Aldose reductase structures: implications for mechanism and inhibition

During chronic hyperglycaemia, elevated vascular glucose level causes increased flux through the polyol pathway, which induces functional and morphological changes associated with secondary diabetic complications. Inhibitors of aldose reductase (ARIs) have been widely investigated as potential therapeutic agents, but to date only epalrestat is successfully marketed for treatment of diabetic neuropathy, in Japan. Promising compounds during in vitro studies or in trials with animal models have failed to proceed beyond clinical trials and to everyday use, due to a lack of efficacy or adverse side effects attributed to lack of inhibitor specificity and likely inhibition of the related aldehyde reductase (ALR1). Knowledge of the catalytic mechanism and structures of the current inhibitors complexed with ALR2 are means by which more specific and tightly bound inhibitors can be discovered. This review will provide an overview of the proposed catalytic mechanism and the current state of structure-based drug design.     

Transcriptional regulation of a metastasis suppressor gene by Tip60 and beta-catenin complexes

Defining the molecular strategies that integrate diverse signalling pathways in the expression of specific gene programmes that are critical in homeostasis and disease remains a central issue in biology. This is particularly pertinent in cancer biology because downregulation of tumour metastasis suppressor genes is a common occurrence, and the underlying molecular mechanisms are not well established. Here we report that the downregulation of a metastasis suppressor gene, KAI1, in prostate cancer cells involves the inhibitory actions of beta-catenin, along with a reptin chromatin remodelling complex. This inhibitory function of beta-catenin-reptin requires both increased beta-catenin expression and recruitment of histone deacetylase activity. The coordinated actions of beta-catenin-reptin components that mediate the repressive state serve to antagonize a Tip60 coactivator complex that is required for activation; the balance of these opposing complexes controls the expression of KAI1 and metastatic potential. The molecular mechanisms underlying the antagonistic regulation of beta-catenin-reptin and the Tip60 coactivator complexes for the metastasis suppressor gene, KAI1, are likely to be prototypic of a selective downregulation strategy for many genes, including a subset of NF-kappaB target genes.     

A TRPV family ion channel required for hearing in Drosophila

The many types of insect ear share a common sensory element, the chordotonal organ, in which sound-induced antennal or tympanal vibrations are transmitted to ciliated sensory neurons and transduced to receptor potentials. However, the molecular identity of the transducing ion channels in chordotonal neurons, or in any auditory system, is still unknown. Drosophila that are mutant for NOMPC, a transient receptor potential (TRP) superfamily ion channel, lack receptor potentials and currents in tactile bristles but retain most of the antennal sound-evoked response, suggesting that a different channel is the primary transducer in chordotonal organs. Here we describe the Drosophila Nanchung (Nan) protein, an ion channel subunit similar to vanilloid-receptor-related (TRPV) channels of the TRP superfamily. Nan mediates hypo-osmotically activated calcium influx and cation currents in cultured cells. It is expressed in vivo exclusively in chordotonal neurons and is localized to their sensory cilia. Antennal sound-evoked potentials are completely absent in mutants lacking Nan, showing that it is an essential component of the chordotonal mechanotransducer.     

Aberrant methylation of donor genome in cloned bovine embryos

Despite recent successes in cloning various animal species, the use of somatic cells as the source of donor nuclei has raised many practically relevant questions such as increased abortion rates, high birth weight and perinatal death. These anomalies may be caused by incomplete epigenetic reprogramming of donor DNA. Genome-wide demethylation occurs during early development, 'erasing' gamete-specific methylation patterns inherited from the parents. This process may be a prerequisite for the formation of pluripotent stem cells that are important for the later development. Here, we provide evidence that cloned bovine embryos may have impaired epigenetic reprogramming capabilities. We found highly aberrant methylation patterns in various genomic regions of cloned embryos. Cloned blastocysts closely resembled donor cells in their overall genomic methylation status, which was very different from that of normal blastocysts produced in vitro or in vivo. We found demethylation of the Bov-B long interspersed nuclear element sequence in normal embryos, but not in cloned embryos, in which the donor-type methylation was simply maintained during preimplantation development. There were also significant variations in the degree of methylation among individual cloned blastocysts. Our findings indicate that the developmental anomalies of cloned embryos could be due to incomplete epigenetic reprogramming of donor genomic DNA.     

Discovery of Middle Jurassic palaeontinids from Inner Mongolia, China (Homoptera: Palaeontinidae)

A new genus and three new species of fossil Palaeontinidae， Papilioncossus conchatus sp. nov., P. giganteus sp. nov.　and P. pteroideus sp. nov.， are described. All of them were collected from Middle Jurassic Jiulongshan Formation in Inner Mongolia, China. Based on distal part of forewing broader and longer than basal and Sc usually with branches, the new taxa are attributed to Palaeontinidae of Homoptera and compared with genus Pseudocossus. A key to species of Papilioncossus gen. nov. is provided. All type specimens are deposited in the Capital Normal University.     

New ommatids of Ommatinae(Coleoptera:Archostemata:Ommatidae)from the Yixian Formation of western Liaoning,China

Four new fossil species of the family Ommatidae from the Yixian Formation of western Liaoning,China are described. Two of them belong to tribe Brochocoleini:Brochocoleus sulcatus sp.nov.and Brochocoleus angustus sp.nov.The other two refer to tribe Ommatini:Cionocoleus planiusculus sp.nov.and Cionocoleus cervicalis sp.nov.The diagnosis of Brochocoleus and Cionocoleus, respectively,are revised.A preliminary analysis of geographical distribution suggests a possible migration pathway of the genus Bro- chocoleus.The relationship between the genus Cionocoleus and the extant family Crowsoniellidae is briefly discussed.     

Energy-dependent regulation of cell structure by AMP-activated protein kinase

AMP-activated protein kinase (AMPK, also known as SNF1A) has been primarily studied as a metabolic regulator that is activated in response to energy deprivation. Although there is relatively ample information on the biochemical characteristics of AMPK, not enough data exist on the in vivo function of the kinase. Here, using the Drosophila model system, we generated the first animal model with no AMPK activity and discovered physiological functions of the kinase. Surprisingly, AMPK-null mutants were lethal with severe abnormalities in cell polarity and mitosis, similar to those of lkb1-null mutants. Constitutive activation of AMPK restored many of the phenotypes of lkb1-null mutants, suggesting that AMPK mediates the polarity- and mitosis-controlling functions of the LKB1 serine/threonine kinase. Interestingly, the regulatory site of non-muscle myosin regulatory light chain (MRLC; also known as MLC2) was directly phosphorylated by AMPK. Moreover, the phosphomimetic mutant of MRLC rescued the AMPK-null defects in cell polarity and mitosis, suggesting MRLC is a critical downstream target of AMPK. Furthermore, the activation of AMPK by energy deprivation was sufficient to cause dramatic changes in cell shape, inducing complete polarization and brush border formation in the human LS174T cell line, through the phosphorylation of MRLC. Taken together, our results demonstrate that AMPK has highly conserved roles across metazoan species not only in the control of metabolism, but also in the regulation of cellular structures.