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Objectives The Iseult MRI is an actively shielded whole-body magnet providing a homogeneous and stable magnetic field of 11.7 T. After nearly 20 years of research and development, the magnet successfully reached its target field strength for the first time in 2019. This article reviews its commissioning status, the gradient–magnet interaction test results and first imaging experience. Materials and methods Vibration, acoustics, power deposition in the He bath, and field monitoring measurements were carried out. Magnet safety system was tested against outer magnetic perturbations, and calibrated to define a safe operation of the gradient coil. First measurements using parallel transmission were also performed on an ex-vivo brain to mitigate the RF field inhomogeneity effect. Results Acoustics measurements show promising results with sound pressure levels slightly above the enforced limits only at certain frequency intervals. Vibrations of the gradient coil revealed a linear trend with the B0 field only in the worst case. Field monitoring revealed some resonances at some frequencies that are still under investigation. Discussion Gradient-magnet interaction tests at up to 11.7 T are concluded. The scanner is now kept permanently at field and the final calibrations are on-going to pave the road towards the first acquisitions on volunteers.

Elisa Giacomini, Valentina Perrone, Davide Alessandrini, Daniela Paoli, Carmela Nappi, Luca Degli Esposti CliCon S.r.l. Health, Economics & Outcomes Research, Ravenna, ItalyCorrespondence: Valentina PerroneClicon S.r.l, Health, Economics and Outcomes Research, Via Salara, 36, Ravenna, 48100, ItalyTel +39 544 38393Fax +39 544 212699Email valentina.perrone@clicon.itAbstract: The 20th century witnessed the dawn of the antibiotic revolution and is now facing the rising phenomenon of antibiotic resistance. In this narrative review, we aim to describe antibiotic resistance in clinical practice settings through population-based studies from different countries reporting the role of misuse of antibiotics in the development of resistance and the clinical and economic burden associated. The misuse of antibiotics was documented in the wide population as well as in hospitals and care facilities. It was mainly reported as over-use and inappropriate prescribing. Improper dosage regimens and longer treatment duration were regarded as pivotal factors related to antibiotic resistance; the emerging strategy of “antibiotic-de-escalation” could be the key to overcome these issues. The investigation of the self-medication attitude revealed widespread antibiotic use without following medical instructions or medical consultation. Moreover, several studies established the association of antibiotic resistance with increased risk of longer hospitalizations and mortality, highlighting the heavy clinical and economic burden of this phenomenon. In this narrative review, the widespread inappropriate use of antibiotics emerged as one of the main causes of antibiotic resistance, which negative outcomes call for the development of antibiotic stewardship programs and global surveillance networks.Keywords: antibiotic utilization, antimicrobial resistance, real-world

Valentina Perrone,1,* Luca Degli Esposti,1,* Elisa Giacomini,1 Chiara Veronesi,1 Valerio Blini,1 Marco Oderda2 1CliCon S.r.l. Health, Economics & Outcomes Research, Ravenna, Italy; 2Department of Surgical Sciences - Urology, Città Della Salute e Della Scienza Di Torino, Molinette Hospital, University of Turin, Turin, Italy*These authors contributed equally to this workCorrespondence: Valentina PerroneClicon S.r.l, Health, Economics and Outcomes Research, Ravenna, ItalyTel +39 544 38393Fax +39 544 212699Email valentina.perrone@clicon.itPurpose: To evaluate and compare the incidence of cardiovascular (CV) events in a large contemporary cohort of patients diagnosed withprostate cancer (PCa) and in treatment with GnRH agonists or GnRH antagonists.Patients and Methods: An Italian observational retrospective cohort study based on administrative databases of three local health units and two Regions was performed. PCa patients treated with GnRH agonists or antagonist were included between January 01, 2013andDecember 31, 2016. Index date (ID) was the date offirst GnRH agonist/antagonist prescriptionduringinclusion period. Follow-up was from ID to December 31, 2017. Patients were excluded if they were under abiraterone treatment or combination therapy with antiandrogens during follow-up. Theincidence rate of CV events (acute myocardial infarction, ischemic heart diseases, cerebrovascular diseases, cardiac dysrhythmias, heart failure, atherosclerosis, aneurism, other CV-related conditions) was calculated among patients not switching toandrogen deprivation therapy (ADT) in the overall cohort and in a sub-cohort of patients without previous CV events.Results: In total, 9785 (mean age 76.8 ± 8.5) patients were included: 9158 (93.6%) were treated with a GnRH agonist and 627 (6.4%) with a GnRH antagonist. Of them, 9627 did not switch toADT and were considered in the analyses. The incidence of CV events was significantly higher in patients treated with GnRH agonists rather than antagonists (8.8 vs 6.2, p=0.002). Mean time to CV event was beyond 1 year of treatment in both groups. In the multivariable regression analysis, the risk of experiencing CV events was significantly lower in patients treated with GnRH antagonist rather than those treated withGnRH agonists [HR(95% CI): 0.76 (0.60– 0.95), p=0.018]. These findings were confirmed in the sub-cohort of patients without previous CV events.Conclusion: This Italian observational study shows that most patients received a GnRH agonist rather than a GnRH antagonist prescription. GnRH antagonist seems to have a better CV risk profile than GnRH agonist, both in patients with and without a history of CV events.Keywords: cardiovascular events, GnRH agonists, GnRH antagonist, prostate cancer, real-world setting

Mentre in Russia iniziano le gare della XX edizione delle Olimpiadi Internazionali, esce il bando per l'edizione 2016 delle Olimpiadi Italiane di Astronomia con un tema di preselezione dedicato alla vita sugli altri pianeti

Concluso il concorso per decidere il nome del sito J della cometa, dove Philae atterrerà il 12 novembre, ESA diffonde delle nuove immagini dove la superficie 67P/C-G risulta sempre più attiva. Una traspirazione maggiore del previsto che, secondo i dati raccolti dallo strumento ROSINA, non ha affatto un buon odore

Uno studio russo pubblicato su Nature misura la quantità di titanio generato dalla Supernova 1987A, misurando le righe di emissione dell'elemento nei raggi X. Un altro brillante risultato permesso dalla missione INTEGRAL dell'ESA, che festeggia i dieci anni. Il commento di Pietro Ubertini (IAPS-INAF).

The stilbene scaffold is a basic element for a number of biologically active natural and synthetic compounds, and it is considered as a privileged structure. Stilbenes exemplified by resveratrol, combretastatin A-4 and pterostilbene are of significant interest for drug research and development because of their potential in therapeutic and preventive application. Resveratrol, present in grapes and other food products, plays a role in the prevention of several human pathological processes and has been suggested as an anticancer agent. Moreover, recent evidence has revealed its potential effect on the aging process, diabetes and neurological dysfunction. Combretastatin A-4, from the bark of South African bush willow Combretum caffrum, also shows significant antitumor activity. Pterostilbene is closely related to resveratrol, sharing the same unique therapeutic potential as anti-inflammatory, antineoplastic and antioxidant agent. Therefore, research and development of stilbene-based medicinal chemistry have become rapidly evolving and increasingly active topics covering almost the whole range of therapeutic fields. In the present review, we provide an overview of the role of stilbenes in medicinal chemistry. In this context, we highlight the chemical methodologies adopted for the synthesis of stilbene derivatives, and outline the successful design of novel stilbene based hybrids in the field of cancer, Alzheimer's and other relevant diseases. This information may be useful in further design of stilbene-based molecules as new leads for the development of novel agents with clinical potential or as effective chemical probes to dissect biological processes.

Leishmaniasis are globally widespread parasitic diseases which often leads to death if left untreated. Currently available drugs present different drawbacks, so there is an urgent need to develop new, safe and cost-effective drugs against leishmaniasis. In this study we tested a small library of trans-stilbene and terphenyl derivatives against promastigote, amastigotes and intramacrophage amastigote forms of Leishmania infantum. Two compounds of the series, the trans-stilbene 3 and the terphenyl 11, presented the best activity and safety profiles. Terphenyl 11 showed a leshmanicidal activity higher than pentostam and the ability to induce apoptosis selectively in Leishmania infantum while saving macrophages and primary epithelial cells. Our data indicate that terphenyl compounds, as well as stilbenes, are endowed with leishmanicidal activity, showing potential for further studies in the context of leishmanial therapy.

Given our interest in finding potential antitumor agents and in view of the multifactorial mechanistic nature of cancer, in the present work, taking advantage of the multifunctional ligands approach, new chimeric molecules were designed and synthesized by combining in single chemical entities structural features of SAHA, targeting histone deacetylases (HDACs), with substituted stilbene or terphenyl derivatives previously obtained by us and endowed with antiproliferative and pro-apoptotic activity. The new chimeric derivatives were characterized with respect to their cytotoxic activity and their effects on cell cycle progression on different tumor cell lines, as well as their HDACs inhibition. Among the other, trans -6 showed the most interesting biological profile, as it exhibited a strong pro-apoptotic activity in tumor cell lines in comparison with both of its parent compounds and a marked HDAC inhibition.

Over the past years, we synthesized a series of new molecules that are hybrids of spirocyclic ketones as complexity-bearing cores with bi- and ter-phenyls as privileged fragments. Some of these newly-shaped small molecules showed antiproliferative, pro-apoptotic and differentiating activity in leukemia cell lines. In the present study, to investigate more in depth the mechanisms of action of these molecules, the protein expression profiles of K562 cells treated with or without the compounds IND_S1, MEL_T1, IND_S7 and MEL_S3 were analyzed using two-dimensional gel electrophoresis coupled with mass spectrometry. Proteome comparisons revealed several differentially expressed proteins, mainly related to cellular metabolism, chaperone activity, cytoskeletal organization and RNA biogenesis. The major results were validated by Western blot and qPCR. To attempt integrating findings into a cellular signaling context, proteomic data were explored using MetaCore. Network analysis highlighted relevant relationships between the identified proteins and additional potential effectors. Notably, qPCR validation of central hubs showed that the compound MEL_S3 induced high mRNA levels of the transcriptional factors EGR1 and HNF4-alpha; the latter to our knowledge is reported here for the first time to be present in K562 cells. Consistently with the known EGR1 involvement in the regulation of differentiation along megakaryocyte lineage, MEL_S3-treated leukemia cells showed a marked expression of glycoprotein IIb/IIIa (CD41) and glycoprotein Ib (CD42), two important cell markers in megakaryocytic differentiation, together with morphological aspects of megakaryoblasts and megakaryocytes.

Extracellular vesicles (EVs) derived from different parts of the male reproductive tract can be internalized by human spermatozoa affecting their maturation and regulating their functions. Here we demonstrate that EVs derived from the female tract can be uptaken by sperm and affect their competence. Primary endometrial cells release EVs with a diameter between 50 and 350 nm and bear the standard vesicle and exosome marker proteins CD63, CD9, TSG101 and ALIX. The uptake of dye-labelled endometrial cell-derived EVs by spermatozoa, quantified as fluorescence intensity, was significantly higher when EVs were derived from cells in the proliferative phase. Vital, motile fluorescent sperm could be appreciated after a 48-hour co-incubation with endometrial cells previously labelled with the Vybrant™ DiO dye. EV internalization by sperm was blocked at 4 °C and by incubation with filipin, suggesting an energy-dependent process probably attributable to the lipid-raft domain mediated-endocytosis. Sperm ability to undergo capacitation and acrosome reaction was stimulated by endometrial cell-derived EVs as manifested by the increased protein tyrosine phosphorylation and evident reactivity when stimulated with a calcium ionophore. Based on these findings, EVs exchange may be suggested as an emerging way through which female reproductive tract cells can interact with the passing spermatozoa.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) deficiency, recurring in 30&ndash, 50% of patients. The common human leukocyte antigen (HLA) variant rs6903608 was found to be associated with prevalent iTTP, but whether this variant is associated with disease relapse is unknown. To estimate the impact of rs6903608 on iTTP onset and relapse, we performed a case-control and cohort study in 161 Italian patients with a first iTTP episode between 2002 and 2018, and in 456 Italian controls. Variation in rs6903608 was strongly associated with iTTP onset (homozygotes odds ratio (OR) 4.68 (95% confidence interval (CI) 2.67 to 8.23), heterozygotes OR 1.64 (95%CI 0.95 to 2.83)), which occurred over three years earlier for each extra risk allele (&beta, &minus, 3.34, 95%CI &minus, 6.69 to 0.02). Of 153 survivors (median follow-up 4.9 years (95%CI 3.7 to 6.1)), 44 (29%) relapsed. The risk allele homozygotes had a 46% (95%CI 36 to 57%) absolute risk of relapse by year 6, which was significantly higher than both heterozygotes (22% (95%CI 16 to 29%)) and reference allele homozygotes (30% (95%CI 23 to 39%)). In conclusion, HLA variant rs6903608 is a risk factor for both iTTP onset and relapse. This newly identified biomarker may help with recognizing patients at high risk of relapse, who would benefit from close monitoring or intensified immunosuppressive therapy.

The study of follicular fluid (FF) content nearby endometriomas may assist in elucidating pathophysiology, possible biomarkers related to this disease and the effect of endometriomas on ovarian physiology. As the question "how endometrioma may intrude the physiology of ovarian tissue?" is still open, we aimed to summarize the molecular evidence supporting the idea that endometriomas can negatively influence the content of the surrounding ovarian follicles. An alteration of the iron metabolism and an increased ROS (reactive oxygen species) generation characterize the intrafollicular environment adjacent to endometriomas. Other potentially negative effects include decreased testosterone and anti-Mullerian hormone FF levels although these have been only partially clarified. Alterations in lipid and proteomic patterns have been also observed in FF samples nearby endometriomas. The possibility that endometriomas per se may influence IVF clinical results as a consequence of the detrimental impact on the local intrafollicular environment is also discussed.

Objective To characterize in depth and investigate the role of exosomes present in seminal plasma in affecting parameters underlying sperm activity. Design In vitro experimental study. Setting Research hospital. Patient(s) Normozoospermic, severe asthenozoospermic, and post-vasectomy azoospermic men 18–55 years of age were considered for the study. Seminal plasma was collected and processed to separate spermatozoa and exosomes. Intervention(s) None. Main Outcomes Measure(s) Exosomes from seminal plasma were isolated and characterized by means of nanoparticle tracking analysis, transmission electron microscopy and Western blot. Exosome uptake by spermatozoa was monitored by means of immunofluorescence and flow cytometry. The effect of exosomes on spermatozoa was determined by evaluating progressive motility and capacitation, the latter assessed by means of tyrosine phosphorylation and acrosome reaction. Result(s) We isolated and characterized exosomes from seminal plasma of normo-, astheno-, and azoospermic patients. They display similar features in terms of shape, size, expression of canonic exosome markers and proteins involved in spermatozoa maturation, and fertilization capacity. After ejaculation, sperm cells are still receptive and are able to take up exosomes in a time- and pH-dependent manner. Exosomes derived from normozoospermic but not from asthenozoospermic individuals improve spermatozoa motility and trigger capacitation. Transfer of cysteine-rich secretory protein 1 from exosomes to spermatozoa may have a role in these phenomena. Conclusion(s) These findings provide evidence that: 1) sperm can still receive vesicle-derived cargo after ejaculation; 2) sperm motility and ability to undergo capacitation can benefit from exosomal transfer; and 3) semen quality is affected by male tract exosomes.

We evaluated the impact of genomic polymorphisms in folate-metabolizing, DNA synthesis and DNA repair enzymes on the clinical outcome of 108 patients with myelodysplastic syndromes (MDS) receiving best supportive care (BSC) or azacitidine. A statistically significant association between methylenetetrahydrofolate reductase (MTHFR) 677T/T, thymidylate synthase (TS) 5'-untranslated region (UTR) 3RG, TS 3'-UTR -6 bp/-6 bp, XRCC1 399G/G genotypes and short survival was found in patients receiving BSC by multivariate analysis (P

Most of the antileishmanial modern therapies are not satisfactory due to high toxicity or emergence of resistance and high cost of treatment. Previously, we observed that two compounds of a small library of trans-stilbene and terphenyl derivatives, ST18 and TR4, presented the best activity and safety profiles against Leishmania infantum promastigotes and amastigotes. In the present study we evaluated the effects of ST18 and the TR4 in 6 different species of Leishmania and the modifications induced by these two compounds in the production of 8 different cytokines from infected macrophages. We observed that TR4 was potently active in all Leishmania species tested in the study showing a leishmanicidal activity higher than that of ST18 and meglumine antimoniate in the most of the species. Moreover, TR4 was able to decrease the levels of IL-10, a cytokine able to render the host macrophage inactive allowing the persistence of parasites inside its phagolysosome, and increase the levels of IL-1β, a cytokine important for host resistance to Leishmania infection by inducible iNOS-mediated production of NO, and IL-18, a cytokine implicated in the development of Th1-type immune response.

Delayed-type hypersensitivity (DTH) is revealing cellular mediated immunity towards an antigen and can be adapted for vaccine compliance tests. This study aimed to confirm this potential for PCV2 vaccination under Italian field conditions. First farm: thirty three-week-old just-weaned piglets born from unvaccinated sows were either vaccinated (n=15) with CIRCOVAC IM 0.5mL or left unvaccinated (n=15). Five weeks later, the pigs were intradermally inoculated with 0.1-0.2mL of CIRCOVAC antigen solution in the lower abdomen area. The diameter of skin reaction (erythema) at the point of inoculation was visually inspected 24h post-inoculation. Second farm: 30 five-week-old piglets born from CIRCOVAC-routinely-vaccinated sows were either vaccinated with CIRCOVAC or left unvaccinated. The DTH reaction was analogously assessed, both before vaccination and 5 weeks post-vaccination. Piglets born from vaccinated sows were bled at weaning and all experimental animals at 5 weeks post-vaccination . Antibodies were titrated using an in-house ELISA or a seroneutralization technique. First farm: only 33% of vaccinated piglets showed high anti-PCV2 ELISA titres following vaccination. Vaccinated pigs exhibited consistent and significantly higher seroneutralizing titres than unvaccinated pigs indicating a proper vaccine take. The proportion of pigs showing erythema (100% vs. 33%) and the average diameter (25±15 mm vs. 4±7 mm) was significantly higher (p

Endometriosis is currently defined as presence of endometrial epithelial and stromal cells at ectopic sites. This simple and straightforward definition has served us well since its original introduction. However, with advances in disease knowledge, endometrial stromal and glands have been shown to represent only a minor component of endometriotic lesions and they are often absent in some disease forms. In rectovaginal nodules, the glandular epithelium is often not surrounded by stroma and frequently no epithelium can be identified in the wall of ovarian endometriomas. On the other hand, a smooth muscle component and fibrosis represent consistent features of all disease forms. Based on these observations, we believe that the definition of endometriosis should be reconsidered and reworded as 'A fibrotic condition in which endometrial stroma and epithelium can be identified'. The main reasons for this change are: (1) to foster the evaluation of fibrosis in studies on endometriosis pathogenesis using animal models; (2) to limit potential false negative diagnoses if pathologists stick stringently to the current definition of endometriosis requiring the demonstration of endometrial stromal and glands; (3) to consider fibrosis as a potential target for treatment in endometriosis. This opinion article is aimed at boosting the attention paid to a largely neglected aspect of the disease. We hope that targeting the fibrotic process might increase success in developing new therapeutic approaches.

Background Reports about the morphologic and functional characteristics of spermatozoa prepared by density gradient centrifugation (DC) or swim-up (SU) have produced discordant results. We have performed a proteomic comparison of cells prepared by DC and SU providing a molecular insight into the differences between these two methods of sperm cell isolation. Methods Protein maps were obtained by 2-dimensional (2-D) separations consisting of isoelectrofocusing (IEF) from pI 3 to 11 followed by SDS-polyacrylamide gel electrophoresis. 2-D gels were stained with Sypro Ruby. Map images of DC and SU spermatozoa were compared using dedicated software. Intensities of a given spot were considered different between DC and SU when their group mean differed by >1.5-fold (p SU and 1 was SU > DC. Proteins present in 3 of the differential spots could be identified. One DC > SU spot contained lactate dehydrogenase C and gamma-glutamylhydrolase, a second DC > SU spot contained fumarate hydratase and glyceraldehyde-3-phosphate dehydrogenase-2, and a SU > DC spot contained pyruvate kinase M1/M2. Conclusions The differences in protein levels found on comparison of DC with SU spermatozoa indicate possible dissimilarities in their glycolytic metabolism and DNA methylation and suggest that DC cells may have a better capacitation potential. Electronic supplementary material The online version of this article (doi:10.1186/s12958-015-0027-y) contains supplementary material, which is available to authorized users.

none 7 si Abstract: The hERG potassium channel is currently emerging as a potential target for the treatment of some forms of arrhythmias or to contrast an unintentional channel block caused by drugs. Despite its therapeutic relevance, so far only few compounds are described as able to enhance channel function by potentiating hERG currents. This gap is also related to the lack of hERG crystal structure which strongly limits the possibility to employ structure-based techniques in the search and design of novel activators. To overcome this limitation, in the present work, a ligand-based virtual screening was performed using as separate search queries two conformations of NS1643, the most deeply investigated and better characterized hERG activator. The library of compounds resulting from the virtual screening was then clustered based on recurring chemical features, and 5 hits were selected to be evaluated for their ability to enhance hERG current in vitro. Compound 3 showed a good activating effect, also displaying a mechanism of action similar to that of NS1643. Moreover, the most interesting compounds were further investigated by synthesizing in a parallel fashion some analogs, with the aim to get insights about structure-activity relationships. Giacomini, E.; Buonfiglio, R.; Masetti, M.; Wang, Y.; Tseng, G.-N.; Roberti, M.; Recanatini, M. Giacomini, E.; Buonfiglio, R.; Masetti, M.; Wang, Y.; Tseng, G.-N.; Roberti, M.; Recanatini, M.

Leishmania parasites are able to undergo apoptosis (programmed cell death), similarly to mammalian cells. Recently it was demonstrated in vitro the anti-leishmanial effect of some natural and synthetic stilbenoids including resveratrol and piceatannol. In this study we evaluated the Leishmanicidal activity of a pool of stilbene derivatives which had previously shown high apoptotic efficacy against neoplastic cells. All the compounds tested were capable to decrease the parasite viability in a dose-dependent manner. Trans-stilbenes proved to be markedly more effective than cis-isomers. This was different from that observed in tumor cells in which cis-stilbenes were more potent cytotoxic agents. Trans-3,4',5-trimethoxy-3'-amino-stilbene (TTAS) was the most active stilbene showing in Leishmania infantum a LD(50) value of 2.6 μg/mL. In contrast TTAS showed a low toxicity when tested on normal hemopoietic cells. This compound induced apoptosis in parasites by disrupting the mitochondrial membrane potential. Moreover it shows the ability to block Leishmania parasites in G(2)-M phase of cell cycle in agreement with the data obtained by affinity chromatography that identify tubulin as the putative target of TTAS. In conclusion, our results indicate that some stilbene derivatives are highly effective as anti-leishmanial agents and TTAS represents a pro-apoptotic agent in Leishmania parasites that merit further in vivo investigation.

One of the most prominent alterations in cancer cells is their strict dependence on the glycolytic pathway for ATP generation. This observation led to the evaluation of glycolysis inhibitors as potential anticancer agents. The inhibition of lactate dehydrogenase (LDH) is a promising way to inhibit tumor cell glucose metabolism without affecting the energetic balance of normal tissues. However, the success of this approach depends chiefly on the availability of inhibitors that display good selectivity. We identified a compound (galloflavin, CAS 568-80-9) which, in contrast to other inhibitors of human LDH, hinders both the A and B isoforms of the enzyme. To determine the mechanism of action, we collected LDH-A and -B inhibition data in competition reactions with pyruvate or NADH and evaluated the results using software for enzyme kinetics analysis. We found that galloflavin inhibits both human LDH isoforms by preferentially binding the free enzyme, without competing with the substrate or cofactor. The calculated Ki values for pyruvate were 5.46 μM (LDH-A) and 15.06 μM (LDH-B). In cultured tumor cells, galloflavin blocked aerobic glycolysis at micromolar concentrations, did not interfere with cell respiration, and induced cell death by triggering apoptosis. To our knowledge, the inhibition of LDH is, to date, the only biochemical effect described for galloflavin. Because galloflavin is not commercially available, we also describe herein a procedure for its synthesis and report its first full chemical characterization.

Il saggio ricerca il rapporto fra etica di cura e responsabilità all'interno della "prospettiva di genere".

The production and analysis frameworks for LHC experiments are demanding advanced features in the middleware functionality and a complete integration with the experiment specific software environment. They also require an effective and distributed test platform where the integrated middleware functionality is verified and certified. The deployment in a production infrastructure of such solutions imposes as well measured performance, documentation and support for correct configuration and operation. In this paper we describe the solutions, tests and results achieved in collaboration with ALICE, ATLAS, CDF, CMS and LHCb experiments to fulfill their production and analysis requirements. The middleware components considered have been the workload management system with the additional bulk submission feature, the replica catalog interface, the Virtual Organization Management System (VOMS) role definition and its integration with the policy system, job and application monitoring.

Controversial results have been obtained in studies of the effect of Mycobacterium tuberculosis on human immunodeficiency virus type 1 (HIV-1) replication in cells of the macrophage lineage. In the present study, monocyte-derived macrophages (MDMs), previously incubated for 2 days with heat-inactivated M. tuberculosis, were infected with HIV-1. M. tuberculosis consistently inhibited viral replication, and a similar result also was observed in the presence of supernatants from M. tuberculosis-stimulated MDMs, which indicates that this effect was mediated by soluble factors. Although CCR5-binding chemokines were induced by M. tuberculosis stimulation, the results of neutralization experiments indicated that it is unlikely that they were responsible for viral suppression. Inhibition occurred mainly after viral entry (demonstrated by use of a vesicular stomatitis virus G-pseudotyped HIV-1 and by analysis of HIV-1 early and late reverse-transcription products). Therefore, M. tuberculosis-induced factors may inhibit in vitro HIV-1 replication in macrophages by affecting an early postentry step in the HIV-1 cycle.