Forum necessitatis e flessibilità dei criteri di giurisdizione nel Diritto internazionale privato nazionale e dellUnione Europea

Riassunto: In molti ordinamenti europei ed extraeuropei è ammessa la possibilità di attribuire giurisdizione alle autorità del foro a titolo eccezionale nelle ipotesi in cui, in relazione a una determinata pretesa, si riveli impossibile o irragionevole adire i giudici di altri ordinamenti e vi sia dunque il rischio di dar luogo a un diniego di giustizia. Una simile possibilità da un lato presuppone una certa flessibilità delle norme relative alla competenza giurisdizionale, dallaltro è la conseguenza del carattere unilaterale delle norme nazionali in materia di giurisdizione. Queste due caratteristiche non sussistono nellambito dello spazio giudiziario europeo. Le istituzioni dellUnione europea hanno infatti stabilito, attraverso regolamenti, criteri di giurisdizione uniformi relativi ad alcune materie ed applicabili in tutti gli Stati membri. E daltro lato la Corte di giustzia ha escluso, al fine di salvaguardare il principio della certezza del diritto, che tali criteri potessero essere applicati in modo flessibile. Nei rapporti tra gli Stati membri il forum necessitatis è dunque utilizzabile entro limiti molto ristretti. Esso assume invece maggiore importanza nei rapporti tra Stati membri e Stati terzi, come emerge dal Libro verde sulla revisione del Regolamento 44/2001 e dallarticolo 7 del Regolamento 4/2009 in materia di obbligazioni alimentari. Parole chiave: Giurisdizione, diniego di giustizia, Regolamento 44/2001, Regolamento 2201/2003, Regolamento 4/2009, fiducia reciproca. Abstract: In many European and non-European legal systems it is possible for the internal courts to assume jurisdiction when, with regard to a specific claim, it would be impossible or unreasonable to resort to a court of another State, and a denial of justice would be likely to occur. Such a possibility on the one hand requires the rules of jurisdiction to be to a certain extent flexible, on the other hand is the consequence of the unilateral character of that rules. These are not two typical features of the European judicial area. The European institutions have set, in fact, through regulations, uniform rules of jurisdiction regarding certain fields, applicable in every Member State. And the European Court of justice, to the purpose of protecting the legal certainty principle, has precluded a flexible application of these rules. As far as the relations between member States are concerned, the forum necessitatis has, thus, a very narrow leeway. On the contrary, it takes much more importance in range of the relations between Member States and third States, as it comes out from the Green Paper on review of Regulation 44/2001 and from article 7 of the Regulation 4/2009 on maintenance obligations. Key words: Jurisdiction, denial of justice, Regulation 44/2001, Regulation 2201/2003, Regulation 4/2009, mutual trust

HLA-C increases HIV-1 infectivity and is associated with gp120

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Potent Sensitisation of Cancer Cells to Anticancer Drugs by a Quadruple Mutant of the Human Deoxycytidine Kinase.

Identifying enzymes that, once introduced in cancer cells, lead to an increased efficiency of treatment constitutes an important goal for biomedical applications. Using an original procedure whereby mutant genes are generated based on the use of conditional lentivector genome mobilisation, we recently described, for the first time, the identification of a human deoxycytidine kinase (dCK) mutant (G12) that sensitises a panel of cancer cell lines to treatment with the dCK analogue gemcitabine. Here, starting from the G12 variant itself, we generated a new library and identified a mutant (M36) that triggers even greater sensitisation to gemcitabine than G12. With respect to G12, M36 presents an additional mutation located in the region that constitutes the interface of the dCK dimer. The simple presence of this mutation halves both the IC50 and the proportion of residual cells resistant to the treatment. Furthermore, the use of vectors with self-inactivating LTRs leads to an increased sensitivity to treatment, a result compatible with a relief of the transcriptional interference exerted by the U3 promoter on the internal promoter that drives the expression of M36. Importantly, a remarkable effect is also observed in treatments with the anticancer compound cytarabine (AraC), for which a 10,000 fold decrease in IC50 occurred. By triggering the sensitisation of various cancer cell types with poor prognosis to two commonly used anticancer compounds M36 is a promising candidate for suicide gene approaches

Transcriptional regulation of NAD metabolism in bacteria: genomic reconstruction of NiaR (YrxA) regulon

A comparative genomic approach was used to reconstruct transcriptional regulation of NAD biosynthesis in bacteria containing orthologs of Bacillus subtilis gene yrxA, a previously identified niacin-responsive repressor of NAD de novo synthesis. Members of YrxA family (re-named here NiaR) are broadly conserved in the Bacillus/Clostridium group and in the deeply branching Fusobacteria and Thermotogales lineages. We analyzed upstream regions of genes associated with NAD biosynthesis to identify candidate NiaR-binding DNA motifs and assess the NiaR regulon content in these species. Representatives of the two distinct types of candidate NiaR-binding sites, characteristic of the Firmicutes and Thermotogales, were verified by an electrophoretic mobility shift assay. In addition to transcriptional control of the nadABC genes, the NiaR regulon in some species extends to niacin salvage (the pncAB genes) and includes uncharacterized membrane proteins possibly involved in niacin transport. The involvement in niacin uptake proposed for one of these proteins (re-named NiaP), encoded by the B. subtilis gene yceI, was experimentally verified. In addition to bacteria, members of the NiaP family are conserved in multicellular eukaryotes, including human, pointing to possible NaiP involvement in niacin utilization in these organisms. Overall, the analysis of the NiaR and NrtR regulons (described in the accompanying paper) revealed mechanisms of transcriptional regulation of NAD metabolism in nearly a hundred diverse bacteria

Editing of misaligned 3′-termini by an intrinsic 3′–5′ exonuclease activity residing in the PHP domain of a family X DNA polymerase

Bacillus subtilis gene yshC encodes a family X DNA polymerase (PolXBs), whose biochemical features suggest that it plays a role during DNA repair processes. Here, we show that, in addition to the polymerization activity, PolXBs possesses an intrinsic 3′–5′ exonuclease activity specialized in resecting unannealed 3′-termini in a gapped DNA substrate. Biochemical analysis of a PolXBs deletion mutant lacking the C-terminal polymerase histidinol phosphatase (PHP) domain, present in most of the bacterial/archaeal PolXs, as well as of this separately expressed protein region, allow us to state that the 3′–5′ exonuclease activity of PolXBs resides in its PHP domain. Furthermore, site-directed mutagenesis of PolXBs His339 and His341 residues, evolutionary conserved in the PHP superfamily members, demonstrated that the predicted metal binding site is directly involved in catalysis of the exonucleolytic reaction. The implications of the unannealed 3′-termini resection by the 3′–5′ exonuclease activity of PolXBs in the DNA repair context are discussed

The Lower Bound to the Evolution of Mutation Rates

Despite substantial attention from theoreticians, the evolutionary mechanisms that drive intra- and interspecific variation in the mutation rate remain unclear. It has often been argued that mutation rates associated with the major replicative polymerases have been driven down to their physiological limits, defined as the point at which further enhancement in replication fidelity incurs a cost in terms of reproductive output, but no evidence in support of this argument has emerged for cellular organisms. Here, it is suggested that the lower barrier to mutation rate evolution may ultimately be defined not by molecular limitations but by the power of random genetic drift. As the mutation rate is reduced to a very low level, a point will eventually be reached at which the small advantage of any further reduction is overwhelmed by the power of drift. This hypothesis is consistent with a number of observations, including the inverse relationship between the per-site mutation rate and genome size in microbes, the negative scaling between the per-site mutation rate and effective population size in eukaryotes, and the elevated error rates associated with less frequently deployed polymerases and repair pathways

New insights into the synergism of nucleoside analogs with radiotherapy

Nucleoside analogs have been frequently used in combination with radiotherapy in the clinical setting, as it has long been understood that inhibition of DNA repair pathways is an important means by which many nucleoside analogs synergize. Recent advances in our understanding of the structure and function of deoxycytidine kinase (dCK), a critical enzyme required for the anti-tumor activity for many nucleoside analogs, have clarified the mechanistic role this kinase plays in chemo- and radio-sensitization. A heretofore unrecognized role of dCK in the DNA damage response and cell cycle machinery has helped explain the synergistic effect of these agents with radiotherapy. Since most currently employed nucleoside analogs are primarily activated by dCK, these findings lend fresh impetus to efforts focused on profiling and modulating dCK expression and activity in tumors. In this review we will briefly review the pharmacology and biochemistry of the major nucleoside analogs in clinical use that are activated by dCK. This will be followed by discussions of recent advances in our understanding of dCK activation via post-translational modifications in response to radiation and current strategies aimed at enhancing this activity in cancer cells