Should I stay or should I go: Protection and maintenance of DNA methylation at imprinted genes

Recent findings shed light on the coordination of two fundamental, yet mechanistically opposing, processes in the early mammalian embryo. During the oocyte-to-embryo transition and early preimplantation development nuclear reprogramming occurs. This resetting of the epigenome in maternal and paternal pronuclei to a ground state is the essential step ensuring totipotency in the zygote, the first embryonic stage. Radical, global DNA demethylation, which occurs actively in the paternal and passively in the maternal genome, is a prominent feature of nuclear reprogramming; yet, this process poses a danger to a subset of methylated sequences that must be preserved for their germline to soma inheritance. Genomic imprinting and its importance were demonstrated three decades ago by a series of experiments generating non-viable mammalian uniparental embryos. Indeed, imprinted loci, gene clusters with parent-of-origin specific gene expression patterns, must retain their differential methylation status acquired during gametogenesis throughout embryogenesis and in adult tissues. It is just recently that the molecular players that protect/maintain imprinting marks during reprogramming in preimplantation embryos have been identified, in particular, an epigenetic modifier complex formed by ZFP57 and TRIM28/KAP1. The interaction of these and other molecules with the newly formed embryonic chromatin and imprinted genes is discussed and highlighted herein.     

The extrapituitary prolactin promoter polymorphism is associated with rheumatoid arthritis and anti-CCP antibodies in Mexican population

Prolactin (PRL) is a hormone–cytokine that has been involved in autoimmunity due to its immunoregulatory and lymphoproliferative effects. It is produced by various extrapituitary sites including immune cells, under control of a superdistal promoter that contains a single nucleotide polymorphism − 1149 G/T previously associated with rheumatoid arthritis (RA) susceptibility in European population. The aim of this study was to investigate the association of the extrapituitary PRL − 1149 G/T promoter polymorphism with clinical parameters, clinical activity and disability indices in RA patients from Western Mexico and to analyze the PRL mRNA expression according to the PRL − 1149 G/T promoter polymorphism in total leucocytes from RA patients and controls. We conducted a case–control study that included 258 RA patients and 333 control subjects (CS). The DNA samples were genotyped using the PCR–RFLP method and the PRL mRNA expression was determined by quantitative real time PCR. PRL serum levels and antibodies to cyclic citrullinated peptides (anti-CCP) were measured with ELISA. We found significant differences in the genotype (p = 0.022) and allelic (p = 0.046) distribution of the polymorphism between RA patients and control subjects. According to the dominant genetic model, there is an association between the T allele (GT + TT genotypes) and decreased RA susceptibility in comparison to the G allele carriers (GG genotype) (OR 0.64, 95% CI 0.45–0.92; p = 0.011). The T allele carriers (GT + TT genotypes) had lower titers of anti-CCP antibodies in comparison to the G allele carriers (GG genotype) (median, 66 U/mL vs. 125 U/mL; p = 0.03). Furthermore, the GG homozygotes had higher PRL mRNA expression in comparison to the GT heterozygotes, and this latter with respect to the TT homozygotes, in both groups (RA: 1 > 0.72 > 0.19; CS: 1 > 0.54 > 0.28). However, PRL serum levels were similar in both groups. Our results suggest that the PRL − 1149 T allele is a genetic marker for decreased RA susceptibility and is associated with lower titers of anti-CCP antibodies in Mexican population. We also suggest influence of genotype upon PRL mRNA expression.     

Phylogeny and taxonomy of European funnel‐web spiders of the Tegenaria−Malthonica complex (Araneae: Agelenidae) based upon morphological and molecular data

The taxonomy and systematics of European house spiders, currently constituting the ill‐defined Tegenaria?Malthonica complex (including Aterigena) in the family Agelenidae, are revised. In Europe four monophyletic genera and 81 species are defined. One genus, Eratigena gen. nov. , and seven species are described as new; at species level 17 new synonyms and 20 new combinations are proposed, and the original combination of 14 species is reinstated. Five species could not be placed (incertae sedis) because of insufficient material and one taxon is regarded as ‘nomen dubium’. On the basis of a detailed morphological assessment, 88 characters were chosen for a cladistic analysis. Phylogenetically informative characters include mostly spination patterns as well as spinneret and genital structures. In addition to morphology, three gene sections [cytochrome c oxidase subunit 1 (CO1), nicotinamide adenine dinucleotide dehydrogenase subunit 1 (NADH1) 28S] were analysed. Morphological and molecular analyses were performed individually and in combination applying maximum parsimony and Bayesian tree search methods. In all resulting trees Malthonica and Tegenaria in their present composition are either polyphyletic or paraphyletic. Consequently, we redefined the two genera and erected a new genus, Eratigena gen. nov. Identification keys are provided for the European agelenid genera as well as for the European species of Tegenaria and Eratigena gen. nov. The genera and most of the constituent species are described and illustrated. The new classification has also been applied to some extra European members of the Tegenaria‐Malthonica complex resulting in additional three new synonyms, seven reversals to the original combination, and four new combinations. © 2013 The Linnean Society of London     

The multiple forms of bovine seminal ribonuclease: Structure and stability of a C-terminal swapped dimer

Bovine seminal ribonuclease (BS-RNase) acquires an interesting anti-tumor activity associated with the swapping on the N-terminal. The first direct experimental evidence on the formation of a C-terminal swapped dimer (C-dimer) obtained from the monomeric derivative of BS-RNase, although under non-native conditions, is here reported. The X-ray model of this dimer reveals a quaternary structure different from that of the C-dimer of RNase A, due to the presence of three mutations in the hinge peptide 111–116. The mutations increase the hinge peptide flexibility and decrease the stability of the C-dimer against dissociation. The biological implications of the structural data are also discussed.     

Recycling antimalarial leads for cancer: Antiproliferative properties of N-cinnamoyl chloroquine analogues

Cinnamic acids and quinolines are known as useful scaffolds in the discovery of antitumor agents. Therefore, N-cinnamoylated analogues of chloroquine, recently reported as potent dual-action antimalarials, were evaluated against three different cancer cell lines: MKN-28, Caco-2, and MCF-7. All compounds display anti-proliferative activity in the micromolar range against the three cell lines tested, and most of them were more active than their parent drug, chloroquine, against all cell lines tested. Hence, N-cinnamoyl-chloroquine analogues are a good start towards development of affordable antitumor leads.     

Cytotoxic Constituents and Mechanism from Peganum harmala

Peganum harmala L. is a traditional Chinese and Uygur medicine used to treat cancer. Bioactivity‐guided fractionation was applied to determine the cytotoxic constituents from P. harmala. A novel triterpenoid and a phenolic glycoside were isolated and identified, as well as seven known compounds. The novel metabolites were elucidated to be 3α‐acetoxy‐27‐hydroxyolean‐12‐en‐28‐oic acid methyl ester ( 1 , OA) and N‐acetyl‐9‐syringinoside ( 9 ). Some compounds exhibited potent cytotoxicity against human tumor cells. Among them, OA showed the highest cytotoxicity against human lung cancer cells A549 with an IC₅₀ value of 8.03 ± 0.81 μm . OA had a potent anti‐NSCLC cell activity by interfering with the epidermal growth factor receptor (EGFR) activation and its downstream signaling, and could exert an antiproliferative effect by inactivation of EGFR‐driven antiapoptotic pathway followed by the release of mitochondrial cytochrome c, which might prove to be a promising leading compound for the development of an anti‐lung cancer drug.