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Histone modifications regulate chromatin remodeling and gene expression in development and diseases. DOT1L, the sole histone H3K79 methyltransferase, is essential for embryonic development. Here, we report that DOT1L regulates male fertility in mouse. DOT1L associates with MLLT10 in testis. DOT1L and MLLT10 localize to the sex chromatin in meiotic and post-meiotic germ cells in an inter-dependent manner. Loss of either DOT1L or MLLT10 leads to reduced testis weight, decreased sperm count and male subfertility. H3K79me2 is abundant in elongating spermatids, which undergo the dramatic histone-to-protamine transition. Both DOT1L and MLLT10 are essential for H3K79me2 modification in germ cells. Strikingly, histones are substantially retained in epididymal sperm from either DOT1L- or MLLT10-deficient mice. These results demonstrate that H3K79 methylation promotes histone replacement during spermiogenesis.

We study spatial isovector J = 1 meson correlators in nf = 2 QCD with dynamical domain-wall fermions on 323 × 8 lattices at temperatures T = 220–380 MeV. We observe an approximate degeneracy of all considered correlators with increasing temperature. This approximate degeneracy suggests emergent SU(2)CS and SU(2nf) symmetries at high temperatures, that mix left- and right-handed quarks. Since these symmetries are symmetries of the chromo-electric interaction in QCD we conclude that at 2Tc temperature the elementary objects are quarks with a definite chirality connected by the chromo-electric field.

We investigate the axial $U(1)$ anomaly of two-flavor QCD at temperatures 190--330 MeV. In order to preserve precise chiral symmetry on the lattice, we employ the M\"obius domain-wall fermion action as well as overlap fermion action implemented with a stochastic reweighting technique. Compared to our previous studies, we reduce the lattice spacing to 0.07 fm, simulate larger multiple volumes to estimate finite size effect, and take more than four quark mass points, including one below physical point to investigate the chiral limit. We measure the topological susceptibility, axial $U(1)$ susceptibility, and examine the degeneracy of $U(1)$ partners in meson/baryon correlators. All the data above the critical temperature indicate that the axial $U(1)$ violation is consistent with zero within statistical errors. The quark mass dependence suggests disappearance of the $U(1)$ anomaly at a rate comparable to that of the $SU(2{)}_{L}\ifmmode\times\else\texttimes\fi{}SU(2{)}_{R}$ symmetry breaking.

We investigate the high-temperature phase of QCD using lattice QCD simulations with $N_f = 2$ dynamical M\"obius domain-wall fermions. On generated configurations, we study the axial $U(1)$ symmetry, overlap-Dirac spectra, screening masses from mesonic correlators, and topological susceptibility. We find that some of the observables are quite sensitive to lattice artifacts due to a small violation of the chiral symmetry. For those observables, we reweight the M\"obius domain-wall fermion determinant by that of the overlap fermion. We also check the volume dependence of observables. Our data near the chiral limit indicates a strong suppression of the axial $U(1)$ anomaly at temperatures $\geq$ 220 MeV., Comment: 7 pages, 4 figures, 1 table; Proceedings of the 37th International Symposium on Lattice Field Theory (Lattice 2019), 16-22 June 2019, Wuhan, China

We train a set of Restricted Boltzmann Machines (RBMs) on one- and two-dimensional Ising spin configurations at various values of temperature, generated using Monte Carlo simulations. We validate the training procedure by monitoring several estimators, including measurements of the log-likelihood, with the corresponding partition functions estimated using annealed importance sampling. The effects of various choices of hyper-parameters on training the RBM are discussed in detail, with a generic prescription provided. Finally, we present a closed form expression for extracting the values of couplings, for every $n$-point interaction between the visible nodes of an RBM, in a binary system such as the Ising model. We aim at using this study as the foundation for further investigations of less well-known systems., 31 pages

Based on a complete set of $J = 0$ and $J=1$ spatial isovector correlation functions calculated with $N_F = 2$ domain wall fermions we identify an intermediate temperature regime of $T \sim 220 - 500$ MeV ($1.2T_c$--$2.8T_c$), where chiral symmetry is restored but the correlators are not yet compatible with a simple free quark behavior. More specifically, in the temperature range $T \sim 220 - 500$ MeV we identify a multiplet structure of spatial correlators that suggests emergent $SU(2)_{CS}$ and $SU(4)$ symmetries, which are not symmetries of the free Dirac action. The symmetry breaking effects in this temperature range are less than 5%. Our results indicate that at these temperatures the chromo-magnetic interaction is suppressed and the elementary degrees of freedom are chirally symmetric quarks bound into color-singlet objects by the chromo-electric component of the gluon field. At temperatures between 500 and 660 MeV the emergent $SU(2)_{CS}$ and $SU(4)$ symmetries disappear and one observes a smooth transition to the regime above $T \sim 1$ GeV where only chiral symmetries survive, which are finally compatible with quasi-free quarks., A new figure and discussion added. Accepted for publication in PRD

We present a non-perturbative lattice study of SU(4) gauge theory with two flavors of fermions in the fundamental representation and two in the two-index antisymmetric representation: a theory closely related to a minimal partial-compositeness model for physics beyond the Standard Model, that was proposed by G. Ferretti. We discuss the phase structure of the lattice theory and report results for various observables of interest, including the masses of states obtained from different combinations of valence fermions and the spectrum of the Dirac operator. Finally, we comment on the extension of this type of studies to other partial-compositeness models (including, in particular, one that was recently suggested by H. Gertov et al.), which could admit lighter top-quark partners, highlighting some key features of our lattice simulation algorithm, that make it suitable for such generalizations., 38 pages, 7 tables, 8 figures, published version

Using lattice QCD simulations with $N_f = 2$ dynamical fermions, we study the axial $U(1)$ symmetry, topological charge, and Dirac eigenvalue spectra in the high-temperature phase in which the chiral symmetry is restored. Our gauge ensembles are generated with M\"obius domain-wall fermions, but the measurements such as susceptibilities are reweighted to those for the overlap fermions by using overlap/domain-wall reweighting technique. We find that the $U(1)_A$ and topological susceptibilities are strongly suppressed in the small quark mass region, which is related to the reduction of chiral-zero and low-nonzero modes on the Dirac spectra. We also examine their volume dependence., Comment: 10 pages, 4 figures, 1 table; Proceedings of The 9th International Workshop on Chiral Dynamics (CD18), 17-21 September, 2018, Durham, NC, USA. arXiv admin note: text overlap with arXiv:1812.06621

We report on the progress of understanding spatial correlation functions in high temperature QCD. We study isovector meson operators in $N_f=2$ QCD using domain-wall fermions on lattices of $N_s=32$ and different quark masses. It has previously been found that at $\sim 2T_c$ these observables are not only chirally symmetric but in addition approximately $SU(2)_{CS}$ and $SU(4)$ symmetric. In this study we increase the temperature up to $5T_c$ and can identify convergence towards an asymptotically free scenario at very high temperatures., 7 pages, 5 figures, version to appear in proceedings of the LATTICE2018 conference

Background Oesophageal atresia is a birth defect occurring in approximately 1 in 2500 live births. Tissue engineering is a promising therapeutic alternative for those patients requiring oesophageal replacement. Aim of this study is to evaluate the engraftment in vivo of the muscle compartment of an engineered rat oesophagus in a mouse model of heterotopic xeno-genic implant and to prove its capability to grow an epithelial layer ex vivo. Methods The detergent-enzymatic protocol was used to produce decellulirised rat oesophagi. Those were subsequently repopulated with smooth muscle (human mesoangioblasts) and neural (mouse neural crest stem cells) precursor. A 3D culture protocol in a bioreactor was used to maximise the cells engraftment, proliferation and differentiation in vitro. 4 engineered oesophagi were implanted in 4 immunodeficient mice and left in situ. After 2 weeks the animals were euthanised and the engineered organs harvested and seeded, on the luminal surface, with epithelial progenitors derived from rat oesophagi. Results Engraftment, proliferation and differentiation of both muscle and neural cells were achieved during the initial in vitro culture as evident from the immunofluorescence. Those features were also preserved after the implant in the mice omentum. The immunofluorescence showed the presence of new vessels inside the artificial oesophagi when harvested from the mice. The engineered oesophagi were able to grow an epithelial layer when progenitors were seeded ex vivo. Conclusion The effectiveness of the in vivo implant of the engineered oesophagi was demonstrated, underlying the survival of both muscle and neural cells thanks to angiogenetic phenomena. The generation, ex vivo, of an epithelial layer is really promising, making realistic a 2 stage surgical approach for clinical translation.

We study the axial $U(1)$ symmetry at a finite temperature in two-flavor lattice QCD. Employing the M\"obius domain-wall fermions, we generate gauge configurations slightly above the critical temperature ${T}_{c}$ with different lattice sizes $L=2--4\text{ }\text{ }\mathrm{fm}$. Our action allows frequent topology tunneling while keeping good chiral symmetry close enough to that of overlap fermions. This allows us to recover full chiral symmetry by an overlap/domain-wall reweighting. Above the phase transition, a strong suppression of the low-lying modes is observed in both overlap and domain-wall Dirac spectra. We, however, find a sizable violation of the Ginsparg-Wilson relation in the M\"obius domain-wall Dirac eigenmodes, which dominates the signals of the axial $U(1)$ symmetry breaking near the chiral limit. We also find that the use of the overlap fermion only in the valence sector is dangerous since it suffers from the artifacts due to partial quenching. Reweighting the M\"obius domain-wall fermion determinant to that of the overlap fermion, we observe the axial U(1) breaking to vanish in the chiral limit, which is stable against the changes of the lattice volume and lattice spacing.

We calculate the form factors of the K→πlν semileptonic decays in three-flavor lattice QCD and study their chiral behavior as a function of the momentum transfer and the Nambu-Goldstone boson masses. Chiral symmetry is exactly preserved by using the overlap quark action, which enables us to directly compare the lattice data with chiral perturbation theory (ChPT). We generate gauge ensembles at a lattice spacing of 0.11 fm with four pion masses covering 290–540 MeV and a strange quark mass ms close to its physical value. By using the all-to-all quark propagator, we calculate the vector and scalar form factors with high precision. Their dependence on ms and the momentum transfer is studied by using the reweighting technique and the twisted boundary conditions for the quark fields. We compare the results for the semileptonic form factors with ChPT at next-to-next-to-leading order in detail. While many low-energy constants appear at this order, we make use of our data of the light meson electromagnetic form factors in order to control the chiral extrapolation. We determine the normalization of the form factors as f+(0)=0.9636(36)(-35+57) and observe reasonable agreement of their shape with experiment.

We study spatial isovector meson correlators in $N_f=2$ QCD with dynamical domain-wall fermions on $32^3\times 8$ lattices at temperatures $T=220-380$ MeV. We measure the correlators of spin-one ($J=1$) operators including vector, axial-vector, tensor and axial-tensor. Restoration of chiral $U(1)_A$ and $SU(2)_L \times SU(2)_R$ symmetries of QCD implies degeneracies in vector--axial-vector ($SU(2)_L \times SU(2)_R$) and tensor--axial-tensor ($U(1)_A$) pairs, which are indeed observed at temperatures above $T_c$. Moreover, we observe an approximate degeneracy of all $J=1$ correlators with increasing temperature. This approximate degeneracy suggests emergent $SU(2)_{CS}$ and $SU(4)$ symmeries at high temperatures, that mix left- and right-handed quarks., This revised version contains all corrections that will appear in the forthcoming erratum

We compute the topological susceptibility $\chi_t$ of lattice QCD with $2+1$ dynamical quark flavors described by the M\"obius domain wall fermion. Violation of chiral symmetry as measured by the residual mass is kept at $\sim$1 MeV or smaller. We measure the fluctuation of the topological charge density in a `slab' sub-volume of the simulated lattice using the method proposed by Bietenholz {\it et al.} The quark mass dependence of $\chi_t$ is consistent with the prediction of chiral perturbation theory, from which the chiral condensate is extracted as $\Sigma^{\overline{\rm MS}} (\mbox{2GeV}) = [274(13)(29)\mbox{MeV}]^3$, where the first error is statistical and the second one is systematic. Combining the results for the pion mass $M_\pi$ and decay constant $F_\pi$, we obtain $\chi_t = 0.229(03)(13)M_\pi^2F_\pi^2$ at the physical point., Comment: 23pages, 10figures, metadata abstract corrected

We study the vector and axial-vector current correlators in perturbative and non-perturbative regimes of QCD. The correlators in Euclidean coordinate space are calculated on the lattice using the M\"obius domain-wall fermion formulation at three lattice spacings covering 0.044--0.080~fm. The dynamical quark effects of $2+1$ light flavors are included. The sum $V+A$ and the difference $V-A$ of the vector ($V$) and axial-vector ($A$) current correlators calculated on the lattice after extrapolating to the physical point agree with those converted from the ALEPH experimental data of hadronic $\tau$ decays. The level of the agreement in the $V+A$ channel is about $1.3\sigma$ or smaller in the region of $|x|\ge0.4$~fm, while that in the $V-A$ channel is about $1.8\sigma$ at $|x|=0.74$~fm and smaller at other distances. We also extract the hiral condensate from the short-distance correlators on the lattice using the PCAC relation. Its result extrapolated to the chiral and continuum limit is compatible with other estimates at low energies., Comment: 32 pages, 19 figures

We investigate the properties of background gauge field configurations that act as disorder for the Anderson localization mechanism in the Dirac spectrum of QCD at high temperatures. We compute the eigenmodes of the M\"obius domain-wall fermion operator on configurations generated for the $SU(3)$ gauge theory with two flavors of fermions. We identify the source of localization of the eigenmodes with gauge configurations that are approximately self-dual and support local negative fluctuations of the Polyakov loop $P_L(x)$, in the bulk of $P_L\sim 1$. We investigate the dependence of these observations on the boundary conditions of the valence operator and interpret the results in terms of monopole-instanton structures. The results presented here are from \cite{Cossu:2016scb}, where we describe more details on the methods and conclusions.

We study the topological charge in $N_f=2$ QCD at finite temperature using M\"obius domain-wall fermions. The susceptibility $\chi_t$ of the topological charge defined either by the index of overlap Dirac operator or a gluonic operator is investigated at several values of temperature $T\ (>T_c)$ varying the quark mass. A strong suppression of the susceptibility is observed below a certain value of the quark mass. The relation with the restoration of $U_A(1)$ is discussed., Comment: 8 pages, 8 figures, Proceedings of the 35th International Symposium on Lattice Field Theory, June 18-24, 2017, Granada, Spain

We determine the renormalization constants for flavor non-singlet fermion bilinear operators of M\"obius domain-wall fermions. The renormalization condition is imposed on the correlation functions in the coordinate space, such that the non-perturbative lattice calculation reproduces the perturbatively calculated counterpart at short distances. The perturbative expansion is precise as the coefficients are available up to $O(\alpha_s^4)$. We employ $2+1$-flavor lattice ensembles at three lattice spacings in the range 0.044--0.080~fm., Comment: 36 pages, 20 figures

We perform a detailed study of the phase diagram of the lattice Higgs SU(2)SU(2) model with fixed Higgs field length. Consistently with previsions based on the Fradkin–Shenker theorem we find a first order transition line with an endpoint whose position we determined. The diagram also shows cross-over lines: the cross-over corresponding to the pure SU(2)SU(2) bulk is also present at nonzero coupling with the Higgs field and merges with the one that continues the line of first order transition beyond the critical endpoint. At high temperature the first order line becomes a crossover, whose position moves by varying the temperature.

Rats with a previous history of heroin self-administration were studied to assess interactions occurring between cannabinoids and opioids in an animal model of reinstatement of heroin-seeking behaviour. Rats were trained to self-administer heroin and after a long-term extinction were primed with one of the following non-contingent non-reinforced drug administrations: saline (or vehicle), heroin, synthetic cannabinoid CB1 receptor agonists (WIN 55,212-2 or CP 55,940), opioid antagonist (naloxone) or CB1 antagonist (SR 141716A), alone or in combination. After primings, lever-pressing activity was recorded and compared to those observed during previous phases of training and extinction. Results of this study showed that (i) priming injections of heroin (0.1 mg/kg) as well as CB1 agonists WIN 55,212-2 (0.15 or 0.30 mg/kg) and CP 55,940 (0.05 or 0.1 mg/kg) completely restore heroinseeking behaviour; (ii) primings of naloxone (1 mg/kg) and SR 141716A (0.3 mg/kg) had no effect when administered alone; (iii) heroin-induced reinstatement was fully prevented by pre-treatment with either naloxone or SR 141716A; (iv) pre-treatment with SR 141716A significantly reduced WIN 55,212-2 and CP 55,940 priming effects. These results suggest that cannabinoid CB1 receptors play an important role in the mechanisms underlying relapse to heroin-seeking and depict CB1 antagonists as possible therapeutic agents for use in the prevention of relapse to heroin abuse. 2005 Elsevier Ltd. All rights reserved.

We report clinical findings, risk factors and neurological and cognitive long-term outcome in three Italian children aged 7, 8 and 5, respectively, who experienced cerebral venous sinus thrombosis (CVST). All children presented with headache, associated to nausea, vomiting and papilloedema. None suffered from epileptic seizures. In two of them a paresis of the sixth cranial nerve with diplopia was found. Diagnosis was confirmed by magnetic resonance imaging angiography (angio MRI) in all cases. In all patients plasma levels of protein C, protein S, antithrombin III (AT III), antiphospholipid antibodies (ApA) and homocysteine were detected. Furthermore, factor V Leiden mutation, prothrombin mutation G20210A and MTHFR mutation were searched for. A Protein C reduction was detected in all patients at onset; this finding, however, was not confirmed at follow-up in all of them. At one-year follow-up, neurological examination was normal in all children and neuropsychological assessment, aimed at excluding linguistic and non-linguistic cognitive deficits, revealed normal performances in two of them. In the third child, cognitive assessment confirmed a previously diagnosed developmental dyslexia.

We recently provided evidence for a functional link between cannabinoid and opioid endogenous systems in relapse to heroin-seeking behaviour in rats. In the present study, we aimed at investigating whether the previously observed cross-talk between cannabinoids and opioids could be extended to mechanisms underlying relapse to cannabinoid-seeking behaviour after a prolonged period of abstinence. In rats previously trained to intravenously self-administer the synthetic cannabinoid receptor (CB1) agonist WIN 55,212-2 (12.5 microg kg(-1) inf(-1)) under a fixed ratio (FR1) schedule of reinforcement, noncontingent nonreinforced intraperitoneal (i.p.) priming injections of the previously self-administered CB1 agonist (0.25 and 0.5 mg kg(-1)) as well as heroin (0.5 mg kg(-1)), but not cocaine (10 mg kg(-1)), effectively reinstate cannabinoid-seeking behaviour following 3 weeks of extinction. The selective CB1 receptor antagonist SR 141716A (0.3 mg kg(-1) i.p.) does not reinstate responding when given alone, but completely prevents the cannabinoid-seeking behaviour triggered by WIN 55,212-2 or heroin primings. The nonselective opioid antagonist naloxone (1 mg kg(-1) i.p.) has no effect on operant behaviour per se, but significantly blocks cannabinoid- and heroin-induced reinstatement of cannabinoid-seeking behaviour. These results provide the first evidence of drug-induced reinstatement of cannabinoid-seeking behaviour, and further strengthen previous findings on a cross-talk between the endogenous cannabinoid and opioid systems in relapse mechanisms to drug-seeking.

There is currently substantial evidence that Cannabis sativa derivates act on brain reward in a way very similar to other drugs of abuse and exert numerous pharmacological effects through their interaction with various neurotransmitters and neuromodulators. Among them, the endogenous opioids seem to play an important role in modulating the addictive properties of cannabinoids. Given the plethora of research activity on such a topic, this brief review is necessarily focused on cannabinoid/opioid interaction in reward-related events and restricted to the recent literature. Recent findings from our and other laboratories concerning cannabinoid reinforcing effects as revealed by behavioral animal models of addiction are here summarized. Evidence is then provided demonstrating a functional cross-talk between the cannabinoid and opioid systems in the mutual modulation of the addictive behavior; accordingly, very recent data from transgenic mice lacking either the cannabinoid CB1 or opioid receptors are also presented. Finally, the role of the endogenous cannabinoid system in relapse to opioids is investigated by means of extinction/reinstatement animal models following a period, even prolonged, of drug abstinence. Altogether, the reviewed studies provided a better understanding of the neurobiological mechanisms involved in cannabinoid actions and revealed a bidirectional interaction between the endogenous cannabinoid and opioid systems in reward that extends to central mechanisms underlying relapsing phenomena. Challenges for the future involve elucidation of the neuroanatomical substrates of cannabinoids action, even in light of the therapeutic potential of these compounds.

Because opioid and cannabinoid systems have been reported to interact in the modulation of addictive behaviour, this study was aimed at investigating the ability of cannabinoid agents to reinstate or prevent heroin-seeking behaviour after a prolonged period of extinction. In rats previously trained to self-administer heroin intravenously, non-contingent non-reinforced priming administrations of heroin and cannabinoids were presented after long-term extinction, and lever pressing following injections was observed. Results showed that: (i) intravenous priming infusions of heroin (0.1 and 0.2 mg/kg) lead to reinstatement of drug-seeking behaviour; (ii) intraperitoneal priming injections of the central cannabinoid receptor agonists R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazinyl) (1-naphthalenyl)methanonemesylate (WIN 55,212-2, 0.15 and 0.3 mg/kg) and (-)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP 55,940, 0.05 and 0.1 mg/kg), but not delta9-tetrahydrocannabinol (delta9-THC, 0.1-1.0 mg/kg), effectively restored heroin-seeking behaviour; (iii) intraperitoneal priming injection of the central cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)4-methyl-1H-pyrazole-3-carboxamide (SR 141716A, 0.3 mg/kg) did not reinstate responding, but (iv) completely prevented heroin-induced reinstatement of drug-seeking behaviour. Moreover, heroin-seeking behaviour was still present for a few days following cannabinoid primings, indicating a long-lasting effect of cannabinoids on responding for heroin. These findings indicate that relapse to heroin after an extended drug-free period is triggered by cannabinoid agonists and that SR 141716A prevents drug-seeking behaviour, suggesting that the use of the cannabinoid antagonist could have some therapeutic benefits in heroin-induced relapse.

We investigate the eigenvalues of nearly chiral lattice Dirac operators constructed with five-dimensional implementations. Allowing small violation of the Ginsparg-Wilson relation, the HMC simulation is made much faster while the eigenvalues are not significantly affected. We discuss the possibility of reweighting the gauge configurations generated with domain-wall fermions to those of exactly chiral lattice fermions., Comment: 7 pages, 3 figures, presented at the 31st International Symposium on Lattice Field Theory (Lattice 2013), 29 July-3 August 2013, Mainz, Germany

The present study was designed to explore the relationship between the cannabinoid and opioid receptors in animal models of opioid-induced reinforcement. The acute administration of SR141716A, a selective central cannabinoid CB1 receptor antagonist, blocked heroin self-administration in rats, as well as morphine-induced place preference and morphine self-administration in mice. Morphine-dependent animals injected with SR141716A exhibited a partial opiate-like withdrawal syndrome that had limited consequences on operant responses for food and induced place aversion. These effects were associated with morphine-induced changes in the expression of CB1 receptor mRNA in specific nuclei of the reward circuit, including dorsal caudate putamen, nucleus accumbens, and septum. Additionally, the opioid antagonist naloxone precipitated a mild cannabinoid-like withdrawal syndrome in cannabinoid-dependent rats and blocked cannabinoid self-administration in mice. Neither SR141716A nor naloxone produced any intrinsic effect on these behavioral models. The present results show the existence of a cross-interaction between opioid and cannabinoid systems in behavioral responses related to addiction and open new strategies for the treatment of opiate dependence.

The rewarding effects of morphine, cocaine, amphetamine and nicotine were evaluated in CB1 receptor knockout mice by means of an intravenous self-administration model. Experiments were carried out on drug-naive animals using a nose-poking response (NPR)-like as operandum. The results of the present study indicate that morphine did not induce intravenous self-administration in mutant CB1 receptor knockout mice, whereas it was significantly self-administered by the corresponding wild type mice. On the contrary, cocaine, amphetamine and nicotine were self-administered to the same extent by both wild type and CB1 receptor knockout mice. These data clearly indicate that the CB1 cannabinoid receptor is essential not only for the expression of cannabinoid reinforcing effects but also for the modulation of morphine rewarding effects. The specificity of such interaction is supported by the finding that contrary to morphine, cocaine, d-amphetamine and nicotine were self-administered by mice at the same extent either in presence or in absence of the CB1 receptor.

It has been reported that, as well as morphine, the cannabinoid CB1 receptor agonist WIN 55,212-2 failed to induce intravenous self- administration in mutant CB1 receptor knockout (CB1(-/-)) mice but not in the corresponding wild type (CB1(+/+)) mice. To verify whether this functional interaction responsible for opioid rewarding effects was specific or could also be extended to other drugs of abuse, we have evaluated the ability of cocaine, amphetamine and nicotine to induce intravenous self- administration in both CB1(-/-) and CB1(+/+) mice. The results showed that, contrary to morphine, the other drugs of abuse were intravenously self- administered to the same extent by both wild type and CB1(-/-) mice. This points to a specific role of the CB1 receptor in the opioid motivational and rewarding properties. In addition, since mesolimbic dopamine transmission is known to have a pivotal role in reward mediation, the effect of morphine on limbic dopamine release in CB1(-/-) and CB1(+/+) mice has been investigated and compared with the effect of cocaine. Morphine did not modify dopamine release in the nucleus accumbens of CB1(-/-) mice whereas it dose- dependently stimulated dopamine release in the corresponding CB1(+/+) mice. In contrast, cocaine increased dopamine release in both strains of mice, showing that its effect on dopamine transmission was not linked to the cannabinoid system. Taken together, our results clearly show that the CB1 receptor is essential for the expression of the behavioural and biochemical effects of morphine. This extends previous observations on a functional specific interaction between endogenous cannabinoid and opiate systems in the central mechanisms of reward.

Knowledge about the balance between heritable and nonheritable risk in multiple sclerosis (MS) is based on twin studies in high-prevalence areas. In a study that avoided ascertainment limitations and directly compared continental Italy (medium-prevalence) and Sardinia (high-prevalence), we ascertained 216 pairs from 34,549 patients. This gives a twinning rate of 0.62% among MS patients, significantly less than that of the general population. In continental Italy, probandwise concordance was 14.5% (95% confidence interval, 5.1-23.8) for monozygotic and 4.0% (95% confidence interval, 0.8-7.1) for dizygotic twins. Results in Sardinia resemble those in northern populations but in limited numbers. Monozygotic concordance was 22.2% (95% confidence interval, 0-49.3) probandwise, but no concordant dizygotic pairs were identified. A questionnaire on 80 items possibly related to disease cause was administered to 70 twin pairs, 135 sporadic patients, and 135 healthy volunteers. Variables positively (7) or negatively (2) associated with predisposition and concordance in twins largely overlapped and were mainly linked to infection. If compared with previous studies, our data demonstrate that penetrance in twins appears to correlate with MS prevalence. They highlight the relevance of nonheritable variables in Mediterranean areas. The apparent underrepresentation of MS among Italian twins draws attention to protective factors, shared by twins, that may influence susceptibility.

In this paper we discuss the effect of microgravity on T cells and we present the data of studies with two new machines for 0 g simulations. Several experiments in space show that mitogenic T cell activation is lost at 0 g. Immunocytochemistry indicates that such effect is associated with changes of the cytoskeleton. Biochemical studies suggest that the lack of expression of the interleukin-2 receptor is one of the major causes of the loss of activity. In fact, interleukin-2 is the third signal required for full activation. In order to deepen our investigations we are now working with the free-fall machine, FFM, invented by D. Mesland, and with the random positioning machine, RPM, or three-dimensional clinostat, developed by T. Hoson. The FFM produces periods of free-fall lasting approximately 800 ms followed by bounces of 15-30 g lasting 45-60 ms. The RPM eliminates the effect of gravity by rotating biological specimen randomly around two orthogonal axes. While the FFM failed to reproduce the results obtained with T lymphocytes in space, the data from the RPM are in good agreement with those in real microgravity. In fact, the inhibition of the mitotic index in the RPM is 89% compared to static controls. The RPM (as the FFM) can carry markedly larger specimen than the fast rotating clinostat and thus allows to conduct comprehensive studies to select suitable biological objects for further investigations in space.

Marijuana is one of the most widely used illicit recreational drugs. However, contrary to the majority of drugs abused by humans, there is a general opinion that rewarding effects are not manifested by animals. We studied a synthetic cannabinoid agonist WIN 55,212-2 using an intravenous self-administration model in drug-naive mice. The results of this study show that WIN 55,212-2 was intravenously self-administered by mice in a concentration-dependent manner according to a bell-shaped curve. Thus, self-administration of WIN 55,212-2 significantly increased, with respect to the vehicle self-administration control group, at concentrations of 0.5 and 0.1 mg/kg per injection. However, at WIN 55,212-2 concentration of 0.5 mg/kg per injection, self-administration significantly decreased. The results obtained show how WIN 55,212-2 is able to elicit both rewarding and aversive effects depending on the concentration used. Pretreatment of mice with the cannabinoid CB1 receptor antagonist SR 141716A (0.25 mg/kg, i.p.) completely prevented WIN 55,212-2 (0.1 mg/kg per injection) self-administration, indicating that WIN 55,212-2 rewarding effects are specifically mediated by cannabinoid CB1 receptors.

Gamma-hydroxybutyric acid (GHB) is an endogenous compound present in mammalian brain suggested as a putative neurotransmitter, which has been shown to affect several aspects of dependence from various classes of drugs of abuse. In the present study, two sets of experiments were performed to investigate the effects of acute pretreatment with GHB on intravenous cocaine self-administration in rats. In the first experiment GHB was administered intragastrically at the doses of 175, 350, and 700 mg/kg to Long–Evans rats trained to self-administer cocaine using nose-poke as operandum. In the second experiment, GHB was administered intraperitoneally at the doses of 100, 200, and 400 mg/kg to Wistar rats trained to self-administer cocaine intravenously using lever-pressing as operandum. In both experiments acute pretreatment with GHB significantly and dose dependently reduced cocaine self-administration. The effectiveness of GHB was similar in both experiments, indicating that the effect of GHB on cocaine self-administration is independent of animal strain, route of administration, and type of operant response required. These results indicate that GHB reduces cocaine-seeking behavior in rats, modulating the acute reinforcing effect of cocaine. The clinical effectiveness of GHB in dependence from various classes of abused drugs warrants further studies to evaluate the possibility that GHB might represent a useful therapeutic agent for cocaine addiction in humans.

We study the non-perturbative determination of the renormalization constants of flavor non-singlet quark bilinear operators on the lattice. The renormalization condition is imposed on correlation functions of bilinear operators in the coordinate space. The results are converted to the value at 2 GeV in the $\rm\overline{MS}$ scheme by a perturbative matching. The calculation is carried out on gauge configurations generated with the Mobius domain-wall fermions at two lattice spacings $a^{-1} = 2.4$ GeV and $a^{-1} = 3.6$ GeV., Comment: 7 pages, 7 figures; talk presented at Lattice 2014 -- 32nd International Symposium on Lattice Field Theory, 23-28 June, 2014, Columbia University New York, NY

Gamma-hydroxybutyric acid (GHB), a putative neurotransmitter or neuromodulator found in the mammalian brain, has been successfully used in clinical practice to alleviate both alcohol and opiate withdrawal symptoms. In the present study we used a conditioned place preference (CPP) paradigm to investigate whether GHB possesses rewarding properties in rats. In order to exclude possible artifacts due to experimental design, we evaluated the possibility of a shift in preference when rats are conditioned either on their non-preferred side or on a randomly assigned side of conditioning. In both experiments GHB was seen to induce CPP. Although to date the physiological role of this compound still remains unclear, there is no doubt that GHB, further to its proven effect on alcohol and opiates, possesses rewarding properties of its own. The abuse liability afforded by this drug suggests the use of particular caution in handling GHB as a clinically useful drug.

IntroductionCardiovascular disease (CVD) remains as the first cause ofdeath worldwide [1, 2]. It is known that a rising heart failureincidence is associated with unhealthy life styles and in-creasing life expectance. Current therapies are typicallysymptomatic and, even though they provide some survivalbenefit, they cannot reverse the loss of contractile cardiactissue due to ischemic injury. For this reason, high expect-ances are associated to the recent developments in stem cellbiology and regenerative medicine that promise to replacedamaged or lost cardiac muscle with healthy tissue and thusto improve the quality of life and survival in patients withvarious cardiomyopathies [3].The recent identification of different classes of cardiacprogenitor cells suggests that the heart, classically considereda terminally differentiated, post-mitotic organ, may rathercontain a stem cell compartment, responsible for both tissueturn-over and regeneration, which follows acute or chronicdamage to the cardiac tissue [4–6]. Several groups havealready reported the isolation of different types of cardiacstem-like cells based on distinct cell surface markers, suchas c-kit, Isl-1 and Sca-1 [7–11] or the ability to generategenuine cardiomyocytes and integrate into heart tissue asinduced pluripotent stem cells [12], or also in relation to theircapacity to influence the neovascularization of the ischemictissue, as satellite cells [13]. These cells are able to restorecardiac function after ischemic injury, although with variableefficiency [7, 14]. Another type of cells associated withthe heart was mesoangioblast, a class of vessel-associatedstem cells that can differentiate into various mesoderm celltypes.Theywereoriginallydescribedinthemouseembryonicdorsal aorta [15] and later similar cells have been identifiedand characterized from postnatal small vessels of humanskeletal muscle [16] and mouse and human heart [4, 17].However, the experiments carried out until now werepredominantly performed on mice and human. This restrictssignificantly the possibility to apply the results obtained inpreclinical studies that cannot be performed using the hu-man as a model and, at the same time, are limited by theevident differences between mouse and humans, such astheir size, mice heart rate and their general anatomy [18,19]. In particular, human and mouse hearts diverge in thecoronary architecture, the variations of which are muchbigger in humans compared to mice. As a consequence,whereas the size and location of the ischemic area are fairlyconstant in the mouse, a much larger variation exists in thehuman [20]. Differences can also be appreciated at thecellular level, as indicated by the higher capillary densityand the larger cross sectional area of the myocytes in hu-man, in comparison to the mouse [21, 22]. Consequently,extrapolation of murine systems, particularly after inductionof cardiovascular stress, must be meticulously monitored,when applied clinically, because of the obvious differences

X.P.S. at various electron take-off angles of the Si 2p and Auger KLL core energy levels, for “scratched” and “unscratched” monocrystalline Si (100) surfaces, has been performed to investigate the causes of diamond nucleation enhancement. Subtle changes in the Si and in the thin Si-oxide overlayer spectra have been observed. In addition, the intensity oscillations due to the emitted electron diffraction and focusing effects, usually occurring for monocrystalline materials, have been observed and found to be considerably damped for the “scratched” sample surfaces. These experimental observations suggest that the overall effect of the “scratching” may be associated with the creation of a certain degree of atomic disorder at the Si substrate surface. The microroughness created by this pretreatment may provide Si dangling bond configurations, otherwise not present or available at the Si (100) or (111) surfaces, suitable to match the C diamond tetrahedra.