Search

In this article, a solution is proposed to the problem of making Marx’s Surplus equation work correctly, by using a version of it adapted to modern economics. In the end, the rate of profit in the economic system results to be ruled by labour exploitation and organic composition of capital, just as Marx had supposed, but this happens through ratios which only refer to Sraffa’s Standard System, not the whole economy.

A geometrical model is presented here which seems to allow some original considerations regarding the scope and results of Science and Technology (S&T) activities, aimed at searching new rational knowledge. Was this ap- proach validated? It may result in deeper thoughts over the nature of such ac- tivities and their reciprocal relationships.

This article is the follow-up of a research work about the foundations of the classical approach to the study of prices and income distribution. The author resumes an old idea put forward by A. Smith, but later rejected by the main- stream analysis. He then examines a link arising among crucial economic va- riables when the Classical and Keynesian perspectives are merged.

In this article, the attempt is made at overcoming some flaws commonly attributed to the economic thought of Adam Smith. It is then argued that such a solution may open up the possibility of fertile links between a Neo-Smithian approach and the John Maynard Keynes’ theory of income and employment.

A suggestion is provided here for an attempt at making the Classical Ap- proach to the study of prices and income distribution neutral with respect to ideological choices, a move which might perhaps promote progress in Political Economics.

The great number of theories of technological change witnesses a difficulty in devising and performing the crucial experiments which would allow a ra- tional choice among alternative explanations. A preliminary step of the methodological process that must be completed to overcome such difficulty is the construction of consistent taxonomies of the S&T Indicators available to test current theories. By rationally defining sound criteria for the measure- ment of S&T activities, a well-founded taxonomy like that will provide schol- ars with clearer and better analytical instruments for theoretical discussion. As a consequence, the empirical investigation, which always ought to be closely linked with theory, could improve as well.

Il gran numero di teorie del cambiamento tecnologico testimonia una difficoltà nell'escogitare e svolgere gli esperi- menti cruciali che permetterebbero una scelta razionale fra spiegazioni alternative. Un passo preliminare nel percorso metodologico che deve essere completato per superare tale difficoltà è la costruzione di tassonomie coerenti degli indicatori di S&T disponibili per mettere alla prova le teorie correnti.

An attempt is made here at proving a controversial intuition: real profits may be determined by prices not by wages.

Summary Primary hyperoxaluria type I (PH1) is an autosomal-recessive inborn error of liver metabolism caused by alanine:glyoxylate aminotransferase (AGT) deficiency. In silico modeling of liver metabolism in PH1 recapitulated accumulation of known biomarkers as well as alteration of histidine and histamine levels, which we confirmed in vitro, in vivo, and in PH1 patients. AGT-deficient mice showed decreased vascular permeability, a readout of in vivo histamine activity. Histamine reduction is most likely caused by increased catabolism of the histamine precursor histidine, triggered by rerouting of alanine flux from AGT to the glutamic-pyruvate transaminase (GPT, also known as the alanine-transaminase ALT). Alanine administration reduces histamine levels in wild-type mice, while overexpression of GPT in PH1 mice increases plasma histidine, normalizes histamine levels, restores vascular permeability, and decreases urinary oxalate levels. Our work demonstrates that genome-scale metabolic models are clinically relevant and can link genotype to phenotype in metabolic disorders., Graphical Abstract, Highlights • In silico model of liver metabolism reveals global metabolic alterations in PH1 • Changes in amino acid metabolism in PH1 result in a reduction of histidine and histamine • GPT overexpression normalizes histamine levels and reduces oxalate in PH1 mice, Pagliarini et al. use a computational model of liver metabolism to predict alterations caused by the loss of alanine:glyoxylate aminotransferase (AGT), resulting in primary hyperoxaluria type I (PH1). In addition to known disease biomarkers, the model predicts a reduction in histidine and histamine levels. GPT overexpression in PH1 mice normalizes histamine and oxalate levels.

The taxonomy considered here would be a crucial preliminary step towards a theory of S&T indicators. Its construction is different from that of other taxonomies in the field of innovation, since it has a methodological character, not a quantitative one. It serves as a caveat against hasty decisions, potentially damaging to progress on the study of indicators.

Expenditure on research and development (R&D) is a key indicator of the innovative efforts of countries. In this paper, we want to examine through a new approach the relationship between basic research and economic benefits. Although we are aware that the topic has already been extensively addressed, this paper differs from the previous literature because it focuses on value added trade instead of gross trade flows. We use an Exponential Random Graph Model for weighted networks to study the impact of private investment in basic research on value-added of exports in high technology, namely the domestic value added absorbed abroad. We want to understand if this measure (without intermediate imports) is able to confirm the results of the previous literature, which used gross flows. Our results show that private investment in basic research has a positive influence on exports, giving a competitive advantage in international trade.

The introduction of citational analysis has caused adaptive responses in the scientific community and its journals, which have been widely discussed in the literature on the evaluation of scientific research. In this work, we deal with the problem of quantitatively measuring the importance of scientific journals when an impact factor is not available, as occurs for most journals in the humanities areas. We conduct a survey to investigate the editorial polices of such journals. We conclude that the 'selectivity of journals in their choice of papers for publication', and the 'journal diffusion are sensitive and useful indicators, which can be used in conjunction with the classical impact indicators already available in order to evaluate the role of the journals.

CONTEXT: Patients with adrenal incidentalomas (AI) may experience detrimental consequences due to a minimal cortisol excess sustained by adrenal adenoma. SNPs of the glucocorticoid receptor gene (NR3C1) modulate individual sensitivity to glucocorticoids and may interfere with the clinical presentation. ----- OBJECTIVE: To compare the frequency of N363S, ER22/23EK and BclI SNPs in patients with AI with the general population and to evaluate whether these SNPs are linked to consequences of cortisol excess. ----- SETTING: Multicentric, retrospective analysis of patients referred from 2010 to 2014 to 4 centers (Orbassano, Milano, Messina [Italy] and Zagreb [Croatia]). ----- PATIENTS: 411 patients with AI; 153 males and 258 females and 186 from blood donors. ----- MAIN OUTCOMES MEASURES: All patients and controls were genotyped for BclI, N363S and ER22/23EK and SNPs frequency was associated with clinical and hormonal features. ----- RESULTS: SNP frequency was: SNP frequency was: N363S 5.4% (MAF 0.027), BclI 54.7% (MAF 0.328), ER22/23EK 4.4% (MAF 0.022), without any significant difference between patients and controls. N363S was more frequent in hypertensive patients (p = 0.03) and was associated with hypertension (p = 0.015) in patients with suppressed cortisol after the 1-mg DST. ----- CONCLUSIONS: Our results demonstrate that SNPs of the glucocorticoid receptor gene do not play a pathogenetic role for AI. The impact of any single SNP on the phenotypic expression of minimal cortisol excess is limited and their analysis does not provide additional data that may be exploited for patient management.

The Frascati and Oslo manuals assemble scientific activities, technological activities and their definitions in generic manner, without attempting to propose a rigorous and cogent organization of the categories. Such uncertainties could possibly be overcome by an attempt to formulate a coherent, holistic classification, retracing the indications of previous scholars concerning the broader characteristics of scientific discovery and tech- nological innovation. From such an attempt, we gather the lesson that scholars of tech- nological innovation and scientific progress must at all times be ready to reopen debate on the assertions that they have thus far formulated.

V(D)J recombination is a mechanism peculiar to the somatic rearrangement of antigen receptor genes. It requires both expression of the RAG-1 and RAG-2 recombinases and accessibility of the substrate to its recombinase and post-cleavage/DNA repair stage. TCR revision is a genetic correction mechanism that changes T cell specificity by re-activating V(D)J recombination in peripheral T cells. This process is now well described in both normal or pathological murine and human settings. Many of its features, such as the question of whether it occurs in truly mature T cells, remain to be elucidated. Its occurrence in human CD8+ T cells is also an open question. We have therefore established an in vitro model of TCR revision in mature human CD8+ T cells to determine whether down-regulation of the TCR/CD3 complex from the cell surface in the presence of IL7 as a factor favouring chromatin remodelling initiates a TCR revision pathway. Only mature CD8+ T cells carrying already-formed antigen receptors were used. CD8+ T cells treated with anti-CD3 and IL7 showed rearrangement intermediates and expressed new Vβ-chains on their surface. Investigation of the molecular pathway thus induced disclosed up-regulation of the RAG-2 transcript, but absence of the ‘canonical’ RAG-1 mRNA. A surprising finding was the demonstration of alternative splice forms of this mRNA, already expressed in untreated CD8+ T cells, encoding for the full-length RAG-1 protein, which was increased three-fold in the treated cells. All the V(D)J requirements were thus fulfilled when mature human CD8+ T cells were stimulated with anti-CD3 and IL7. Induction of TCR revision in vitro in mature T cells is an easily controllable system that could be employed in further studies to elucidate the molecular pathways involved in secondary V(D)J rearrangements in peripheral cells.

We analyzed interleukin (IL) 12 and IL-23 production by monocyte-derived dendritic cells (mono-DCs). Mycobacterium tuberculosis H37Rv and zymosan preferentially induced IL-23. IL-23 but not IL-12 was efficiently induced by the combination of nucleotide-binding oligodimerization domain and Toll-like receptor (TLR) 2 ligands, which mimics activation by M. tuberculosis, or by the human dectin-1 ligand beta-glucan alone or in combination with TLR2 ligands, mimicking induction by zymosan. TLR2 ligands inhibited IL-12 and increased IL-23 production. DC priming with interferon (IFN) gamma strongly increased IL-12 production, but was not required for IL-23 production and inhibited IL-23 production induced by beta-glucan. The pattern of IL-12 and IL-23 induction was reflected in accumulation of the IL-12p35 and IL-23p19 transcripts, respectively, but not IL-12/23p40. Although IL-23, transforming growth factor beta, and IL-6 contained in the supernatants of activated mono-DCs played a role in the induction of IL-17 by human CD4(+) T cells, IL-1beta, in combination with one or more of those factors, was required for IL-17 production, and its production determined the differential ability of the stimuli used to elicit mono-DCs to produce soluble factors directing IL-17 production. Thus, the differential ability of pathogens to induce antigen-presenting cells to produce cytokines regulates the immune response to infection.

Spinocerebellar ataxia type 8 (SCA8) (MIM 608768) is a dominantly inherited ataxia typically occurring in adulthood, with onset of the disease that may range from age 1 to 65 years [1–6]. Common initial symptoms are scanning dysarthria with a characteristic drawn-out slowness of speech and gait instability. Some individuals present with nystagmus, dysmetric saccades and, occasionally ophthalmoplegia. Hyperreflexia and extensor plantar responses are present in some severely affected individuals. Life span is typically not shortened. SCA8 is caused by repeat expansions initially thought to involve a non-coding CTG tract in the ATXN8OS gene— formerly known as SCA8 (MIM 603680)—an untranslated antisense transcript partially overlapping the Kelch-like 1 gene (KLHL1) (MIM 605332) [7]. The CTG repeat was later found to be transcribed also in the opposite direction as (CAG)n repeat in the ATXN8 gene, encoding a nearly pure polyglutamine protein [8]. An RNA toxic effect of the CUG expanded repeats has been suggested, together with the possibility of non-ATG translation (RAN translation) which occurs across long, hairpin-forming repeats and results in the accumulation of potentially toxic SCA8 polyalanine [9, 10]. The (CTG.CAG)n repeat length most often associated with ataxia ranges from 80 to 250. However, repeats from 71 to more than 1300 have been occasionally found in individuals with ataxia. The disease is characterized by a reduced penetrance most often with alleles of fewer than 100 repeats. We report two unrelated families with genomic deletions completely overlapping ATXN8OS gene and great part of KLHL1 gene. These deletions were present in a healthy parent in both families. A total of four subjects with ATXN8OS/ KLHL1 genes deletion could be studied and did not show any cerebellar symptoms or MRI changes in cerebellum.

The caspase recruitment domain gene CARD15/NOD2, encoding a cellular receptor involved in an NF-kappaB-mediated pathway of innate immunity, was first identified as a major susceptibility gene for Crohn's disease (CD), and more recently, as responsible for Blau syndrome (BS), a rare autosomal-dominant trait characterized by arthritis, uveitis, skin rash and granulomatous inflammation. While CARD15 variants associated with CD are located within or near the C-terminal leucine-rich repeat domain and cause decreased NF-kappaB activation, BS mutations affect the central nucleotide-binding NACHT domain and result in increased NF-kappaB activation. In an Italian family with BS, we detected a novel mutation E383K, whose pathogenicity is strongly supported by cosegregation with the disease in the family and absence in controls, and by the evolutionary conservation and structural role of the affected glutamate close to the Walker B motif of the nucleotide-binding site in the NACHT domain. Interestingly, substitutions at corresponding positions in another NACHT family member cause similar autoinflammatory phenotypes.

Brugada syndrome is characterised by a typical ECG with ST segment elevation in the right precordial leads. Individuals with this condition are susceptible to ventricular arrhythmias and sudden cardiac death. The principal gene responsible for this syndrome is SCN5A, which encodes the α-subunit of the Nav1.5 voltage-gated sodium channel. Mutations involving other genes have been increasingly reported, but their contribution to Brugada syndrome has been poorly investigated. Here we focused on the SCN1B gene, which encodes the β1-subunit of the voltage-gated sodium channel and its soluble β1b isoform. SCN1B mutations have been associated with Brugada syndrome as well as with other cardiac arrhythmias and familial epilepsy. In this study, we have analysed SCN1B exons (including the alternatively-spliced exon 3A) and 3'UTR in 145 unrelated SCN5A-negative patients from a single centre. We took special care to report all identified variants (including polymorphisms), following the current nomenclature guidelines and considering both isoforms. We found two known and two novel (and likely deleterious) SCN1B variants. We also found two novel changes with low evidence of pathogenicity. Our findings contribute more evidence regarding the occurrence of SCN1B variants in Brugada syndrome, albeit with a low prevalence, which is in agreement with previous reports.

This paper analyses the importance of basic research in the Italian manufacturing sector. Analysis is based mainly on the results of a specific survey on the subject, and the resulting data are processed to test general hypotheses on the innovative strategies of firms and to describe the present situation in Italian industry. From the theoretical point of view, test results appear consistent with the hypotheses put forward on the spontaneous behaviour of firms. From the descriptive point of view, the prospects for Italian industry are far from being reassuring as far as basic research is concerned.

SummaryDeletions encompassing the 5′ termini of the paired type IV collagen genes COL4A5 and COL4A6 on chromosome Xq22 give rise to Alport syndrome (AS) and associated diffuse leiomyomatosis (DL), a syndrome of disseminated smooth-muscle tumors involving the esophagus, large airways, and female reproductive tract. In this study, we report isolation and characterization of two deletion junctions. The first, in a patient described elsewhere, arose by a nonhomologous recombination event fusing a LINE-1 (L1) repetitive element in intron 1 of COL4A5 to intron 2 of COL4A6, resulting in a 13.4-kb deletion. The second, in a previously undescribed family, arose by unequal homologous recombination between the same L1 and a colinear L1 element in intron 2 of COL4A6, resulting in a >40-kb deletion. L1 elements have contributed to the emergence of this locus as a site of frequent recombinations by diverse mechanisms. These give rise to AS-DL by disruption of type IV collagen and perhaps other as yet unidentified genes, evidenced by deletions as small as 13.4 kb.

In order to implement appropriate policies to face the difficulties and remove the obstacles that hinder interdisciplinary research, it is necessary to clarify how this ever broader and more dynamic portion of science works and which incentives best support the activities of scientists. Interdisciplinary studies are a peculiar aspect of the activities performed by researchers operating at the frontier of science, for instance in cutting-edge sectors. They might encompass fields of investigation that already exist, but they cannot be exclusively ascribed to any one of them. Abstract answers regarding the very unusual matters investigated by interdisciplinary research would make it extremely difficult to provide quantitative output measurements and evaluations. Yet, the shift from general abstract answers to specific empirical problems, which is the objective of most interdisciplinary research, turns out to be an advantage when assessing this type of research. Concentrating on problems and on approaching their solutions in objective quantitative terms can allow for output measurement and assessment also in the case of interdisciplinary research. This can be achieved by using precision and efficiency parameters able to provide public policies and entrepreneurial activities with content that is as clearly defined and as rigorous as that of specialist research.

The designing of a new knowledge model – to be tested on particularly significant cultural areas such as Islands and on their historic urban spaces, taking into account the tangible and intangible elements of their historical cultural heritage – is a concrete opportunity to resume a debate aimed at identifying a scientifically correct and interdisciplinary methodology of analysis to attain thorough knowledge of the various factors that contribute to the definition of historical, architectural, anthropological, and landscape-based features of towns and historic centres, particularly those of islands. This knowledge process should strive to overcome an approach, focused mostly on the protection of individual architectural features of great historical-artistic importance. This perspective concentrates on monumental structures and major architectural works rather than on a much wider heritage, made up of artefacts displaying various levels of quality, which take on specific scientific relevance because of their mutual functional and structural relations and the historical, social, anthropological, and landscape context which they express. However, following such a method, the various disciplines involved in the research activity can assess their mutual ability to relate to one another when they deal with a wide subject, which actually includes several areas of common interest. A methodologically correct research view must provide a knowledge framework that is both detailed and comprehensive in describing the mutual relations among the features of historic centres as well as how the latter are linked to the surrounding environment and landscape. Last but not least, it can be clearly seen that such an operation would pave the way for specific sector-based interventions with great economic potential for the areas involved; even if adequate tools of such economic analysis are still lacking.

Illavoro affronta la problematica della misurazione quantitativa della scienza e della tecnologia basandosi sugli approcci più recenti al problema.

This paper considers the matter of possible links between Schumpeter’s theory of technological change and the economic theory of the classical or neo-Ricardian school. The paradigm of the neo-Ricardian theory adopted here is that found in Sraffa’s book Production of Commodities by Means of Commodities. The idea of investigating how distribution changes as technology changes take place by adapting a method originally conceived for the determination of rentes is put forth. Shifts in the hierarchy of dominant-dominated techniques are explicitly taken into account here. This way, the model helps explain the shifts in prices and production efficiency caused by the diffusion of innovation as well as the related changes in the volume of surplus generated by the economic system and how such surplus is shared among the various classes.

Uromodulin is exclusively expressed in the thick ascending limb and is the most abundant protein secreted in urine where it is found in high-molecular-weight polymers. Its biological functions are still elusive, but it is thought to play a protective role against urinary tract infection, calcium oxalate crystal formation, and regulation of water and salt balance in the thick ascending limb. Mutations in uromodulin are responsible for autosomal-dominant kidney diseases characterized by defective urine concentrating ability, hyperuricemia, gout, tubulointerstitial fibrosis, renal cysts, and chronic kidney disease. Previous in vitro studies found retention in the endoplasmic reticulum as a common feature of all uromodulin mutant isoforms. Both in vitro and in vivo we found that mutant isoforms partially escaped retention in the endoplasmic reticulum and reached the plasma membrane where they formed large extracellular aggregates that have a dominant-negative effect on coexpressed wild-type protein. Notably, mutant uromodulin excretion was detected in patients carrying uromodulin mutations. Thus, our results suggest that mutant uromodulin exerts a gain-of-function effect that can be exerted by both intra- and extracellular forms of the protein. © 2012 International Society of Nephrology.

The tumor suppressor p53 and its negative regulator MDM2 have crucial roles in a variety of cellular functions such as the control of the cell cycle, senescence, genome stability and apoptosis, and are frequently deregulated in carcinogenesis. Previous studies have highlighted the contribution of the common functional polymorphisms p53 p.Arg72Pro and MDM2 309SNP to the risk of both common cancers and Li–Fraumeni syndrome. Their possible role in retinoblastoma has recently been addressed by Castera et al, who however only studied the MDM2 309SNP. Here, for the first time, we analyzed both single nucleotide polymorphisms (SNPs) in a case–control study of 111 Italian hereditary retinoblastoma patients. We found a significant association of the p53 Pro/Pro genotype with the disease (odds ratio=3.58, P=0.002). The MDM2 309SNP showed a weak negative association of allele G that deserves further investigation. These findings further support the hypothesis that genetic variability of the p53 pathway contributes to the individual susceptibility to retinoblastoma, as shown for Li–Fraumeni syndrome and a variety of non-hereditary cancers.

Small frameshift deletions within the COL4A5 gene were identified in three Alport syndrome Italian families by non-isotopic single-strand conformation polymorphism (SSCP) screening: in family RMA, a 7-bp deletion (GGGTGAA) in exon 39; in family DGR, a 4-bp deletion (TGGA) in exon 41; in family MIB, deletion of a G in exon 50. The phenotype was characterized by juvenile-onset renal failure with sensorineural hearing loss in males, and a milder clinical pattern in heterozygous females.

Background Recent studies suggested a role for hypocretins in the neurobiology of Major Mood Disorders (MMD). The purpose of this study was to investigate hypocretin involvement in MMD evaluating whether particular alleles or genotypes of the hypocretin pathway genes (HCRT, HCRTR1 and HCRTR2) would modify the occurrence and clinical features of the disease. Methods We selected for the study 229 MMD patients and 259 healthy age-, sex- and ethnicity-matched controls. Cases and controls were genotyped for several single-nucleotide polymorphisms (SNPs) of the HCRT, HCRTR1, and HCRTR2 genes. Results We found that allelic and genotypic frequencies of the rs2271933 G > A polymorphism (Ile408Val) in the HCRTR1 gene were significantly different between cases and controls (p = 0.003 and p = 0.0004, respectively). The carriage of the A allele was associated with a significantly increased disease risk (OR:1.60, 95% C.I. 1.22–2.10). In addition, we found a significant association between HCRTR1 haplotypes and the disease (permutation p A polymorphism on the hypocretin-1 receptor function are unknown. Conclusions Our study suggests that the HCRTR1 gene or a linked locus may modulate the risk for Major Mood Disorders and supports recent studies suggesting an involvement of hypocretin neurotransmitter system in affective disorders.

In this paper we deal with the fixed capital nature of the means of production and labour employed in research and development which generate scientific and technological knowledge. We argue that these R&D current expenditures typically have the nature of fixed investments. We then present an empirical analysis which shows that expenditures on industrial R&D are more strongly linked to the formation of fixed capital than to the formation of capital in general. Applying this conclusion to the economics of research and innovation would make it possible to analyse investments in the production of scientific and technological knowledge with a higher degree of clarity and precision.

We have previously shown that whereas T-cells from normal individuals undergo accumulation of p53 and apoptosis when treated with the genotoxic agent Actinomycin D (ActD), those from Ataxia Telangiectasia (AT) and Nijmegen Breakage Syndrome (NBS) patients resist ActD-induced apoptosis [1]. We have now found similar resistance by the p53-null Jurkat T-cell line and by siRNA p53-knockdown normal T-cells. This evidence that ActD initiates a p53-dependent apoptotic responce prompted us to look for defective p53 accumulation by AT and NBS T-cells. Surprisingly the total p53 level was only slightly reduced compared to normal T cells but its intracellular localization was highly defective: p53 was poorly accumulated in the cytosol and nearly undetectable in mitochondria. In accordance with the dependence of ActD-induced apoptosis on a mitochondrial p53 function, in control T-cells specific inhibition of mitochondrial p53 translocation with μ pifithrin reduced apoptosis by 86%, whereas treatment with α pifithrin, which blocks p53-mediated transcription, had no effect. We also showed that nuclear export is not required for mitochondrial p53 translocation. Observation of an altered p53 ubiquitination pattern and Mdm2 accumulation in ActD-treated AT and NBS T-cells provided a mechanistic link to their defective extranuclear p53 localization. Our results disclose an undescribed defect in mitochondrial p53 accumulation in AT and NBS T-cells that makes them resistant to apoptosis following unrepairable DNA damage.

Mutations of the AGXT gene encoding the alanine:glyoxylate aminotransferase liver enzyme (AGT) cause primary hyperoxaluria type 1 (PH1). Here we report a molecular modeling study of selected missense AGXT mutations: the common Gly170Arg and the recently described Gly47Arg and Ser81Leu variants, predicted to be pathogenic using standard criteria.Taking advantage of the refined 3D structure of AGT, we computed the dimerization energy of the wild-type and mutated proteins.Molecular modeling predicted that Gly47Arg affects dimerization with a similar effect to that shown previously for Gly170Arg through classical biochemical approaches. In contrast, no effect on dimerization was predicted for Ser81Leu. Therefore, this probably demonstrates pathogenic properties via a different mechanism, similar to that described for the adjacent Gly82Glu mutation that affects pyridoxine binding.This study shows that the molecular modeling approach can contribute to evaluating the pathogenicity of some missense variants that affect dimerization. However, in silico studies--aimed to assess the relationship between structural change and biological effects--require the integrated use of more than 1 tool.

Background Current chemotherapy of human cancers focuses on the DNA damage pathway to induce a p53-mediated cellular response leading to either G1 arrest or apoptosis. However, genotoxic treatments may induce mutations and translocations that result in secondary malignancies or recurrent disease. In addition, about 50% of human cancers are associated with mutations in the p53 gene. Nongenotoxic activation of apoptosis by targeting specific molecular pathways thus provides an attractive therapeutic approach. Methods Normal and leukemic cells were evaluated for their sensitivity to 5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) through cell viability and caspase activation tests. The apoptotic pathway induced by DRB was analysed by immunfluorescence and immunoblot analysis. H2AX phosphorylation and cell cycle analysis were performed to study the dependance of apoptosis on DNA damage and DNA replication, respectively. To investigate the role of p53 in DRB-induced apoptosis, specific p53 inhibitors were used. Statistical analysis on cell survival was performed with the test of independence. Results Here we report that DRB, an inhibitor of the transcriptional cyclin-dependent kinases (CDKs) 7 and 9, triggers DNA replication-independent apoptosis in normal and leukemic human cells regardless of their p53 status and without inducing DNA damage. Our data indicate that (i) in p53-competent cells, apoptosis induced by DRB relies on a cytosolic accumulation of p53 and subsequent Bax activation, (ii) in the absence of p53, it may rely on p73, and (iii) it is independent of ATM and NBS1 proteins. Notably, even apoptosis-resistant leukemic cells such as Raji were sensitive to DRB. Conclusion Our results indicate that DRB represents a potentially useful cancer chemotherapeutic strategy that employs both the p53-dependent and -independent apoptotic pathways without inducing genotoxic stress, thereby decreasing the risk of secondary malignancies.

Nowadays, the notion that the advancement of science and that of technology are fundamental for cultural, social and economic progress has become incontestable. The growing awareness of this has led to a markedly increased interest in empirical studies about technological and scientific development and to the proposal and testing of new quantitative indicators of research and innovation.

Blau syndrome (BS) is a rare familial disease transmitted as an autosomal dominant trait, characterized by arthritis, uveitis, skin rash and granulomatous inflammation. Until now BS has been observed in 136 persons belonging to 28 families as well as in 4 sporadic cases. The gene responsible for BS has recently been identified in the nucleotide-binding domain (NBD) of caspase recruitment domain (CARD15/NOD2), also involved in the pathogenesis of Crohn's disease. In addition to three missense mutations (R334Q, R334W and L469F) previously identified, a new CARD 15 mutation (E383K) has recently been described in a family followed by us for the past 25 years. The characteristics of this family which, to our knowledge, is the only one affected with BS in Italy, are the object of this manuscript. Both the proband and her daughter were originally affected with a papulonodular skin eruption and then with mild arthritis of the hands and feet. The proband, but not the daughter, complained of severe chronic bilateral uveitis, followed by glaucoma and, a few years later, by cataracts. Histological examination of skin biopsies from both subjects and a joint biopsy (daughter only), showed non-caseating granulomas with multinucleated giant cells which, at electron microscopy, revealed "comma-shaped bodies" in epithelioid cells, thought to be a marker for BS. The disease is presently well controlled with low doses of prednisone for the mother and non-steroidal anti-inflammatory drugs (NSAIDs) plus low doses of prednisone, when necessary, for the daughter. As in Crohn's disease, CARD15/NOD2 mutation is believed to be responsible for the granulomatous autoinflammatory reactions probably triggered by microorganisms in BS.

Background and purpose Ataxia Telangiectasia (A-T) heterozygotes constitute 0.36–1% of the general population. They have a higher risk of developing several types of cancer and may be more likely to suffer side-effects following radiotherapy than the general population. Their identification is both labor- and time-consuming and the sensitivity and specificity of the methods employed has not been evaluated. This paper describes a new approach to the identification of A-T heterozygotes based on a two-tier analysis of histone H2AX phosphorylation. Materials and methods We compared the T-cell phenotype after exposure to 2 Gy in nine obligate A-T heterozygotes and 17 normal donors. Examined end points were histone H2AX phosphorylation by flow cytometry 1 h after irradiation (kinase proficiency) and the residual γ-H2AX foci by confocal microscopy 72 h after irradiation (DSB repair proficiency). Results The sequential use of these two methods results in 100% positive predictive value (PPV), 67% negative predictive value (NPV), 78% sensitivity, and 100% specificity. The overall hit rate, i.e. the ratio between the true positives plus the true negatives and the total number of observations was 85%. Conclusions A-T heterozygotes can be identified by analysing irradiated T-cell H2AX phosphorylation level and residual γ-H2AX foci.

The repair of DNA double-strand breaks is critical for genome integrity and tumor suppression. Here we show that following treatment with the DNA-intercalating agent actinomycin D (ActD), normal quiescent T cells accumulate double-strand breaks and die, whereas T cells from ataxia telangiectasia (AT) and Nijmegen breakage syndrome (NBS) patients are resistant to this death pathway despite a comparable amount of DNA damage. We demonstrate that the ActD-induced death pathway in quiescent T lymphocytes follows DNA damage and H2AX phosphorylation, is ATM- and NBS1-dependent and due to p53-mediated cellular apoptosis. In response to genotoxic 2-Gy gamma-irradiation, on the other hand, quiescent T cells from normal donors survive following complete resolution of the damage thus induced. T cells from AT and NBS patients also survive, but retain foci of phosphorylated H2AX due to a subtle double-strand break (DSB) repair defect. A common consequence of these two genetic defects in the DSB response is the apparent tolerance of cells containing DNA breaks. We suggest that this tolerance makes a major contribution to the oncogenic risk of patients with chromosome instability syndromes.

In our analysis we have recalled the general results of recent studies on innovation according to which innovation within the manufacturing industry is a complex phenomenon which does not lend itself to description or explanation utilising simplistic analytical models. We have then taken into account clues garnered from various descriptions of the innovative behaviour of companies utilising several indicators of how innovative they are. Our results confirm the belief that notable differences exist between the two sub-sectors into which the chemical industry is divided: pharmaceutical and basic chemicals. Regarding the policy implications of our research, the close correlation between patents and basic research expenditure suggests that the Italian Fund for Basic Research might play a useful role in promoting innovation in the chemical industry.

The definitions of Experimental Development and Applied Research currently suggested by OECD bring about inconsistent R&D data. Here, coherent definitions, based on the criterion of generality, are proposed.

In our analysis, we have remembered the general result reached by studies on innovation of late, according to which innovation in manufacturing industry is a complex phenomenon and does not lend itself to be described and explained through simplistic analytical models. We have then taken clue from a variegated description of the firms’ innovative behaviour, based on several indicators of their innovativeness. Our results confirm the idea that remarkable differences exist between the two sub-sectors into which chemical industry is broken down: pharmaceutical and basic chemicals. As for policy implications, the close correlation between patents and basic-research expenditure suggests that the Italian Fund for basic research (FIRB) might be useful in order to promote innovation in chemical industry.

In The traditional explanations of Italian industry’s low commitment to R&D activities mainly rest on the firms’ size and relative specialisation of the national economy. We argue that they are not sufficient to justify the Italian anomaly; instead, in our opinion, it above all depends on the well-known rigidity of the Italian labour market. To show this, we first take into account the variability of innovation patterns through the economic system by adopting Pavitt’s taxonomy as our analytical instrument. We then demonstrate that the main factor underlying Italian industry’s management strategies in research is that supplier-dominated and scale-intensive industries in Italy are desperately superficial in their commitment to R&D as a source of innovation. This situation, as unusual as it appears at first sight, has been so far economically viable, because in the supplier-dominated and scale-intensive categories, and within the limits of technology, research and investment in machinery are interchangeable to some extent as means of innovation. Our results seem to suggest that a substitution effect between spending on R&D and investment in machinery indeed is working in Italy in these two sectors. The fact that the low R&D commitment continues at all stages of the economic cycle suggests that the Italian phenomenon may be the result of a constant tendency among companies to counter the rigidity inherent in the deployment of labour as a factor of production. This rigidity is a circumstance very frequently accounted for in the explanation of the higher economic growth in the US with respect to European countries. The novel and major finding of our study is that the rigidity of the labour market - besides being classifiable in economic models as a generic cause of the slower growth in a European country - emerges as a specific cause in models based on innovation theory, via firms’ lower commitment to R&D.

Ataxia-telangiectasia (AT) is a rare recessive disease with pleiotropic involvement of the nervous and lymphoid systems. AT heterozygotes have a population frequency of about 1%, and although not manifesting any overt clinical symptoms, they have an increased mortality, mainly because of cancer and ischemic heart disease. We and others have described a mature T lymphocyte population with an altered T cell receptor surface expression ("TCR variant") that reactivates the recombination activating genes (RAG) and is expanded in the blood of patients with AT. In view of the known role of V(D)J recombination in the onset of tumorigenic translocations, we proposed that the increased RAG activity was responsible for the predisposition of AT homozygotes to develop mature-type T leukemia/lymphoma. In the present report, we used cytofluorimetry to quantify the TCR variant population and the memory/naive T-cell compartments in the blood of AT heterozygotes compared with AT patients and controls. We assessed the expression of different recombinase genes through RT-PCR/oligotyping and cytofluorometric analysis and searched for rearrangement intermediates by ligase-mediated PCR in T-cell lines from four heterozygous carriers. We found the TCR variant population was increased on average 2x in AT heterozygotes (vs 10x in homozygotes) compared with controls, and naive CD4(+) T lymphocytes were reduced on average 0.5x (vs 0.1x in homozygotes). We were able to demonstrate recombinase gene expression in all four heterozygous T-cell lines, and rearrangement intermediates, indicative of ongoing V(D)J recombination, in two. These rearrangements were compatible with V-gene replacement, a mechanism of receptor editing described for Ig and TCRalpha genes, to our knowledge not previously documented for TCRbeta. In conclusion, we found that RAG reactivation and secondary V(D)J rearrangements, potential risk factors of mature-type leukemia in AT homozygotes, also take place in AT heterozygous carriers and might place this large population fraction at an increased risk of leukemia/lymphoma.

Udgivelsesdato: 2003-Oct Alport syndrome (AS) is a type IV collagen hereditary disease characterized by progressive hematuric nephritis, hearing loss, and ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease characterized by much less severe disease in girls and women. A "European Community Alport Syndrome Concerted Action" (ECASCA) group was established to delineate the Alport syndrome phenotype in each gender and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X-linked transmission, were collected. Characteristics of heterozygous girls and women belonging to the 195 families with proven COL4A5 mutation are compared with those of hemizygous boys and men. Hematuria was observed in 95% of carriers and consistently absent in the others. Proteinuria, hearing loss, and ocular defects developed in 75%, 28%, and 15%, respectively. The probability of developing end-stage renal disease or deafness before the age of 40 yr was 12% and 10%, respectively, in girls and women versus 90 and 80%, respectively, in boys and men. The risk of progression to end-stage renal disease appears to increase after the age of 60 yr in women. Because of the absence of genotype-phenotype correlation and the large intrafamilial phenotypic heterogeneity, early prognosis of the disease in X-linked Alport syndrome carriers remains moot. Risk factors for developing renal failure have been identified: the occurrence and progressive increase in proteinuria, and the development of a hearing defect.

COL4A3/COL4A4 mutations: From familial hematuria to autosomal-dominant or recessive Alport syndrome . Background Mutations of the type IV collagen COL4A5 gene cause X-linked Alport syndrome (ATS). Mutations of COL4A3 and COL4A4 have been reported both in autosomal-recessive and autosomal-dominant ATS, as well as in benign familial hematuria (BFH). In the latter conditions, however, clinical features are less defined, few mutations have been reported, and other genes and non-genetic factors may be involved. Methods We analyzed 36 ATS patients for COL4A3 and COL4A4 mutations by polymerase chain reaction–single strand conformational polymorphism (PCR-SSCP) and direct sequencing. Sporadic patients who had tested negative for COL4A5 mutations were included with typical cases of autosomal recessive ATS to secure a better definition of the phenotype spectrum. Results We identified seven previously undescribed COL4A3 mutations: in two genetic compounds and three heterozygotes, and one in COL4A4 . In agreement with the literature, some of the mutations of compound heterozygotes were associated with microhematuria in healthy heterozygous relatives. The mutations of heterozygous patients are likely dominant, since no change was identified in the second allele even by sequencing, and they are predicted to result in shortened or abnormal chains with a possible dominant-negative effect. In addition, both genes showed rare variants of unclear pathogenicity, and common polymorphisms that are shared in part with other populations. Conclusions This study extends the mutation spectrum of COL4A3 and COL4A4 genes, and suggests a possible relationship between production of abnormal COL IV chains and dominant expression of a continuous spectrum of phenotypes, from ATS to BFH.