Searches for heavy Higgs bosons in two-Higgs-doublet models and for t→ch decay using multilepton and diphoton final states in pp collisions at 8 TeV

Searches are presented for heavy scalar (H) and pseudoscalar (A) Higgs bosons posited in the two doublet model (2HDM) extensions of the standard model (SM). These searches are based on a data sample of pp collisions collected with the CMS experiment at the LHC at a center-of-mass energy of root s = 8 TeV and corresponding to an integrated luminosity of 19.5 fb(-1). The decays H -> hh and A -> Zh, where h denotes an SM-like Higgs boson, lead to events with three or more isolated charged leptons or with a photon pair accompanied by one or more isolated leptons. The search results are presented in terms of the H and A production cross sections times branching fractions and are further interpreted in terms of 2HDM parameters. We place 95% C.L. cross section upper limits of approximately 7 pb on sigma B for H -> hh and 2 pb for A -> Zh. Also presented are the results of a search for the rare decay of the top quark that results in a charm quark and an SM Higgs boson, t -> ch, the existence of which would indicate a nonzero flavor-changing Yukawa coupling of the top quark to the Higgs boson. We place a 95% C.L. upper limit of 0.56% on B(t -> ch).

Illustrated key for the identification of the known zoeal stages of brachyuran crabs (Crustacea: Decapoda) from tropical and subtropical Brazil, southwestern Atlantic

Approximately 370 brachyuran species have so far been recorded from the Brazilian coast, 123 of which have had their larval stages fully or partially described. The pictorial guide allows the identification of the first zoea of 110 species. The remaining 13 species with known larval stages are treated to the genus level because of difficulties in the morphological differentiation of closely related species.

Dental caries associated factors in 12 year-old schoolchildren from a municipality in the state of São Paulo, Brazil

Objective To analyze the possible association between dental caries, fluorosis and the need for treatment in 12 year-old schoolchildren and the socioeconomic conditions of parents/guardians in the city of Franca, in the state of São Paulo. Methods A random sample of schoolchildren aged 12 was obtained from the school records in Franca, using a systematic random technique. The epidemiological survey was carried out by a single calibrated examiner, on 258 public and private schoolchildren in order to obtain the prevalence of dental caries, the need for treatment and the severity of dental fluorosis. Parents/guardians were also interviewed to assess their socioeconomic conditions (education and per capita income). We used multiple correlation analysis to investigate associations between category variables. Results It was possible to identify two distinct groups, with associations between the variables: the first group, represented by schoolchildren with average prevalence of caries, need for treatment, low level of parental education and income; and a second group represented by schoolchildren with low prevalence of caries, no need for treatment, high parental education and income. The two dimensions explained approximately 35% of total inertia. The factors within each group are related. Conclusion High income and parental education are associated with the low prevalence of dental caries but there is no association with dental fluorosis.

Intrinsic uncoupling in the ATP synthase of Escherichia coli. Studies on WT and ε-truncated mutants

The H+/ATP ratio in the catalysis of ATP synthase has generally been considered a fixed parameter. However, Melandri and coworkers have recently shown that, in the ATP synthase of the photosynthetic bacterium Rb.capsulatus, this ratio can significantly decrease during ATP hydrolysis when the concentration of either ADP or Pi is maintained at a low level (Turina et al., 2004). The present work has dealt with the ATP synthase of E.coli, looking for evidence of this phenomenon of intrinsic uncoupling in this organism as well. First of all, we have shown that the DCCD-sensitive ATP hydrolysis activity of E.coli internal membranes was strongly inhibited by ADP and Pi, with a half-maximal effect in the submicromolar range for ADP and at 140 µM for Pi. In contrast to this monotonic inhibition, however, the proton pumping activity of the enzyme, as estimated under the same conditions by the fluorescence quenching of the ΔpH-sensitive probe ACMA, showed a clearly biphasic progression, both for Pi, increasing from 0 up to approximately 200 µM, and for ADP, increasing from 0 up to a few µM. We have interpreted these results as indicating that the occupancy of ADP and Pi binding sites shifts the enzyme from a partially uncoupled state to a fully coupled state, and we expect that the ADP- and Pi-modulated intrinsic uncoupling is likely to be a general feature of prokaryotic ATP synthases. Moreover, the biphasicity of the proton pumping data suggested that two Pi binding sites are involved. In order to verify whether the same behaviour could be observed in the isolated enzyme, we have purified the ATP synthase of E.coli and reconstituted it into liposomes. Similarly as observed in the internal membrane preparation, in the isolated and reconstituted enzyme it was possible to observe inhibition of the hydrolytic activity by ADP and Pi (with half-maximal effects at few µM for ADP and at 400 µM for Pi) with a concomitant stimulation of proton pumping. Both the inhibition of ATP hydrolysis and the stimulation of proton pumping as a function of Pi were lost upon ADP removal by an ADP trap. These data have made it possible to conclude that the results obtained in E.coli internal membranes are not due to the artefactual interference of enzymatic activities other than the ones of the ATP synthase. In addition, data obtained with liposomes have allowed a calibration of the ACMA signal by ΔpH transitions of known extent, leading to a quantitative evaluation of the proton pumping data. Finally, we have focused our efforts on searching for a possible structural candidate involved in the phenomenon of intrinsic uncoupling. The ε-subunit of the ATP-synthase is known as an endogenous inhibitor of the hydrolysis activity of the complex and appears to undergo drastic conformational changes between a non-inhibitory form (down-state) and an inhibitory form (up-state)(Rodgers & Wilce, 2000; Gibbons et al., 2000). In addition, the results of Cipriano & Dunn (2006) indicated that the C-terminal domain of this subunit played an important role in the coupling mechanism of the pump, and those of Capaldi et al. (2001), Suzuki et al. (2003) were consistent with the down-state showing a higher hydrolysis-to-synthesis ratio than the up-state. Therefore, we decided to search for modulation of pumping efficiency in a C-terminally truncated ε mutant. A low copy number expression vector has been built, carrying an extra copy of uncC, with the aim of generating an ε-overexpressing E.coli strain in which normal levels of assembly of the mutated ATP-synthase complex would be promoted. We have then compared the ATP hydrolysis and the proton pumping activity in membranes prepared from these ε-overexpressing E.coli strains, which carried either the WT ε subunit or the ε88-stop truncated form. Both strains yielded well energized membranes. Noticeably, they showed a marked difference in the inhibition of hydrolysis by Pi, this effect being largely lost in the truncated mutant. However, pre-incubation of the mutated enzyme with ADP at low nanomolar concentrations (apparent Kd = 0.7nM) restored the hydrolysis inhibition, together with the modulation of intrinsic uncoupling by Pi, indicating that, contrary to wild-type, during membrane preparation the truncated mutant had lost the ADP bound at this high-affinity site, evidently due to a lower affinity (and/or higher release) for ADP of the mutant relative to wild type. Therefore, one of the effects of the C-terminal domain of ε appears to be to modulate the affinity of at least one of the binding sites for ADP. The lack of this domain does not appear so much to influence the modulability of coupling efficiency, but instead the extent of this modulation. At higher preincubated ADP concentrations (apparent Kd = 117nM), the only observed effects were inhibition of both hydrolysis and synthesis, providing a direct proof that two ADP-binding sites on the enzyme are involved in the inhibition of hydrolysis, of which only the one at higher affinity also modulates the coupling efficiency.

Francesco Platone de' Benedetti, il principe dei tipografi bolognesi. Annali tipografici (1482-1496).

This work is focused on the reconstruction of the intellectual biography of Francesco Platone de' Benedetti, prince of the Bologna's printers (1482-1486), that is the same with his typographical outputs. The research had been divided in two parts: the first, with his life, invesitigated by archive documents, and the second part, focused on the census of his editions, with a particular attention to his types. The research on the typographical types had been developed with Adobe Photoshop, that had allowed me to virtually reconstruct the cases of the Gotic and Roman types used by de' Benedetti.

Immunoconiugati contenenti tossine vegetali o siRNA per la deplezione selettiva di cellule leucemiche. Preparazione, citotossicità e studi di mutagenesi sito-specifica.

CD33 is a myeloid cell surface marker absent on normal hematopoietic stem cells and normal tissues but present on leukemic blasts in 90% of adult and paediatric acute myeloid leukaemia (AML) cases. By virtue of its expression pattern and its ability to be rapidly internalized after antibody binding, CD33 has become an attractive target for new immunotherapeutic approaches to treat AML. In this study two immunoconjugates were constructed to contain a humanised single-chain fragment variable antibody (scFv) against CD33 in order to create new antibody-derived therapeutics for AML. The first immunoconjugate was developed to provide targeted delivery of siRNAs as death effectors into leukemic cells. To this purpose, a CD33-specific scFv, modified to include a Cys residue at its C-terminal end (scFvCD33-Cys), was coupled through a disulphide bridge to a nona-d-arginine (9R) peptide carrying a free Cys to the N-terminal. The scFvCD33-9R was able to completely bind siRNAs at a protein to nucleic acid ratio of about 10:1, as confirmed by electrophoretic gel mobility-shift assay. The conjugate was unable to efficiently transduce cytotoxic siRNA (siTox) into the human myeloid cell line U937. We observed slight reductions in cell viability, with a reduction of 25% in comparison to the control group only at high concentration of siTox (300 nM). The second immunoconjugate was constructed by coupling the scFvCD33-Cys to the type 1 ribosome inactivating protein Dianthin 30 (DIA30) through a chemical linking The resulting immunotoxin scFvCD33-DIA30 caused the rapid arrest of protein synthesis, inducing apoptosis and leading ultimately to cell death. In vitro dose-dependent cytotoxicity assays demonstrated that scFvCD33-DIA30 was specifically toxic to CD33-positive cell U937. The concentration needed to reach 50 % of maximum killing efficiency (EC50) was approximately 0.3 nM. The pronounced antigen-restricted cytotoxicity of this novel agent makes it a candidate for further evaluation of its therapeutic potential.

Identificazione di un profilo molecolare di rischio nei pazienti pediatrici affetti da Linfoma di Hodgkin

Obiettivi: nonostante i miglioramenti nel trattamento, circa il 30% dei pazienti pediatrici affetti da Linfoma di Hodgkin (LH) in stadio avanzato recidiva o muore per progressione di malattia e i correnti metodi predittivi biologico-clinici non consentono di individuare tali pazienti. L’obiettivo dello studio è stato quello di definire un profilo molecolare di rischio che correli con l’outcome in questi pazienti. Materiali e metodi: studio retrospettico condotto su pazienti pediatrici affetti da LH omogeneamente trattati dal 2004 in poi. Su tali pazienti è stato intrapreso uno studio di validazione di marcatori molecolari già identificati in studi esplorativi precedenti. 27 geni sono stati analizzati in RT PCR su campioni di tessuto istologico prelevato alla diagnosi fissato in formalina e processato in paraffina relativi a una coorte di 37 pazienti, 12 ad outcome sfavorevole e 25 ad outcome favorevole. Risultati: dall’analisi univariata è emerso che solo l’espressione di CASP3 e CYCS, appartenenti al pathway apoptotico, è in grado di influenzare l’EFS in modo significativo nella nostra coorte di pazienti. Lo studio delle possibili combinazioni di questi geni ha mostrato l’esistenza di 3 gruppi di rischio che correlano con l’EFS: alto rischio (down regolazione di entrambi i geni), rischio intermedio (down regolazione di uno solo dei 2 geni), basso rischio (up regolazione di entrambi i geni). Dall’analisi multivariata è emerso che CASP3 è l’unica variabile che mantiene la sua indipendenza nell’influenzare la prognosi con un rischio di eventi di oltre il doppio di chi ha un’espressione bassa di questo gene. Conclusioni: i risultati ottenuti sulla nostra coorte di pazienti pediatrici affetti da LH confermano l’impatto sulla prognosi di due marcatori molecolari CASP3 e CYCS coinvolti nel patwhay apoptotico. La valutazione del profilo di espressione di tali geni, potrebbe pertanto essere utilizzata in corso di stadiazione, come criterio di predittività.

Proposta di traduzione e analisi di parti del libro “La Collina” di Andrea Delogu e Andrea Cedrola

At first, the main author of the book was presented together with the Italian source text: it was pointed out her double role of author and protagonist of the very events narrated in the book, inspired from facts which truly happened and which have to do with the story of her family. Afterwards, the translation part itself follows. Some pages taken from the original Italian book were translated into English; the parts which have been chosen are various extracts which were thought as a leading thread to understand the meaning and the intention of the entire book. After the translation, the analysis part was presented, where idiomatic expressions which can be found in great quantity throughout the book, are explained and commented. Here, clarifications can also be found concerning geographical and historical references, and something about the main characters who stand for people that truly existed. Finally some other little extracts from the book were included: they were translated and some translating choices were explained. These extra parts were integrated in the thesis in order to point out the main difficulty of translating the book La Collina, that is, the presence of a great deal of idiomatic and slang expressions both of everyday colloquial use and concerning the field of drugs. The English translation of these parts had to sound natural and spontaneous to an English-speaking readership, which should not notice they were translated from Italian. A great deal of research on the Internet was carried out in order to make sure those expressions didn’t seem contrived and unnatural in English: this was one of the main concerns of the translation.

Feasibility and diagnostic effectiveness of new capsule endoscopy techniques

Since its approval by FDA in 2001, capsule endoscopy revolutionized the study of small bowel. One of the main limitations of its diffusion has been the high cost. More recently, a new videocapsule system (OMOM CE) has been developed in China and obtained the CE mark. Its cost is approximately half that of other capsule systems. However, there are few studies regarding the clinical experience with this new videocapsule system and none of them has been performed in the western world. Among the limitations of capsule endoscopy, there is also one linked to the diagnostic yield. The rapid transit of the device in the proximal segments implies a high risk of false negatives; an indirect confirmation of this limit is offered by the poor ability to identify the papilla of Vater. In addition, recent studies show that in patients with obscure gastrointestinal bleeding, the negative outcome of capsule endoscopy is correlated to a significant risk of recurrence of anemia in the short term, as well as the presence of small bowel lesions documented by a second capsule endoscopy. It was recently approved the use of a new device called "CapsoCam" (CapsoVision, Inc. Saratoga) characterized by four side cameras that offer a panoramic view of 360 degrees, instead of the front to 160°. Two recent pilot studies showed comparable safety profiles and diagnostic yield with the more standardized capsule. Namely, side vision has made possible a clear visualization of the papilla in 70% of cases. The aim of our study is to evaluate the feasibility and diagnostic yield of these two new devices, which first may allow a reduction in costs. Moreover, their complementary use could lead to a recovery diagnostic in patients with false negative results in an initial investigation.

Cannabinoid receptor 1 and 2 agonists increase lipid accumulation in hepatocytes

Cannabinoid receptors CB1 and CB2 are expressed in the liver, but their regulation in fatty hepatocytes is poorly documented. The aim of this study was to investigate the effects of selective CB1 or CB2 agonists on the expression of key regulators of lipid metabolism.

Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study

Hepatitis C virus (HCV) induces chronic infection in 50% to 80% of infected persons; approximately 50% of these do not respond to therapy. We performed a genome-wide association study to screen for host genetic determinants of HCV persistence and response to therapy.

In vivo evaluation in cynomolgus monkey brain and metabolism of [¹⁸F]fluorodeprenyl: a new MAO-B pet radioligand

In this study, we evaluated the in vivo characteristics of a new monoamine oxidase type B (MAO-B) radioligand, [¹⁸F]fluorodeprenyl, by positron emission tomography (PET) in two cynomolgus monkeys. The brain uptake of [¹⁸F]fluorodeprenyl was more than 7% (600% SUV) of the total injected radioactivity and similar to that of [¹¹C]deprenyl, an established MAO-B radioligand. The highest uptake was observed in the striatum, one of the MAO-B-rich regions, with a peak at approximately 2-3 min after injection, followed by lower uptake in the thalamus and the cortex and lowest uptake in the cerebellum. Brain uptake of [¹⁸F]fluorodeprenyl was largely inhibited by preadministration of the MAO-B inhibitor, L-deprenyl, whereas clorgyline, a MAO Type A blocker, had no significant inhibitory effect, thus demonstrating selectivity for MAO-B. [¹⁸F]Fluorodeprenyl showed relatively slow metabolism with the presence of two radiometabolite peaks with similar retention time as the labeled metabolites of [¹¹C]deprenyl. These results suggest that [¹⁸F]fluorodeprenyl is a potential PET radioligand for visualization of MAO-B activity.

Characterisation of extreme winter precipitation in Mediterranean coastal sites and associated anomalous atmospheric circulation patterns

We present an analysis of daily extreme precipitation events for the extended winter season (October–March) at 20 Mediterranean coastal sites covering the period 1950–2006. The heavy tailed behaviour of precipitation extremes and estimated return levels, including associated uncertainties, are derived applying a procedure based on the Generalized Pareto Distribution, in combination with recently developed methods. Precipitation extremes have an important contribution to make seasonal totals (approximately 60% for all series). Three stations (one in the western Mediterranean and the others in the eastern basin) have a 5-year return level above 100 mm, while the lowest value (estimated for two Italian series) is equal to 58 mm. As for the 50-year return level, an Italian station (Genoa) has the highest value of 264 mm, while the other values range from 82 to 200 mm. Furthermore, six series (from stations located in France, Italy, Greece, and Cyprus) show a significant negative tendency in the probability of observing an extreme event. The relationship between extreme precipitation events and the large scale atmospheric circulation at the upper, mid and low troposphere is investigated by using NCEP/NCAR reanalysis data. A 2-step classification procedure identifies three significant anomaly patterns both for the western-central and eastern part of the Mediterranean basin. In the western Mediterranean, the anomalous southwesterly surface to mid-tropospheric flow is connected with enhanced moisture transport from the Atlantic. During ≥5-year return level events, the subtropical jet stream axis is aligned with the African coastline and interacts with the eddy-driven jet stream. This is connected with enhanced large scale ascending motions, instability and leads to the development of severe precipitation events. For the eastern Mediterranean extreme precipitation events, the identified anomaly patterns suggest warm air advection connected with anomalous ascent motions and an increase of the low- to mid-tropospheric moisture. Furthermore, the jet stream position (during ≥5-year return level events) supports the eastern basin being in a divergence area, where ascent motions are favoured. Our results contribute to an improved understanding of daily precipitation extremes in the cold season and associated large scale atmospheric features.

Influence of Durotomy on Laser-Doppler Measurement of Spinal Cord Blood Flow in Chondrodystrophic Dogs with Thoracolumbar Disk Extrusion

OBJECTIVES: To assess influence of durotomy on spinal cord blood flow (SCBF) in chondrodystrophic dogs with thoracolumbar disk extrusion. STUDY DESIGN: Prospective cohort study. ANIMALS: Chondrodystrophic dogs with thoracolumbar disk extrusion (n = 11). METHODS: Diagnosis was based on neurologic signs, magnetic resonance imaging (MRI) findings, and surgical confirmation. Regional SCBF was measured 3 times intraoperatively by laser-Doppler flowmetry: (1) before surgical decompression; (2) immediately after decompression by hemilaminectomy-durotomy; and (3) after 15 minutes of lesion lavage. A standardized hemilaminectomy and durotomy performed by the same neurosurgeon, was used to minimize factors that could influence measurement readings. RESULTS: A significant increase in intraoperative SCBF was found immediately after spinal cord decompression and durotomy in dogs but SCBF returned to previous levels or lower after 15 minutes of lavage. Changes in SCBF were not associated with duration of clinical signs; neurologic status, degree of spinal cord compression, or signal intensity changes as assessed by MRI. CONCLUSION: Durotomy does not increase SCBF in dogs with disk extrusion associated spinal cord compression.