Microbilobata,a new genus of earliest terebratulid brachiopod from the lower Silurian of Northwestern Canada: Implications for the origin of higher taxa

Microbilobata avalanchensis n. gen. and n. sp. from the Lower Silurian (upper Wenlock) carbonate rocks of the lower Delorme Group in the Avalanche Lake area, northwestern Canada, is described here as the earliest known terebratulid brachiopod. These small shells (less than 2 mm long) are subtriangular, anteriorly emarginate, possibly punctate, with both valves being sulcate at their anterior halves, the ventral sulcus bearing one prominent plica, and the dorsal sulcus marked by two plicae. Internally, M. avalanchensis has a centronelliform loop extending for about three fifths of the total shell length. The shells are silicified in carbonate rocks of mid to outer shelf origin. M. avalanchensis is relatively rare, with about 40 specimens so far found from samples collected at 58–60 m above the base of section AV5 in the Avalanche Lake area. Its presence in rocks of Wenlock age extends the earliest known terebratulids back about 16 million years from the oldest previously recorded terebratulids (earliest Devonian age). The small size and simple form of the new species suggest that heterochrony (progenesis) could have played a role in the origin of the Terebratulida. M. avalanchensis serves as a good example of Cope's Rule, indicating that the terebratulids evolved from a very small, unspecialized ancestor. The unusually small size of this taxon also offers one explanation as to why some ancestors or transitional forms of major taxonomic groups are extremely difficult to find in the fossil record.     

Non-peptidic substrate-mimetic inhibitors of Akt as potential anti-cancer agents

Akt has emerged as a critical target for the development of anti-cancer therapies. It has been found to be amplified, overexpressed, or constitutively activated in numerous human malignancies with oncogenesis derived from the simultaneous promotion of cell survival and suppression of apoptosis. A valuable alternative to the more common ATP-mimetic based chemotherapies is a substrate-mimetic approach, which has the potential advantage of inherent specificity of the substrate-binding pocket. In this paper we present the development of high affinity non-peptidic, substrate-mimetic inhibitors based on the minimum GSK3β substrate sequence. Optimization of initial peptidic leads resulted in the development of several classes of small molecule inhibitors, which have comparable potency to the initial peptidomimetics, while eliminating the remaining amino acid residues. We have identified the first non-peptidic substrate-mimetic lead inhibitors of Akt 29a–b, which have affinities of 17 and 12 μM, respectively. This strategy has potential to provide a useful set of molecular probes to assist in the validation of Akt as a potential target for anti-cancer drug design.     

Classification of hybrid and altered Vibrio cholerae strains by CTX prophage and RS1 element structure

Analysis of the CTX prophage and RS1 element in hybrid and altered Vibrio cholera O1 strains showed two classifiable groups. Group I strains contain a tandem repeat of classical CTX prophage on the small chromosome. Strains in this group either contain no element(s) or an additional CTX prophage or RS1 element(s) on the large chromosome. Group II strains harbor RS1 and CTX prophage, which has an E1 Tor type rstR and classical ctxB on the large chromosome.     

Genetic structure of endangered Emmenopterys henryi Oliv. based on ISSR polymorphism and implications for its conservation

Inter-simple sequence repeat (ISSR) markers were used to determine the genetic variation and genetic differentiation of nine populations of Emmenopterys henryi Oliv., an endangered plant endemic to China. Relatively low genetic diversity was detected at population level (the percentage of polymorphic loci P=22.56%, the number of alleles per locus A=1.183+/-0.045, the effective number of alleles per locus A(E)=1.007+/-0.345, Nei's gene diversity h=0.071+/-0.017, Shannon information index I=0.104+/-0.025). However, the genetic diversity at species level was relatively high (P=56.05%; A=1.561+/-0.498, A(E)=1.325+/-0.371, h=0.191+/-0.199, I=0.287+/-0.284). Analysis of molecular variance showed that most of the ISSR variation (68.03%) in E. henryi occurred among populations. The estimated Nm from F (ST )was 0.235. It indicated that the fragmentation and isolation of populations might result from specific evolutionary history and anthropogenic activity. Consequently, genetic drift might play an important role in determining the genetic structure of E. henryi. Conservation strategies for this endangered species are proposed based on the genetic data.     

Epigenetic inactivation of the miR-124-1 in haematological malignancies

miR-124-1 is a tumour suppressor microRNA (miR). Epigenetic deregulation of miRs is implicated in carcinogenesis. Promoter DNA methylation and histone modification of miR-124-1 was studied in 5 normal marrow controls, 4 lymphoma, 8 multiple myeloma (MM) cell lines, 230 diagnostic primary samples of acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL), MM, and non-Hodgkin's lymphoma (NHL), and 53 MM samples at stable disease or relapse. Promoter of miR-124-1 was unmethylated in normal controls but homozygously methylated in 4 of 4 lymphoma and 4 of 8 myeloma cell lines. Treatment of 5-Aza-2'-deoxycytidine led to miR-124-1 demethylation and re-expression of mature miR-124, which also associated with emergence of euchromatic trimethyl H3K4 and consequent downregulation of CDK6 in myeloma cells harboring homozygous miR-124-1 methylation. In primary samples at diagnosis, miR-124-1 methylation was absent in CML but detected in 2% each of MM at diagnosis and relapse/progression, 5% ALL, 15% AML, 14% CLL and 58.1% of NHL (p<0.001). Amongst lymphoid malignancies, miR-124-1 was preferentially methylated in NHL than MM, CLL or ALL. In primary lymphoma samples, miR-124-1 was preferentially hypermethylated in B- or NK/T-cell lymphomas and associated with reduced miR-124 expression. In conclusion, miR-124-1 was hypermethylated in a tumour-specific manner, with a heterochromatic histone configuration. Hypomethylation led to partial restoration of euchromatic histone code and miR re-expression. Infrequent miR-124-1 methylation detected in diagnostic and relapse MM samples showed an unimportant role in MM pathogenesis, despite frequent methylation found in cell lines. Amongst haematological cancers, miR-124-1 was more frequently hypermethylated in NHL, and hence warrants further study.