The joint Task Group on clinical utility of labelled antibodies of the Society of Nuclear Medicine Europa (SNME) and the European Nuclear Medicine Society (ENMS)

In September 1985 a task group on the clinical utility of labelled antibodies was founded by the Society of Nuclear Medicine - Europe. This document was elaborated to report the aims and the programs of the group. In September 1986 the European Nuclear Medicine Society decided to participate in this initiative and a joint task group was created. INITIAL DOCUMENT: A. The aims to the Task Group are to monitor, co-ordinate and promote research and clinical application of techniques using radiolabelled antibodies in nuclear medicine. A.1. The Group should develop into a major point of reference, giving scientific and technical support to each member of the Society involved in this field. B. To pursue these purposes it will be necessary to develop the following: B.1. Criteria to evaluate the suitability of antigen-antibody systems for tumour detection and/or therapy. B.2. Criteria for quality control of radioimmunoreagents. B.3. Criteria for the prevention of adverse reactions or damage due to the reagent. B.4. Selection of suitable dosimetric methods for diagnostic or therapeutic applications. B.5. Elaboration of protocols for clinical experiments, including appropriate techniques to be applied in single cases. B.6. Organization of cooperative studies. C. The Task Group should promote: C.1. Informal meetings between the members of the Group. C.2. Workshops open to the members of the Society and other researchers. C.3. Publication of reports in appropriate journals.     

Prediction of multi-criteria optimization (MCO) parameter efficiency in volumetric modulated arc therapy (VMAT) treatment planning using machine learning (ML)

PurposeTo predict the impact of optimization parameter changes on dosimetric plan quality criteria in multi-criteria optimized volumetric-modulated-arc therapy (VMAT) planning prior to optimization using machine learning (ML).MethodsA data base comprising a total of 21,266 VMAT treatment plans for 44 cranial and 18 spinal patient geometries was generated. The underlying optimization algorithm is governed by three highly composite parameters which model a combination of important aspects of the solution. Patient geometries were parametrized via volume- and shape properties of the voxel objects and overlap-volume histograms (OVH) of the planning-target-volume (PTV) and a relevant organ-at-risk (OAR). The impact of changes in one of the three optimization parameters on the maximally achievable value range of five dosimetric properties of the resulting dose distributions was studied. To predict the extent of this impact based on patient geometry, treatment site, and current parameter settings prior to optimization, three different ML-models were trained and tested. Precision-recall curves, as well as the area-under-curve (AUC) of the resulting receiver-operator-characteristic (ROC) curves were analyzed for model assessment.ResultsSuccessful identification of parameter regions resulting in a high variability of dosimetric plan properties depended on the choice of geometry features, the treatment indication and the plan property under investigation. AUC values between 0.82 and 0.99 could be achieved. The best average-precision (AP) values obtained from the corresponding precision/recall curves ranged from 0.71 to 0.99.ConclusionsMachine learning models trained on a database of pre-optimized treatment plans can help finding relevant optimization parameter ranges prior to optimization.     

Analysis of the compartmentalization of myristoyl-CoA:protein N-myristoyltransferase in Saccharomyces cerevisiae.

Myristoyl-CoA:protein N-myristoyltransferase (NMT) catalyzes the cotranslational, covalent attachment of a rare fatty acid, myristic acid (C14:0), to the amino-terminal glycine residue of a number of eukaryotic proteins involved in cellular growth and signal transduction as well as several viral proteins necessary for assembly-replication. NMT has become a target for both anti-viral and anti-fungal therapy. Analysis of purified Saccharomyces cerevisiae NMT plus yeast strains with conditional lethal nmt1 mutations have provided insights about how this process is regulated in vivo. We have now defined the location of NMT in two strains of S. cerevisiae to better understand the functional and spatial relationships between this enzyme and cellular systems that generate its acyl-CoA and peptide ligands. Western blot studies using an affinity purified antibody raised in rabbits against purified S. cerevisiae NMT indicate that the acyltransferase represents 0.06% of total cellular proteins in an exponentially growing haploid strain with a wild type NMT1 allele. Another strain containing a single, integrated copy of a GAL1/NMT1 fusion gene and a nmt1 null allele had 12-fold higher levels of NMT when grown on galactose-containing media. This increase in NMT production had no detectable effects on growth or cellular morphology. Cell fractionation studies, confocal fluorescence immunocytochemical analysis, and immunogold electron microscopic surveys of fixed, gelatin-embedded cryosections of both strains revealed that NMT is a cytosolic protein that is not associated with cellular membranes (including the endoplasmic reticulum and plasma membrane), the nucleus, mitochondria, Golgi apparatus, or vacuoles. This finding is discussed in light of what is known about the location and activities of enzymes involved in de novo fatty acid biosynthesis and in amino-terminal processing of nascent proteins.     

Italian activities in biomass gasification

The role of ENEA (Italian Commission for Nuclear and Alternative Energy Sources) in supporting and promoting technological research in biomass gasification is illustrated. The main interests are: (a) biomass (wood and agricultural residues) gasificaiton for its application in the Developing Countries and/or in specific industrial applications and (b) RDF gasification as an energy supply for some industrial sectors. The more active Italian firms involved in manufacturing gasifiers are indicated. The performance of several producer gas systems has been examined and experimental tests have been carried out for long-term operation in field trials.Standards and procedures for the evaluation of technical performance and safety requirements of wood gasifiers have been developed and tested.     

Design of radiolabelled ligands for the imaging and treatment of cancer

The specialised medical field of Nuclear Medicine is concerned with the use of unsealed sources of radioactivity either to diagnose or treat a range of diseases. In this regard it can be distinguished from the field of Radiotherapy which uses sealed radioactive sources for treatment. The range of diseases in which Nuclear Medicine plays a role is wide and includes, among others, the fields of microbiology, endocrinology, neurology, oncology and cardiovascular medicine. However, cancer probably represents the most important and growing area of application for this modality. Nuclear Medicine employs radiopharmaceuticals. These are radiolabelled ligands that have the ability to interact with molecular targets that are relevant in the aetiology or treatment of cancer and in many respects Nuclear Medicine can be considered the archetype for the application of 'Molecular Medicine'. An example of a Nuclear Medicine Positron Emission Tomography (PET) scan is shown in Fig. 2. There is great interest in developing new radioligands that allow us to image the expression of the ever increasing range of biological pathways being discovered in the post-genomic area. Designing effective radiopharmaceuticals, however, requires an understanding of a number of radiopharmaceutical sciences including aspects of chemistry, physics, cell and molecular biology, and physiology.     

Two N-myristoyltransferase isozymes play unique roles in protein myristoylation, proliferation, and apoptosis

N-myristoyltransferases (NMT) add myristate to the NH(2) termini of certain proteins, thereby regulating their localization and/or biological function. Using RNA interference, this study functionally characterizes the two NMT isozymes in human cells. Unique small interfering RNAs (siRNA) for each isozyme were designed and shown to decrease NMT1 or NMT2 protein levels by at least 90%. Ablation of NMT1 inhibited cell replication associated with a loss of activation of c-Src and its target FAK as well as reduction of signaling through the c-Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathway. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assays showed that depletion of either NMT isozyme induced apoptosis, with NMT2 having a 2.5-fold greater effect than NMT1. Western blot analyses revealed that loss of NMT2 shifted the expression of the BCL family of proteins toward apoptosis. Finally, intratumoral injection of siRNA for NMT1 or for both NMT1 and NMT2 inhibited tumor growth in vivo, whereas the same treatment with siRNA for NMT2 or negative control siRNA did not. Overall, the data indicate that NMT1 and NMT2 have only partially overlapping functions and that NMT1 is critical for tumor cell proliferation.     

Molecular cloning and expression analysis of the replacement histone H3 gene of Italian ryegrass (Lolium multiflorum)

The replacement histone H3 gene and its 5'-flanking sequence were isolated from Italian ryegrass by polymerase chain reaction and inverse polymerase chain reaction, respectively. Expression analysis showed that this gene is constitutively expressed in the entire plant. The expression level in leaves was found to be significantly low when compared with that in other tissues. However, the gene expression level in leaves was increased by the treatment with abscisic acid and abiotic stresses such as cold, heat and high-salinity (NaCl). The motif search of the 5'-flanking sequence of the replacement histone H3 gene revealed the presence of several potential cis-acting elements that could respond to the above-mentioned abiotic stresses. In addition to defence-related elements, we also found type I and II-/III-like elements, which are highly conserved motifs in the 5'-regulatory sequence of plant histone genes that are expressed specifically during the S-phase. Experiments using transgenic Italian ryegrass plants proved that the isolated 5'-flanking sequence of the replacement histone H3 gene, which was fused to a beta-glucuronidase reporter gene, was fully functional for inducing gene expression under various abiotic stress conditions.     

Levels of uroporphyrinogen decarboxylase (URO-D) in erythrocytes of Italian porphyria cutanea tarda patients.

Porphyria cutanea tarda (PCT) is a human metabolic disorder due to the acquired or genetic impairment of uroporphyrinogen decarboxylase (URO-D) activity, the fifth enzyme of the heme biosynthetic pathway. A classification of inherited and non-inherited forms is based on the enzyme activity levels in red blood cells (RBC). Clinical manifestations of PCT are often precipitated by triggering factors such as alcohol, drug abuse, estrogens, virus infections, hepatotoxic chemicals and hepatic siderosis. We measured URO-D activity in RBC from a large sample of Italian PCT patients in order to define the enzyme activity distribution and to attempt a correlation among activity, risk factors and clinical outcome. Three classes of patients with low, normal and over-normal URO-D activity were defined according to control values. Low URO-D levels were present in 25.8% of patients, suggesting the familial form of PCT (type II). In this group, the outcome of PCT seems to be less influenced by risk factors. Patients with over-normal URO-D activity in RBC deserve further investigation.     

An (R)-specific N-methyltransferase involved in human morphine biosynthesis

The biosynthesis of morphine, a stereochemically complex alkaloid, has been shown to occur in plants and animals. A search in the human genome for methyltransferases capable of catalyzing the N-methylation of benzylisoquinoline alkaloids, as biosynthetic precursors of morphine, yielded two enzymes, PNMT (EC 2.1.1.28) and NMT (EC 2.1.1.49). Introduction of an N-terminal poly-histidine tag enabled purification of both proteins by immobilized metal affinity chromatography. Recombinant PNMT and NMT were characterized for their catalytic activity towards four benzylisoquinolines: tetrahydropapaveroline (THP), 6-O-methyl-THP, 4′-O-methyl-THP and norreticuline. Human PNMT accepted none of the offered alkaloids and was only active with its established substrate, phenylethanolamine. The second enzyme, human NMT, converted all four benzylisoquinolines, however, with a strict preference for (R)-configured morphine precursors. Determination of kinetic parameters of NMT for the four (R)-configured benzylisoquinoline alkaloids by LC–MS/MS revealed (R)-norreticuline to be the best substrate with an even higher catalytic activity as compared to the previously reported natural substrate tryptamine. In addition, isolation of the morphine precursor salutaridine from urine of mice injected (i.p.) with (R)-THP provides new evidence that the initial steps of morphine biosynthesis in mammals occur stereochemically and sequentially differently than in plants and suggests an involvement of the herein characterized (R)-specific NMT.     

A new mitochondrial haplotype confirms the distinctiveness of the Italian wolf (Canis lupus) population

In the past century the Italian wolf has been repeatedly indicated as a distinct subspecies, Canis lupus italicus, due to its unique morphology and its distinctive mtDNA control region (CR) monomorphism. However, recent studies on wolf x dog hybridization in Italy documented the presence of a second mtDNA CR haplotype (W16), previously found only in wolves from Eastern Europe, casting doubts on the genetic uniqueness of the Italian wolves. To test whether this second haplotype belongs to the Italian wolf population, we genotyped 92 wolf DNA samples from Italy, Slovenia, Greece and Bulgaria at four mtDNA regions (control-region, ATP6, COIII and ND4 genes) and at 39 autosomal microsatellites. Results confirm the presence of two mtDNA multi-fragment haplotypes (WH14 and WH19) in the Italian wolves, distinct from all the other European wolves. Network analyses of the multi-fragment mtDNA haplotypes identified two strongly differentiated clades, with the Italian wolf WH14 and WH19 multi-fragment haplotypes rooted together. Finally, Bayesian clustering clearly assigned all the wolves sampled in Italy to the Italian population, regardless of the two different multi-fragment haplotypes. These results demonstrate that the W16 CR haplotype is part of the genetic pool of the Italian wolf population, reconfirming its distinctiveness from other European wolves. Overall, considering the presence of unique mtDNA and Y-linked haplotypes, the sharply different frequencies of genome-wide autosomal alleles and the distinct morphological features of Italian wolves, we believe that this population should be considered a distinct subspecies.     

Potential role of N-myristoyltransferase in pathogenic conditions

N-Myristoyltransferase (NMT) is the enzyme that catalyzes the covalent transfer of myristic acid to the N-terminal glycine residue of a protein substrate. In this review article, I summarize that NMT may have a potential role in cardiac muscle in the experimentally induced ischemia-reperfusion rat model and also in the streptozotoein-induced diabetic rat. Both the expression and activity of NMT were increased by ischemia-reperfusion. Immunohistochemical studies showed cytosolic localization of NMT in normal rat heart and predominant nuclear localization after ischemia followed by reperfusion. However, the localization of NMT is reversed by treatment with a calpain inhibitor (ALLM N-Ac-Leu-Leu-methioninal). During ischemia-reperfusion, the degradation of c-Src, which is a substrate of NMT, was observed. These findings suggested that the Src signaling may be impaired in ischemia-reperfusion owing to the altered localization of NMT from cytoplasm to nucleus. Streptozotocin-induced diabetes (an animal model for insulin-dependent diabetes mellitus) resulted in a 2.0-fold increase in rat liver NMT activity as compared with control animals. In obese (fa/fa) Zucker rats (an animal model for non-insulin-dependent diabetes mellitus), there was an approximately 4.7-fold lower liver particulate NMT activity as compared with control lean rat livers. Administration of sodium orthovanadate to the diabetic rats normalized liver NMT activity. These results would indicate that rat liver particulate NMT activity appears to be inversely proportional to the level of plasma insulin, implicating insulin in the control of N-myristoylation. These are the first studies demonstrating the role of NMT in the pathogenesis of ischemia-reperfusion and diabetes mellitus. These conditions remain an important area of investigation.     

Types of the Italian freshwater goby Padogobius nigricans (Canestrini, 1867)

The location of type material of the Italian freshwater goby Gobius fluviatilis var. nigricans Canestrini, 1867 was previously unknown. However, syntypes of this taxon have been identified now in the Museo Universitario di Storia Naturale e della Strumentazione Scientifica, Modena, Italy. Also this material is the type series of Gobius avernensis , described by Canestrini in 1868. Vestigial predorsal squamation in Padogobius nigricans is noted.     

Solid-phase microextraction (SPME) analysis of six Italian populations of Ephedra nebrodensis Tineo ex Guss. subsp. nebrodensis

Headspace solid-phase microextraction (HS-SPME) coupled with GC/FID and GC/MS was applied for the first time in the analysis of the volatile fraction of an Ephedra species. Notably, six Italian populations (Marche, Abruzzo, and Sardinia) of Ephedra nebrodensis subsp. nebrodensis, covering almost the entire Italian area, were investigated to examine the chemical variability and to support the taxonomy of the species. A fiber screening with polymethylsiloxane (PDMS), Carboxen(TM) /polymethylsiloxane (CAR/PDMS), and polymethylsiloxane/divinylbenzene (PDMS/DVB) coatings, together with an optimization of the extraction conditions were carried out before analysis of the six populations. A total of 119 volatiles were identified in the headspace of different samples, accounting for 63.35-100.00% of the total volatiles. A great variability was found in the qualitative composition of different samples, since only 18 components were in common among all populations. The headspace composition was dominated by sesquiterpene hydrocarbons (52.30-88.32%), with β-maaliene (traces-7.49%), β-patchoulene (traces-1.29%), β-panasinsene (traces-6.85%), α-isocomene (traces-31.25%), α-trans-bergamotene (traces-6.95%), alloaromadendrene (traces-33.20%), α-acoradiene (traces-9.41%), and γ-muurolene (0.61-16.33%) being the most abundant constituents. Noteworthy is the occurrence in a sample of two major unknown sesquiterpenes, one hydrocarbon (24.49%, RI: 1396) and one oxygenated compound (10.37%, RI: 1591), whose mass spectra were reported for the first time. Multivariate chemometric techniques, such as cluster analysis (CA) and principal component analysis (PCA), were used to characterize the samples according to the geographical origin.     

Evaluation of isotope discrimination in (13)C-based metabolic flux analysis

This paper describes a modified noninvasive microtest electrophysiological technology (NMT) for vacuolar H⁺ flux detection. In this NMT system, the vacuole isolation procedure and buffer slope were modified, and the measuring errors from small spherical geometry were corrected. The trends in changes of vacuolar H⁺ flux (ΔH⁺ flux) after ATP or PP_i supply calculated by NMT were consistent with the activities of V-ATPase and PPase measured by traditional methods. These findings indicate that our modified NMT is an appropriate method for vacuolar H⁺ flux detection.     

Dysplasie fibreuse des os en imagerie hybride TEMP/TDM

Fibrous dysplasia of the bone (FDB) is a benign congenital but non-hereditary bone disorder in which normal bone is replaced by pseudofibrous tissue containing an immature osteogenesis. It is frequently fortuitously discovered during a radiological or nuclear medicine scan. The main goal of this article is to give useful clinical and imaging information for the diagnosis of FDB in the daily practice of Nuclear Medicine.     

Surprising longhorned beetle (Coleoptera, Cerambycidae) richness along an Italian alpine valley

In this paper we report about 88 longhorned beetles (Cerambycidae) species found in 6929 hectares and distributed along an altitudinal gradient of 1500 m of an Italian alpine valley (Val Genova, central-eastern Italian Alps). The species richness, result merging data from sixty years (1947-2007) of entomological surveys, corresponds to the 32% of the Italian cerambycid fauna confirming the high richness/surface ratio, probably unique in the Alps. The effect of thirteen environmental variables was tested on the species richness, but only the elevation resulted able to affect it. The species richness decrease with altitude not gradually, but experience a strong step above 1700 m a.s.l.. The highest species richness (average values of 42 species) was recorded at the lowest and mid elevations (between 800 and 1600 m a.s.l.). The species turnover along the altitudinal gradient is low suggesting moderate habitat turnover along the valley.One of the eighty-eight observed species, Tragosoma depsarium,is classified near threatened by the IUCN. Our data suggest that the wilderness of the valley close to the suitable management of grasslands and forests, help to support high level of cerambycids diversity. This biodiversity is good indicators of health of the wood saproxylic assemblages, as well an important food source for many vertebrate predators.     

Science under politics. An Italian nightmare

Is political interference in science unavoidable? A look at the situation in Italy highlights what can happen if scientists do not defend their independence and their science.The second half of the twentieth century has seen the relationship between society, politics and science become increasingly complex and controversial. Particularly in democratic countries—where the application of scientific research and the diffusion of knowledge have contributed to a significant increase in the well-being of citizens—scientists have had to face interference from political, religious and ideological interest groups. Even the seemingly powerful scientific community in the USA was affected by an ‘epidemic of politics'' under the administration of President George W. Bush. This ‘infection of science'' was characterized by inappropriate political meddling in research driven by political prejudices and religious arguments, especially in more controversial research fields. During his tenure, Bush established science and health policies that went against expert advice, and in several cases made controversial appointments to key positions in scientific and health agencies (Kennedy, 2003; Mooney, 2005). This was all the more shocking because science and scientists in the USA have generally enjoyed a great deal of political independence.Even the seemingly powerful scientific community in the USA was affected by an ‘epidemic of politics'' under the administration of President George W. BushSuch ‘epidemics of politics'' are not exclusive to the USA; political interference in scientific research and its applications is endemic in many countries. Such meddling can take various forms depending on the country in question, the different democratic decision-making processes at work, the relative influences of politics, economics and society on the scientific community and, to some extent, the level of scientific literacy of the public. During the past two decades, science in Italy has been suffering from a particularly severe form of political interference that we believe deserves international consideration, if only to act as a warning for other countries.Italian science has often found itself entangled in political controversy. After the unification of the country in 1861, during the last two decades of the nineteenth century and the first decade of the twentieth century, Italian scientists actively participated in political debates about how to improve and integrate the fragments of Italian society, culture, economy, health, and so on. But from the beginning, they often confused political battles with their professional status and/or scientific disagreements (Casella et al, 2000). Throughout the fascist era, the scientific community—similarly to the rest of the country—was subjected to the rule of Benito Mussolini''s regime (Maiocchi, 2004). After the Second World War, both Catholic and Marxist ideologies prevented the rise of an autonomous scientific community, so Italian scientists had and still have little cultural or political influence.During the past two decades, science in Italy has been suffering from a particularly severe form of political interference…Yet Italians are far from hostile to science; they follow advances in research and technology with keen interest and expectation, as shown by a fairly recent survey (Eurobarometer, 2005a, b). Politicians, influential intellectuals and lobbyists who oppose research and innovation for various reasons have therefore adopted a strategy of trying to manipulate and censor facts. Rather than confronting the scientific evidence directly, they maintain a high degree of political control over scientific research and its applications. As a result, the validity of scientific evidence has become optional and its use arbitrary in public and political discussions.This situation has been virtually de rigueur since the advent of Silvio Berlusconi in 1994, although it would be unfair to say that the current Italian Prime Minister is the main culprit. Indeed, many factors have acted together to make Italian science prey to political influence, including the predominance of non-transparent and nepotistic approaches to the public funding of research, the chronic cultural and political impotence of Italian scientists and the waning professional quality of the national political and intellectual elites (Corbellini, 2009). The examples provided here should illustrate the weaknesses of the Italian scientific community and how politicians—irrespective of their political colour—have been reluctant to understand and respect the value of scientific procedures and evidence.In 1997, the Italian media regaled its readers with stories about a new and supposedly effective treatment for cancer, which had been developed by the physician and professor Luigi Di Bella, then at the University of Modena. The media storm was so convincing that a judge in Apulia ordered the local public health authorities to provide patients with the drug cocktail required for the therapy, despite the absence of a scientific basis for the claims or clinical evidence for the efficacy of the treatment (Remuzzi & Schieppati, 1999). The Di Bella multi-therapy (DBM)—as the treatment was called—soon became a topic for political wrangling between the members of right-wing parties who supported the treatment, and the more sceptical, ruling centre-left party. This continued until the health ministry, backed by prominent Italian oncologists, eventually agreed to sponsor a controversial clinical trial. This exposed the Italian medical community to international scorn (Müllner, 1999) and highlighted the lack of accurate and factual scientific information in the public debate (Passalacqua et al, 1999).Politicians, influential intellectuals and lobbyists who oppose research and innovation for various reasons have therefore adopted a strategy of manipulating and censoring factsIn late 2000 and early 2001, Italian plant biotechnologists were up in arms over a decree proposed by the centre-left government''s agricultural ministry that would have banned funding for any plant research involving genetic modification (Frank, 2000). The decree was eventually withdrawn as the result of a political move to prevent the opposition from exploiting the dispute. However, when the centre-right coalition came to power in May 2001, the new Ministry of Agriculture proved equally averse to the use of genetically modified plants. As a result, research in the field of plant genetics in Italy remains virtually devoid of public funding and a series of byzantine regulations still prevent Italian farmers from using genetically modified crops, despite the lack of scientific evidence that they are dangerous. In fact, the law does not explicitly ban their use and they are routinely imported as livestock feed.Striking examples of the manipulation and censorship of science were seen during the fierce debate that followed the introduction of Law 40—which was issued in 2004 with the apparent unofficial support of the Catholic Church—that limited the use of in vitro fertilization (IVF) procedures and banned research on human embryos. According to this law, each IVF procedure is allowed to create only three embryos, all of which must be implanted into the recipient mother (Boggio, 2005). This is in contrast to international guidelines on clinical practice (www.eshre.eu). Law 40 also prohibits pre-implantation diagnosis and the cryopreservation of embryos, as well as the generation of embryonic stem-cell lines, even when these are obtained from superfluous embryos that were created before the law was enforced and are destined to be stored frozen indefinitely.In 2005, patient advocacy groups and left parties called for a referendum to abrogate Law 40. This ignited a fierce dispute with Catholic politicians, backed by a handful of scientists, who called on voters to boycott the referendum and claimed that the law was scientifically sound and improved safety for patients (Vogel, 2005; Boggio & Corbellini, 2009). Interestingly, rather than attempting to justify their position with ethical, legal, scientific or religious arguments, the supporters of Law 40 often adopted the strategy of denigrating scientific research and facts and spreading misleading information (Corbellini, 2006). They claimed, for example, that pre-implantation diagnosis did not work, that the cryopreservation of embryos was not clinically necessary and that research with embryonic stem cells was pointless because adult stem cells had been proven to be effective for treating dozens of diseases (Corbellini, 2007).According to the Italian Constitution, the referendum was invalidated as less than 50% of the electorate voted. The proportion of Italian citizens who usually vote in a referendum is about 60%, and analysis shows that most non-voters decided not to participate because they did not understand what was at stake (Corbellini, 2006). Six years later, Law 40 has finally been revised by a series of decisions at Italy''s Constitutional Court and now, in some circumstances, pre-implantation diagnosis and the cryopreservation of embryos is permitted.The preceding examples have highlighted how Italian politicians and special interest groups have stifled scientific progress and liberty within Italy. The following examples highlight how political meddling and influence are jeopardizing the competitiveness of Italian research on the international stage.The teaching of evolution came frighteningly close to being scrapped from primary school curricula in Italy under a reform instigated by the 2003 centre-right government. It was reinstated only when the issue led to a political brawl between the Cabinet and the left-wing press (Frazzetto, 2004).Italy lacks an independent agency for research and also compulsory, transparent and unbiased selection processesThe same right-wing government was also opposed to the creation of the European Research Council (ERC), arguing that the agency would be too independent from political control (ftp://ftp.cordis.europa.eu/pub/italy/docs/positionfp7_it.pdf). This is not surprising for a country in which the chairs of public research institutions and the scientific directors of research hospitals are appointed by the government (with a few notable exceptions, see Anon, 2008) and where funding is often granted in a top-down manner by governmental decree to specific institutes, without public calls or peer review (Margottini, 2008).Even when funding is subject to peer review, cases in which money ends up at laboratories that are directly affiliated with members of the evaluating commission are, unfortunately, not the exception (Italian Parliament, 2006), which highlights the widespread conflicts of interest that are allowed. Italy lacks both an independent agency for research and compulsory, transparent and unbiased selection processes. As such, the guidelines and criteria that determine which research activities receive public funding are often established directly by the respective ministries, thereby increasing the risk of political interference. This was the case in 2007, when peers of Barbara Ensoli—then at the Istituto Superiore di Sanità (ISS) in Rome—felt that she was receiving a disproportionate amount of government funding, without peer review and in spite of the fact that her work on an HIV/AIDS vaccine was, at least to some scientists, unconvincing (Cohen, 2007).Conversely, in 2009 the Ministry of Health arbitrarily excluded projects involving human embryonic stem-cell lines from a call for proposals on stem-cell research funding—one of the authors of this article, Elena Cattaneo, is now appealing in court against the ministry''s decision (Cattaneo et al, 2010). Further, in October 2010 the Italian Ministry of Health decided, motu proprio, to grant €3 million to a private foundation that claimed to have created adult human stem cells that can be tested in patients with neurodegenerative diseases. This happened in spite of the Ministry''s declarations a few months previously that allocation of public money for research should be subject to peer review.If Italian scientists want to have a leading role in shaping society and the future, they must demand, reinstate and maintain sound principles of transparency and competitiveness in the allocation of public funding. This means that individual researchers—who enjoy the ephemeral benefits gained by deference to politicians and the exploitation of conflicts of interests—should be highlighted as negative examples to the scientific community, as their behaviour is damaging not only science, but also the practice of science as a model for public ethics.We hope that international experts in sociology and science policy find that the censorship of science, the manipulation of facts and the lack of objective peer review and evaluation in Italy deserve their attention and intervene on behalf of Italian science. They would be up against an interesting paradox: such abnormal conducts are often defended in the name of alleged democratic principles. The introduction of Law 40, for example, was justified publicly under the assumption that most Italian citizens were against the use of embryonic stem cells in research—which is, incidentally, false (Eurobarometer, 2006)—and the Apulia judge''s ruling on DBM was made on the grounds of individual freedom of access to therapy, laid down by the Italian constitution.… is Italy an exception, or simply a vision of things to come in other countries?One could ask whether the situation in Italy is simply a local consequence of a deteriorating relationship between science and society, or between scientists and politicians. In other words, is Italy an exception, or simply a vision of things to come in other countries? Regardless, the predicament of Italian science and scientists should stand as a warning of what happens when the rules of transparency are overridden, the scientific community remains largely silent, scientific facts have marginal political influence and science communication is helpless against ideologically driven propaganda that manipulates facts on a large scale (Corbellini, 2010). The experience of scientists in the USA during the Bush administration shows that for other countries this possibility is not too far-fetched and that, to paraphrase the British statesman Edmund Burke (1729–1797): bad science flourishes when good scientists do nothing.? Open in a separate windowElena CattaneoOpen in a separate windowGilberto Corbellini     

Saccharomyces cerevisiae contains four fatty acid activation (FAA) genes: an assessment of their role in regulating protein N- myristoylation and cellular lipid metabolism

Saccharomyces cerevisiae has been used as a model for studying the regulation of protein N-myristoylation. MyristoylCoA:protein N- myristoyl-transferase (Nmt1p), is essential for vegetative growth and uses myristoylCoA as its substrate. MyristoylCoA is produced by the fatty acid synthetase (Fas) complex and by cellular acylCoA synthetases. We have recently isolated three unlinked Fatty Acid Activation (FAA) genes encoding long chain acylCoA synthetases and have now recovered a fourth by genetic complementation. When Fas is active and NMT1 cells are grown on media containing a fermentable carbon source, none of the FAA genes is required for vegetative growth. When Fas is inactivated by a specific inhibitor (cerulenin), NMT1 cells are not viable unless the media is supplemented with long chain fatty acids. Supplementation of cellular myristoylCoA pools through activation of imported myristate (C14:0) is predominantly a function of Faa1p, although Faa4p contributes to this process. Cells with nmt181p need larger pools of myristoylCoA because of the mutant enzyme's reduced affinity for this substrate. Faa1p and Faa4p are required for maintaining the viability of nmt1-181 strains even when Fas is active. Overexpression of Faa2p can rescue nmt1-181 cells due to activation of an endogenous pool of C14:0. This pool appears to be derived in part from membrane phospholipids since overexpression of Plb1p, a nonessential lysophospholipase/phospholipase B, suppresses the temperature-sensitive growth arrest and C14:0 auxotrophy produced by nmt1-181. None of the four known FAAs is exclusively responsible for targeting imported fatty acids to peroxisomal beta-oxidation pathways. Introduction of a peroxisomal assembly mutation, pas1 delta, into isogenic NMT1 and nmt1-181 strains with wild type FAA alleles revealed that when Fas is inhibited, peroxisomes contribute to myristoylCoA pools used by Nmt1p. When Fas is active, a fraction of cellular myristoylCoA is targeted to peroxisomes. A NMT1 strain with deletions of all four FAAs is still viable at 30 degrees C on media containing myristate, palmitate, or oleate as the sole carbon source--indicating that S. cerevisiae contains at least one other FAA which directs fatty acids to beta-oxidation pathways.     

Copper(II) and manganese(III) complexes of N'-[(2-hydroxy phenyl) carbonothioyl] pyridine-2-carbohydrazide: novel therapeutic agents for cancer

c-Src is a non-receptor tyrosine kinase which plays a significant role in the growth mediated signaling pathway impacting cellular proliferation, differentiation, mobility, survival and transformation. Myristoylation of pp60(c-src) leads to its membrane association and activation, a process catalyzed by N-myristoyltransferase (NMT). We have shown earlier increased NMT activity in the early stages of colon cancer. A novel sulfur nitrogen donor ligand and its Cu(II) and Mn(III) complexes have been prepared and characterized using various physicochemical analyses. These Cu(II) and Mn(III) complexes showed cytotoxicity against the colon cancer cell line HT29. The IC(50) for Cu(II) and Mn(III) complexes were 12.2 and 16.1 microM, respectively. HT29 cells treated with Cu(II) and Mn(III) complexes induced apoptosis and inhibited endogenous NMT activity. Furthermore, they induced higher levels of hsc70 and inhibited the expression of c-Src. Inhibition of endogenous NMT activity by metal complexes was demonstrated for the first time. This study also suggested that NMT activity is crucial for cell survival and demonstrated that cessation in activity results in apoptosis. These metal complexes may prove to be novel therapeutic agents for cancer targeting NMT.