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.

Riassunto Obiettivi Lo scopo del presente studio e effettuare una revisione della letteratura al fine di mettere a confronto le metodiche self-ligating e quelle convenzionali. Materiali e metodi E stata eseguita una ricerca nel database della US National Library of Medicine tramite il servizio PubMed, utilizzando le seguenti parole chiave: “active self-ligating brackets”, “passive self-ligating brackets”, “conventional brackets”, “dental movement”, orthodontics”. Risultati Sono stati trovati 209 articolie da questo screening sono stati selezionati 38 articoli affini alla nostra ricerca, dicui e stata valutata la versione full text. Conclusioni Il sistema self-ligating sembra offrire un vantaggio significativo per quanto riguarda il risparmio di tempo alla poltrona ed evidenzia una leggera minore proinclinazione degli incisivi inferiori.

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.

Riassunto Obiettivi Scopo del lavoro e presentare un caso clinico trattato con apparecchiature elastodontiche. Materiali e metodi La paziente presenta un quadro di grave seconda classe scheletrica e deep bite scheletrico in fase dinamica di crescita tale da richiedere un trattamento ortopedico-funzionale al fine di guidare e stimolare la crescita mandibolare. E stato applicato il dispositivo OCCLUS-o-GUIDE® serie H, che presenta un morso di costruzione preformato rilevato 5 mm oltre il rapporto di testa a testa. Risultati Dal controllo radiografico e clinico dopo il trattamento e emersa la risoluzione del quadro clinico. Conclusioni L’utilizzo del dispositivo elastodontico e una valida opzione terapeutica per la risoluzione di situazioni cliniche di seconda classe e deep bite in fase di crescita.

Riassunto Obiettivi Lo scopo di questo lavoro e quello di valutare l’incidenza e la prevalenza delle agenesie nella popolazione e di analizzare le possibili opzioni terapeutiche. Materiali e metodi Lo studio e basato su una revisione della letteratura e la ricerca e stata condotta tramite PubMed© US National Library of Medicine. Risultati e conclusioni I dati presenti in letteratura indicano che la prevalenza delle agenesie e maggiore nella dentizione permanente che in quella decidua. Vengono descritte differenze nella prevalenza di agenesie nei due sessi e il sesso femminile risulta quello piu colpito. I terzi molari, gli incisivi laterali superiori e i secondi premolari inferiori sono i denti maggiormente affetti dalle agenesie. Diverse opzioni terapeutiche possono essere considerate in presenza di agenesie e per ciascun paziente deve essere stilato uno specifico piano di cura basato sul proprio giudizio clinico.

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.

Synthesis is described of the partially protected nonapeptide tert-butyloxycarbonyl-valylleucylisoleucylglutaminyl-N-trifluoroacetyllsylserylglycylprolyl-S-acetamido-methylcysteine corresponding to positions 44-52 of the amino acid sequence of porcine pancreatic secretory trypsin inhibitor II. The hexapeptide free base glutaminyl-N-trifluoroacetyllsylserylglycylprolyl-S-acetamidomethylcysteine, prepared by two alternative routes, was acylated by the azide procedure, with the tripeptide tert-butyloxycarbonylvalylleucylisoleucine hydrazide. The stereochemical homogeneity of the resulting nonapeptide was assessed, after partial deprotection by treatment with aqueous 90% trifluoroacetic acid, by digestion with papain and aminopeptidase M followed by quantitative amino acid analysis.

Using the potent cyclic peptide T analog-Thr-Thr-Asn-Tyr-Thr-Asp- as parent compound, a series of analogues were synthesized and their potencies in a monocyte chemotaxis assay were compared with those of correspondingly modified linear peptides. Structure-activity relationships observed with cyclic compounds did not always parallel those determined with linear analogues. -Thr-Hse-Asn-Tyr-Thr-Asp- showed the highest affinity to CD4 receptor of monocytes of any peptide thus far studied. It also proved to be highly resistant to degradation by plasma or brain enzymes.

Seven dermorphin hepta- and tetrapeptide analogues containing [3,4] amide bond replacement by a carbon-carbon double and single bond were prepared. 1H NMR studies of the pseudoheptapeptide in DMSO indicate the presence of extended conformations with stacking of the side chains in the N-terminal part and an inverse gamma-turn around Ser7 in the conformational equilibrium. The binding data show that the affinity of the analogues for the mu-receptor is only slightly diminished in the D-Ala2 series and is more affected in the D-Arg2 series. Since the Gly4NH is not present in these compounds we conclude that this NH is not required to stabilize the bioactive conformation nor is it directly involved in binding to the receptor.

The N-terminal dipeptide Tyr-d-Ala of a mu-selective agonist, dermorphin tetrapeptide (DT, H-Tyr-D-Ala-Phe-Gly-NH2) and delta-selective agonist deltorphin C (DEL-C, H-Tyr-D-Ala-Phe-Asp-Val-Val- Gly-NH2) was changed into an aminodiacyl moiety. The relevant synthetic step is a nucleophilic substitution of bromine from a chiral 2-bromopropanamide by the amino group of tyrosine, with overall retention of configuration. The resulting pseudo tetra- and heptapeptides I-VI were characterized for mu- and delta-opioid receptor binding properties using [3H]DAGO and [3H]DPDPE, respectively, and in a bioassay using guinea pig ileum (GPI) and mouse vas deferens (MVD). As a result of chemical alteration of N-terminal depeptide moiety, all synthesized analogs showed considerable reduction in opioid receptor affinity compared to mu- and delta-prototypes (500-fold on the mu-site, analog I, and 125-fold on the delta-site, analog IV). Interestingly, analogs I and IV showed moderate antagonist activity, respectively, on GPI and MVD, with pA2 values of 6.05 and 6.82. Analog IV did not exhibit the delta-antagonist potency and delta-selectivity of TIPP peptides.

Neuropeptide S (NPS) regulates different biological functions by selectively activating a G protein coupled receptor named NPSR. Previous studies identified [d-Pen5]NPS as a NPSR antagonist. This study investigated the structure activity relationship of [d-Pen5]NPS by alkylation of the thiol group of d-Pen with different aliphatic and aromatic moieties. Nine compounds were synthesised and assayed in calcium mobilization studies, performed in HEK293 cells expressing the recombinant mouse NPSR. All compounds behaved as pure NPSR antagonists of moderate to high potency, in a similar manner to the reference peptide. The most potent compounds were obtained using alkylating groups as cyclic aromatic moieties. [d-Pen(p- t BuBzl)5]NPS, the best compound of this series, was further investigated in vivo, where it fully prevented the stimulatory effects of supraspinal NPS on mouse locomotor activity. [d-Pen(p- t BuBzl)5]NPS is proposed as a novel pharmacological tool which could be useful to investigate in vitro and in vivo biological functions regulated by the NPS/NPSR receptor system.

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.

Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the NOP receptor, regulates several central functions such as pain transmission, learning and memory, fear and anxiety and feeding and locomotor activity. It has been recently reported that NOP receptor antagonists induce antidepressant-like effects in the mouse forced swimming test (FST), i.e. reduce immobility time. This assay was used in the present study for further investigating the involvement of the NOP receptor in depression states. In male Swiss mice, intracerebroventricular injection (i.c.v) of the novel NOP receptor antagonist, UFP-101 (1-10 nmol) dose-dependently reduced the immobility time (control 192 +/- 14 s, UFP-101 91 +/- 15 s). The effect of 3 or 10 nmol UFP-101 was fully or partially reversed, respectively, by the coadministration of 1 nmol N/OFQ, which was inactive per se. NOP receptor knockout mice showed a reduced immobility time compared with their wild-type littermates (wild-type 215 +/- 10 s, knockout 143 +/- 12 s). Moreover, i.c.v. injected UFP-101 (10 nmol) significantly reduced immobility time in wild-type mice but not in NOP receptor knockout animals. In conclusion, these results, obtained using a combined pharmacological and genetic approach, indicate that blockade of the N/OFQ-NOP receptor signalling in the brain produces antidepressant-like effects in the mouse FST. These findings support the NOP receptor as a candidate target for the development of innovative antidepressant drugs.

Peripheral neuropathy is characterized by abnormal pain responses triggered by the release of several mediators and neuronal hyperexcitability at the spinal cord level. Emerging evidence indicates that the enhanced activity of dorsal horn neurons requires communication with glia and microglia, cells that are physiologically involved in neuronal wellbeing. Prokineticins (PKs), which include PK1 and PK2, represent a novel family of chemokines characterized by a unique structural motif comprising five disulfide bonds. They are expressed in the peripheral and central nervous system. PKs bind two G protein coupled receptors, PKR1 and PKR2, and participate in the regulation of several biological processes, including pain sensation. This study aimed to investigate the anti-nociceptive effect of PC1, a non-peptide PKR1-preferring antagonist, in a mouse model of neuropathic pain. To do this, we assessed the activity of spinal cord nociceptive neurons as well as astrocyte and microglia phenotypes after repeated administration of PC1 in vivo. PC1 treatment strongly delayed the development of thermal hyperalgesia and tactile and mechanical allodynia. It also reduced spinal microglial and glial activation 8 days post injury in spared nerve injury (SNI) mice. Neuropathic mice showed an increased level of PK2 protein in the spinal cord, mostly in astrocytes. PC1 treatment completely reversed the increased responsiveness to mechanical stimuli, the decreased threshold of neuronal activation, and the increased spontaneous activity that were observed in nociceptive specific (NS) neurons of SNI mice.

Phe4 in the nociceptin (NC) sequence has been identified as the most critical residue for receptor interaction. In the present study, we investigated the pharmacological activity of a series of NC(1-13)NH2 analogues, in which the hydrogen atom in the para position of Phe4 was substituted with F, NO2, CN, Cl, Br, I, CH3, OH or NH2. In receptor binding studies, performed using CHO cells expressing the recombinant human NC receptor (CHOhOP4) and in rat cerebral cortex membranes, [(pF)Phe4]NC(1-13)NH2, [(pNO2)Phe4]NC(1-13)NH2, and [(pCN)Phe4]NC(1-13)NH2 displayed higher affinity than NC(1-13)NH2. The affinity of [(pCl)Phe4]NC(1-13)NH2 was essentially identical to that of NC(1-13)NH2, while the remaining compounds displayed reduced affinity. In a series of functional assays (stimulation of GTPγS binding in CHOhOP4 cells and rat cerebral cortex membranes and inhibition of cAMP accumulation in CHOhOP4 cells), the para substituted analogues behaved as full agonists (with the exception of [(pOH)Phe4]NC(1-13)NH2 which acted as a partial agonist in the GTPγS binding assays) with the following rank order potency: ${\rm pF = pNO}_{\rm 2} \ge {\rm pCN} \ge {\rm NC = NC(1 - 13)NH}_{\rm 2} {\rm = pCl} \ge {\rm pBr > pI = pCH}_{\rm 3} {\rm > pOH > pNH}_{\rm 2} $ [(pF)Phe4]NC(1-13)NH2 and [(pNO2)Phe4]NC(1-13)NH2 were either inactive or displayed micromolar potencies in cAMP accumulation experiments performed on cells expressing classical opioid receptors. All compounds were full agonists in isolated tissues from various species (guinea pig ileum, mouse colon and mouse/rat vas deferens) with the exception of [(pOH)Phe4]NC(1-13)NH2 which displayed partial agonist/weak antagonist activities. The rank order of potency was similar to that found in the other assays. The effects of all analogues were not modified by naloxone. The selective OP4 receptor antagonist [Nphe1]NC(1-13)NH2, tested in all preparations against one or both of the highly potent derivatives [(pF)Phe4]NC(1-13)NH2 and [(pNO2)Phe4]NC(1-13)NH2, showed pA2 values similar to those found against NC, the pA2 in the GTPγS binding/rat cerebral cortex assay being much higher (ca. 7.5) than in the other functional assays (ca. 6). This study further supports the notion that Phe4 of NC is the critical residue for receptor occupation and activation. Moreover, as part of this study, we have identified two novel, highly potent and selective agonists for the OP4 receptor, [(pF)Phe4]NC(1-13)NH2 and [(pNO2)Phe4]NC(1-13)NH2.

Aim of the present study was to present a case report of a patient suffering from pycnodysostosis and assess how it may manifest and affect the dental/ orthodontic treatment.An 11-year-old patient who was diagnosed with pycnodysostosis at the age of 18 months, attended the orthodontics department requiring treatment for extensive carious lesions, periodontal disease and severe crowding.After an accurate radiographic, clinical and orthodontic assessment of the patient taking into consideration the severity of the condition and the patient's necessities, we have formulated a treatment plan, which was accepted by both the patient and parents. We took into consideration the risks and benefits of the options available and the requests of the patient.We have decided to opt for the extraction of teeth to relieve the crowding as this was impeding good oral hygiene and hence increasing the risk of caries and periodontal disease. Such patients must be placed under an oral hygiene prevention scheme, a treatment plan must be accurately designed and the patient must be constantly motivated.