Inhibition of secretory phospholipase A2. 2-Synthesis and structure-activity relationship studies of 4,5-dihydro-3-(4-tetradecyloxybenzyl)-1,2,4-4H-oxadiazol-5-one (PMS1062) derivatives specific for group II enzyme

We have recently reported the discovery of a series of specific inhibitors of human group IIA phospholipase A(2) (hGIIA PLA(2)) to display promising in vitro and in vivo properties. Here we describe the influence of different structural modifications on the specificity and potency against hGIIA PLA(2) versus porcine group IB PLA(2). The SAR results, as well as the logP and pK(a) values of oxadiazolone determined in this work, provide important information towards the comprehension of the mode of action of this kind of compounds.     

MIDDLE LLANDOVERY (AERONIAN) GRAPTOLITES OF THE WESTERN MURZUQ BASIN AND AL QARQAF ARCH REGION, SOUTH-WEST LIBYA

Abstract:  The taxonomy and biostratigraphy of the Aeronian graptoloid graptolites of the Tanezzuft Formation (Murzuq Basin and Al Qarqaf Arch area) is presented and discussed with respect to their palaeoenvironmental setting and palaeobiogeographical links. The gregarius-libycus , ' leptotheca ', convolutus and sedgwickii assemblage biozones and tenuis Subzone are recognized and correlated with the generalized zonal scheme and with graptoloid successions in peri-Gondwanan Europe. The Rhuddanian/Aeronian boundary is tentatively placed at the base of the gregarius-libycus Biozone. Telychian faunas have not been identified. Fourteen of the 23 species recorded herein belong to the middle Aeronian convolutus Biozone assemblage. The overall low diversity may be the result of inhabiting unstable, occasionally turbulent and/or oxic environments. The lowest diversity, but with abundant graptoloid rhabdosomes, is observed in proximal silty and sandy deposits. The presence of ' Paraclimacograptus' libycus suggests biogeographical links to Aeronian graptolite faunas of Jordan and South America. The convolutus Zone assemblage is very similar to the coeval faunas of the Saudi Arabian Qusayba shales. The occurrence of several species endemic to northern and north-western Gondwana and peri-Gondwana provides further evidence for a distinct palaeoclimatic/palaeolatitudinal control on graptolite distribution.     

Phospholipids and inositol phosphates linked to the epigenome

Even though the majority of knowledge about phospholipids comes from their cytoplasmic functions, in the last decade, it has been shown that nuclear phospholipids and their building blocks, inositol phosphates, have many important roles in the cell nucleus. There are clear connections of phospholipids with the regulation of gene expression and chromatin biology, however, this review focuses on less known functions of nuclear phospholipids in connection with the epigenome regulation. In particular, we highlight the roles of nuclear phospholipids and inositol phosphates that involve histone modifications, such as acetylation or methylation, tightly connected with the cell physiology. This demonstrates the importance of nuclear phospholipids in the regulation of cellular processes, and should encourage further research of nuclear phospholipids and inositol phosphates.     

A New Entodiniomorphid Ciliate,Troglocorys cava n. g., n. sp., from the Wild Eastern Chimpanzee (Pan troglodytes schweinfurthii) from Uganda

ABSTRACT. Troglocorys cava n. g., n. sp. is described from the feces of wild eastern chimpanzee, Pan troglodytes schweinfurthii, in Uganda. This new species has a spherical body with a frontal lobe, a long vestibulum, a cytoproct located at the posterior dorsal side of the body, an ovoid macronucleus, a contractile vacuole near the cytoproct, and a large concavity on the left surface of the body. Buccal ciliature is non‐retractable and consists of three ciliary zones: an adoral zone surrounding the vestibular opening, a dorso‐adoral zone extending transversely at the basis of the frontal lobe, and a vestibular zone longitudinally extending in a gently spiral curve to line the surface of the vestibulum. Two non‐retractable somatic ciliary zones comprise arches over the body surface: a short dorsal ciliary arch extending transversely at the basis of the frontal lobe and a wide C‐shaped left ciliary arch in the left concavity. Because of the presence of three ciliary zones in the non‐retractable buccal ciliature, the present genus might be a member of the family Blepharocorythidae, but the large left concavity and the C‐shaped left ciliary arch are unique, such structures have never been described from other blepharocorythids.     

Karyotype differentiation in Chromaphyosemion killifishes (Cyprinodontiformes, Nothobranchiidae): patterns, mechanisms, and evolutionary implications

Chromaphyosemion killifishes are a karyotypically highly diverse group of small, sexually dimorphic fishes living in rainforest rivulets in tropical West and Central Africa. In the present study, we used various chromosome banding and staining techniques to analyse the karyotypes of 13 populations representing seven described species ( Chromaphyosemion loennbergii , Chromaphyosemion punctulatum , Chromaphyosemion splendopleure , Chromaphyosemion volcanum , Chromaphyosemion malumbresi , Chromaphyosemion melanogaster , Chromaphyosemion bitaeniatum ) and two undescribed forms ( Chromaphyosemion cf. lugens , Chromaphyosemion sp. Rio Muni GEMHS00/41). Diploid chromosome numbers (2 n ) and the number of chromosome arms (NF) ranged from 2 n  = 24 in C. malumbresi to 2 n  = 40 in C. bitaeniatum and from NF = 40 in C. volcanum and C. cf. lugens to NF = 54 in one population of C. loennbergii . A tentative XX/XY sex chromosome system was revealed in C. loennbergii , C. melanogaster , C. malumbresi , and Chromaphyosemion sp. Rio Muni GEMHS00/41. Mapping cytogenetic data for all described Chromaphyosemion species onto a recently published mitochondrial DNA phylogeny revealed a complex pattern of chromosomal evolution with several independent reductions of 2 n and independent modifications of NF and nucleolus organizer region phenotypes. Together with the results of preliminary crossing and mate choice experiments, the cytogenetic and molecular phylogenetic data suggest that, contrary to previous hypotheses, chromosomal rearrangements are probably not the most important and certainly not the only factor driving speciation in Chromaphyosemion killifishes.  © 2008 The Linnean Society of London, Biological Journal of the Linnean Society , 2008, 94 , 143–153.     

The Concerted Action of Msh2 and UNG Stimulates Somatic Hypermutation at A · T Base Pairs

Mismatch repair plays an essential role in reducing the cellular mutation load. Paradoxically, proteins in this pathway produce A·T mutations during the somatic hypermutation of immunoglobulin genes. Although recent evidence implicates the translesional DNA polymerase η in producing these mutations, it is unknown how this or other translesional polymerases are recruited to immunoglobulin genes, since these enzymes are not normally utilized in conventional mismatch repair. In this report, we demonstrate that A·T mutations were closely associated with transversion mutations at a deoxycytidine. Furthermore, deficiency in uracil-N-glycolase (UNG) or mismatch repair reduced this association. These data reveal a previously unknown interaction between the base excision and mismatch repair pathways and indicate that an abasic site generated by UNG within the mismatch repair tract recruits an error-prone polymerase, which then introduces A·T mutations. Our analysis further indicates that repair tracts typically are ∼200 nucleotides long and that polymerase η makes ∼1 error per 300 T nucleotides. The concerted action of Msh2 and UNG in stimulating A·T mutations also may have implications for mutagenesis at sites of spontaneous cytidine deamination.The affinity maturation of the antibody response depends on the somatic hypermutation (SHM) process. The enzyme activation-induced cytidine deaminase (AID) initiates SHM in germinal center B cells by deaminating C within immunoglobulin (Ig) genes, yielding a G·U lesion that is resolved by several mechanisms (29). Replication across the U generates G·C to A·T transition mutations, while the removal of the U by uracil-N-glycolase (UNG) leads to transversion and transition mutations at the original G·C base pair (33). The AID-generated G·U lesion is also a substrate for the mismatch repair (MMR) proteins Msh2, Msh6, and Exo1. Unlike their normal role in DNA repair, the processing of this lesion by these MMR proteins during SHM paradoxically leads to the production of mutations at A·T base pairs (see below).MMR is a DNA repair process utilized by prokaryotes and eukaryotes (25). This pathway repairs DNA errors caused by the misincorporation of nucleotides during DNA synthesis. The initial mismatch is detected by MutSα, which consists of Msh2 and Msh6 in mammalian cells. The ability of MMR to discriminate between the mutated and unmutated strands of DNA is thought to be dictated by nicks or gaps on the newly synthesized lagging strand between Okazaki fragments or by strand ends on the leading strand at the replication fork (18). The MutLα endonuclease (Mlh1/Pms2) uses the DNA nick or end as a marker of the newly synthesized, and therefore mutated, strand to introduce a new nick on either side of the mismatch (15). This nicked strand is then excised by the 5′-to-3′ exonuclease Exo1, and the ensuing gap is repaired by the replicative polymerase δ. However, since AID acts primarily during G₁ of the cell cycle (11, 36), it is unclear whether Msh2/6 is capable of distinguishing between the AID-mutated and unmutated strands prior to strand excision.Consistently with their role in DNA repair, deficiency in Msh2, Msh6, or Exo1 generally leads to an increase in mutation frequencies in different tissues (40). However, in the case of SHM of Ig genes, the loss of these MMR proteins reduces the frequency of mutations at A·T base pairs (4, 5, 10, 16, 22, 30, 32, 37, 41, 42). One possible difference between conventional and mutagenic MMR is the involvement of the error-prone DNA polymerase η in the latter process. Indeed, both mice and humans lacking polymerase η resemble Msh2-deficient mice, in that mutations at A·T base pairs in the V region are less frequent (6, 7, 47). Moreover, the error spectrum of polymerase η on undamaged DNA matches the mutation spectrum of A·T mutations in the V region (35). While it is now well established that mutations at A·T base pairs are produced largely by proteins involved in the MMR pathway, it is not known how DNA polymerase η is recruited during SHM.One possible explanation for the use of error-prone polymerases is the occurrence of replication-blocking lesions, such as an abasic site or a modified nucleotide, in the V region of Ig genes. Evidence that a replication block leads to mutagenic MMR comes from recent studies showing the requirement of ubiquitinated PCNA for mutagenic MMR (1, 19, 34). Monoubiquitination at the K164 residue of PCNA in response to DNA damage leads to translesional synthesis (1), and SHM at A·T base pairs is reduced in PCNA^K164R/K164R mice to levels observed in MMR-deficient mice (19, 34). In addition, the finding that translesional DNA polymerases are involved in SHM (9, 31, 45-47) suggests that replication-blocking lesions are common at the Ig locus during SHM. Taken together, these observations suggest a model in which replication-blocking lesions recruit error-prone polymerases, which then generate mutations at nearby A·T base pairs. As reported here, we have tested this model by examining the correlated mutations in V region sequences from hypermutating Ramos cells and in murine centroblasts.     

Solitary epileptic seizure--the risk of recurrence

Patients experiencing solitary unprovoked epileptic seizure have different risks of recurrence. The possible risk factors include in particular: structural cerebral lesion and its cause, history of febrile seizures, family history of epilepsy, the type of seizure, epileptiform EEG discharges and the problem of initiation or (or not initiation) of antiepileptic treatment after the first paroxysm. The factors shown above were evaluated in a group of 30 patients with solitary unprovoked epileptic seizure. Regarding recurrence of epileptic seizure, the only significant factor appeared to be initiation of treatment after the first unprovoked paroxysm (p<0.001). We observed a 30% and 33.33% risk of recurrence following the initial epileptic seizure in patients after the first unprovoked seizure in less than 1 and 3 years, respectively.