in reducing tail withdrawal latency or in preventing morphine analgesia. 4 [Phe1ψ(CH2-NH)Gly2]NC(1–13)NH2 ([F/G]NC(1–13)NH2), which has been shown to antagonize NC effects in the mouse vas deferens, acted as an agonist, mimicking NC effects in both the experimental paradigms. In addition, when NC and [F/G]NC(1–13)NH2 were given together, their effects were additive. 5 These results demonstrate that both the direct hyperalgesic action and the anti-morphine effect of NC can be studied under the same experimental conditions in the mouse tail withdrawal assay. Moreover, the pharmacological characterization of the NC functional site responsible for these actions compared with the peripherally active site, indicates the existence of important differences between peripheral and central NC receptors. British Journal of Pharmacology (1998) 125, 373–378; doi:10.1038/sj.bjp.0702087

Background In this study we aimed at quantifying the possible errors which may occur when assessing specific reference planes and linear derivants on cephalometric radiographs traced manually and digitally. Furthermore, we have compared the precision of the tracings according to both the two- and three-dimensional (2D and 3D respectively) techniques and between clinicians. Findings We have obtained via cone beam computed tomography (CBCT) archive of the orthodontics department of the University of Milan 20 cone beam CT radiographs from which we have obtained 20 latero-lateral radiographs. Five independent clinicians referred to as A, B, C, D, E have been randomly selected to trace both radiographs maintaining the same working and lighting conditions to minimize the possibility of operator- and environment-dependent errors from occurring. The results have been statistically assessed by Student’s t test. The comparison of the data gathered from the tracings in 2D and 3D shows that certain measurements have statistically significant differences. Particularly, the difference in the measurements of the sagittal dimension of the mandible and the anterior and posterior nasal spines has resulted to be statistically significant. The results of the intra-operator comparison proved that the 3D technique is extremely precise. Conclusion Our study determines that the 3D technique allows to obtain more precise results and with several advantages when compared to the conventional technique such as a true representation of the anatomical structures, less risk of errors occurring due to clinician skills and absence of overlapping anatomical structures.

In Computational Fluid Dynamics (CFD) is possible to identify namely two uncertainties: epistemic, related to the turbulence model, and aleatoric, representing the random-unknown conditions such as the boundary values and or geometrical variations. In the field of epistemic uncertainty, Large Eddy Simulation (LES and DES) is the state of the art in terms of turbulence closures to predict the heat transfer in internal channels. The problem concerning the stochastic variations and how to include these effects in the LES studies is still open. In this paper, for the first time in literature, a stochastic approach is proposed to include these variations in LES. By using a classical Uncertainty Quantification approach, the Probabilistic Collocation Method is coupled to Numerical Large Eddy Simulation (NLES) in a duct with pin fins. The Reynolds number has been chosen as a stochastic variable with a normal distribution. It is representative of the uncertainties associated to the operating conditions, i.e. velocity and density, and geometrical variations such as the pin fin diameter. This work shows that by assuming a Gaussian distribution for the value of Reynolds number of +/−25%, is possible to define the probability to achieve a specified heat loading under stochastic conditions, which can affect the component life by more than 100%. The same method, applied to a steady RANS, generates a different level of uncertainty. This procedure proves that the uncertainties related to the unknown conditions, aleatoric, and those related to the physical model, epistemic, are strongly interconnected. This result has directed consequences in the Uncertainty Quantification science and not only in the gas turbine world.

The title compound, C 28 H 28 N 2 O 5 , is a terminally blocked dipeptide, conformationally constrained by the presence of a 1,2,3,4-tetrahydroisoquinoline residue (Tic). The conformation of the peptide linkage is trans [ω 1 =-177.0 (3) o ] and the main chain conformation is determined by the parameters φ 1 =-86.7 (4), ψ 1 =171.5 (3), φ 2 =-77.2 (4), ψ τ =160.1 (3) o . The side chain of Tic is in a g + conformation [χ 1 1 =56.0 (4) o ], whereas the phenylalanine side chain is in a g - conformation [χ 2 1 =- 68.8 (5) o ]

Neuropeptide S (NPS) was recently identified as the endogenous ligand of an orphan receptor, now referred to as the NPS receptor. In vivo, NPS produces a unique behavioural profile by increasing wakefulness and exerting anxiolytic-like effects. In the present study, we further evaluated the effects of in vivo supraspinal NPS in mice.Effects of NPS, injected intracerebroventricularly (i.c.v.), on locomotor activity (LA), righting reflex (RR) recovery and on anxiety states (measured with the elevated plus maze (EPM) and stress-induced hyperthermia (SIH) tests) were assessed in Swiss mice.NPS (0.01-1 nmol per mouse) caused a significant increase in LA in naive mice, in mice habituated to the test cages and in animals sedated with diazepam (5 mg kg(-1)). In the RR assay, NPS dose dependently reduced the proportion of animals losing the RR in response to diazepam (15 mg kg(-1)) and their sleeping time. In the EPM and SIH test, NPS dose dependently evoked anxiolytic-like effects by increasing the time spent by animals in the open arms and reducing the SIH response, respectively.We provide further evidence that NPS acts as a novel modulator of arousal and anxiety-related behaviours by promoting a unique pattern of effects: stimulation associated with anxiolysis. Therefore, NPS receptor ligands may represent innovative drugs for the treatment of sleep and anxiety disorders.

Delta-opioid receptors (DOP receptors) could represent a novel target in the treatment of depressive disorders. To explore this new field of interest, the development of highly selective DOP receptor agonists is essential. UFP-512 [H-Dmt-Tic-NH-CH(CH2-COOH)-Bid], was recently shown to behave in vitro as a selective and potent DOP receptor agonist and to promote antidepressant- and anxiolytic-like effects in vivo (Vergura et al., 2007). Here, we have characterized the pharmacological properties of UFP-512 and established a link between desensitization and tolerance.Studies were performed in the human neuroblastoma SK-N-BE cells to establish i) binding parameters for UFP-512 ii) signalling pathways activated after acute and chronic treatment iii) regulation (phosphorylation and trafficking) of human DOP (hDOP) receptors after sustained activation by UFP-512. In vivo, we studied UFP-512-induced antidepressant-like effects after acute or chronic treatment in the mouse forced swimming test.In vitro, UFP-512 was a high affinity agonist for DOP receptors. While UFP-512 induced marked phosphorylation of DOP receptors on Ser363, we observed a low desensitization of the cAMP pathway, associated with receptor endocytosis and recycling without any reduction on extracellular signal-regulated protein kinase 1/2 activation. In vivo, acute administration of UFP-512 produced an antidepressant-like effect, without any sign of tolerance after chronic administration.There was a correlation between weak desensitization, significant internalization and recycling of the human DOP receptors and lack of tolerance to UFP-512. This suggests that this compound would be a promising drug prototype for exploring innovative treatments for mood disorders.

BACKGROUND: Tyr-Tic (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) and Tyr-Tic-Ala were the first peptides with delta opioid antagonist activity lacking Phe, considered essential for opioid activity based on the N-terminal tripeptide sequence (Tyr-D-Xaa-Phe) of amphibian skin opioids. Analogs were then designed to restrain the rotational flexibility of Tyr by the substitution of 2,6-dimethyl-L-tyrosine (Dmt). MATERIALS AND METHODS: Tyr and Dmt peptides were synthesized by solid phase and solution methods using Fmoc technology or condensing Boc-Dmt-OH or Boc-Tyr(But)-OH with H-L-Tic-OBut or H-D-Tic-OBut, respectively. Peptides were purified (> 99%) by HPLC and characteristics determined by 1H-NMR, FAB-MS, melting point, TLC, and amino acid analyses. RESULTS: H-Dmt-Tic-OH had high affinity (Ki delta = 0.022 nM) and extraordinary selectivity (Ki mu/Ki delta = 150,000); H-Dmt-Tic-Ala-OH had a Ki delta = 0.29 nM and delta selectivity = 20,000. Affinity and selectivity increased 8700- and 1000-fold relative to H-Tyr-Tic-OH, respectively. H-Dmt-Tic-OH and H-Dmt-Tic-NH2 fitted one-site receptor binding models (eta = 0.939-0.987), while H-Dmt-Tic-ol, H-Dmt-Tic-Ala-OH and H-Dmt-Tic-Ala-NH2 best fitted two-site models (eta = 0.708-0.801, F 18.9-26.0, p < 0.0001). Amidation increased mu affinity by 10- to 100-fold and acted synergistically with D-Tic2 to reverse selectivity (delta-->mu). Dmt-Tic di- and tripeptides exhibited delta antagonist bioactivity (Ke = 4-66 nM) with mouse vas deferens and lacked agonist mu activity (> 10 microM) in guinea-pig ileum preparations. Dmt-Tic analogs weakly interacted with kappa receptors in the 1 to > 20 microM range. CONCLUSIONS: Dmt-Tic opioidmimetic peptides represent a highly potent class of opioid peptide antagonists with greater potency than the nonopioid delta antagonist naltrindole and have potential application as clinical and therapeutic compounds.

This study presents a new measure of the hemodynamic changes to an auditory stimulus in newborns. Nineteen newborns born at 28-41 wk and aged 1 to 49 d were studied in waking and/or sleeping state, for a median time of 4 min 40 s before, 2 min 40 s during, and 3 min 5 s after an acustic stimulus (tonal sweep of frequency increasing from 2 to 4 kHz, intensity 90 dB SPL) originating 5 cm from the external auditory meatus. The emitter and detector optodes were placed over the left or right temporal region, corresponding to T3 or T4 EEG electrodes. The concentration changes in cerebral chromophores Delta[HbO2], Delta[Hb] and Deltaoxidized-reduced cytochrome aa(3) were recorded every 5 s. Changes in cerebral blood volume were calculated from the changes in total Hb x 0.89/large vessel Hb concentration. Increased oxyhemoglobin, Delta[HbO2], total Hb, Delta[Hb (sum)], and cerebral blood volume, DeltaCBV, were found in 13/19 neonates, with the exception of a neonate who only had increased in Delta[Hb], Delta[Hb (sum)] and DeltaCBV. During the stimulation phase there was a significant increase in DeltaCBV (t test, p = 0.00006) in the responsive newborns from a mean value of 0.006 (+/-0.02) mL/100 g in the pretest phase to 0.09 (+/-0.06) mL/100 g during the auditory stimulus. After the test DeltaCBV decreased to 0.04 (+/-0.07) mL/100 g (t test, p = 0.01), so did Delta[Hb (sum)] (p = 0.02). Hemodynamic responses of the subjects who showed increases in Delta[Hb (sum)] and Delta[HbO(2)] were analyzed to study the Delta[Hb]. The responder subjects could be classified into two groups according to Delta[Hb] changes: 8/13 (61.5%) showed an increase of Delta[Hb] (pattern A), while 5/13 (38.4%) showed a decrease (pattern B) (t test, p = 0.03). These two patterns did not show differences related to Delta[HbO(2)] and Delta[Hb (sum)]. The DeltaCBV changes in nonresponders presented a decrease during the test phase (t test, p = 0.04). CBV did not return to pretest values, suggesting a fronto-temporal brain pathway for storing unusual sounds. The increase in CBV followed the local increase in oxyhemoglobin and total Hb concentrations due to a greater use of oxygen in the homolateral temporal cortex of the newborns.

Major and 5S ribosomal genes have been localized in the chromosomes of Micropterus salmoides. By C-banding, Ag-staining, CMA3-staining and 45S and 5S fluorescence in-situ hybridization (FISH), we demonstrate that the 45S and 5S ribosomal genes are clustered in two different chromosome pairs and both are located in heterochromatic GC-rich regions. PCR amplification and sequencing of the 5S intergenic non-transcribed sequences have allowed us to identify variability essentially due to a trinucleotide tandem repeat (GCT).