DNA-dependent protein kinase (DNA-PK) inhibitors: structure-activity relationships for O-alkoxyphenylchromen-4-one probes of the ATP-binding domain

Introduction of an O-alkoxyphenyl substituent at the 8-position of the 2-morpholino-4H-chromen-4-one pharmacophore enabled regions of the ATP-binding site of DNA-dependent protein kinase (DNA-PK) to be probed further. Structure-activity relationships have been elucidated for inhibition of DNA-PK and PI3K (p110α), with N-(2-(cyclopropylmethoxy)-4-(2-morpholino-4-oxo-4H-chromen-8-yl)phenyl)-2-morpholinoacetamide 11a being identified as a potent and selective DNA-PK inhibitor (IC₅₀ = 8 nM).     

A framework for comparing processes of speciation in the presence of gene flow

How common is speciation‐with‐gene‐flow? How much does gene flow impact on speciation? To answer questions like these requires understanding of the common obstacles to evolving reproductive isolation in the face of gene flow and the factors that favour this crucial step. We provide a common framework for the ways in which gene flow opposes speciation and the potential conditions that may ease divergence. This framework is centred on the challenge shared by most scenarios of speciation‐with‐gene‐flow, i.e. the need for coupling among different components of reproductive isolation. Using this structure, we review and compare the factors favouring speciation with the intention of providing a more integrated picture of speciation‐with‐gene‐flow.     

The circadian clock genes affect reproductive capacity in the desert locust Schistocerca gregaria

The circadian clocks govern many metabolic and behavioral processes in an organism. In insects, these clocks and their molecular machinery have been found to influence reproduction in many different ways. Reproductive behavior including courtship, copulation and egg deposition, is under strong influence of the daily rhythm. At the molecular level, the individual clock components also have their role in normal progress of oogenesis and spermatogenesis. In this study on the desert locust Schistocerca gregaria, three circadian clock genes were identified and their expression profiles were determined. High expression was predominantly found in reproductive tissues. Similar daily expression profiles were found for period (per) and timeless (tim), while the clock (clk) mRNA level is higher 12 h before the first per and tim peak. A knockdown of either per or tim resulted in a significant decrease in the progeny produced by dsRNA treated females confirming the role of clock genes in reproduction and providing evidence that both PER and TIM are needed in the ovaries for egg development. Since the knockdown of clk is lethal for the desert locust, its function remains yet to be elucidated.     

PET imaging using 64Cu-labeled sulfophthalocyanines: synthesis and biodistribution

Sulfonated metallo phthalocyanines (MPcS(n)) are second generation photosensitizers advanced for photodynamic therapy of various medical applications. A series of ZnPcS(n) was demetallated and subsequently converted to the corresponding [(64)Cu]CuPcS(n) in 40-50% isolated yields and >98% radiochemical purities. Tumor-bearing mice were injected with the (64)Cu-labeled products and subjected to 3-h dynamic PET imaging studies. Biodistribution patterns showed characteristic differences between the various derivatives. Tumor uptake was detected only for the amphiphilic derivatives [(64)Cu]CuPcS(2) and [(64)Cu]CuPcS(3)C(6) (1-1.5%ID/g). The biological data suggest that PET imaging with [(64)Cu]CuPc can be used to establish structure-PDT efficacy relationships for Pc-based photosensitizers.     

Novel cyclohexyl-amides as potent antibacterials targeting bacterial type IIA topoisomerases

As part of our wider efforts to exploit novel mode of action antibacterials, we have discovered a series of cyclohexyl-amide compounds that has good Gram positive and Gram negative potency. The mechanism of action is via inhibition of bacterial topoisomerases II and IV. We have investigated various subunits in this series and report advanced studies on compound 7 which demonstrates good PK and in vivo efficacy properties.     

Novel amino-piperidines as potent antibacterials targeting bacterial type IIA topoisomerases

We have identified a series of amino-piperidine antibacterials with a good broad spectrum potency. We report the investigation of various subunits in this series and advanced studies on compound 8. Compound 8 possesses good pharmacokinetics, broad spectrum antibacterial activity and demonstrates oral efficacy in a rat lung infection model.     

Split introns in the genome of Giardia intestinalis are excised by spliceosome-mediated trans-splicing

Spliceosomal introns are hallmarks of most eukaryotic genomes and are excised from premature mRNAs by a spliceosome that is among the largest, and most complex, molecular machine in cells. The divergent unicellular eukaryote Giardia intestinalis, the causative agent of giardiasis, also possesses spliceosomes, but only four canonical (cis-spliced) introns have been identified in its genome to date. We demonstrate that this organism has a novel form of spliceosome-mediated trans-splicing of split introns that is essential for generating mature mRNAs for at least two important genes: one encoding a heat shock protein 90 (HSP90), which controls the conformation of a suite of cellular proteins, and the other encoding a dynein molecular motor protein, involved in the motility of eukaryotic flagella. These split introns have properties that distinguish them from other trans-splicing systems known within eukaryotes, suggesting that Giardia independently evolved a unique system to splice split introns.     

THRUMIN1 is a light-regulated actin-bundling protein involved in chloroplast motility

Chloroplast movement in response to changing light conditions optimizes photosynthetic light absorption. This repositioning is stimulated by blue light perceived via the phototropin photoreceptors and is transduced to the actin cytoskeleton. Some actin-based motility systems use filament reorganizations rather than myosin-based translocations. Recent research favors the hypothesis that chloroplast movement is driven by actin reorganization at the plasma membrane, but no proteins affecting chloroplast movements have been shown to associate with both the plasma membrane and actin filaments in vivo. Here we identified THRUMIN1 as a critical link between phototropin photoreceptor activity at the plasma membrane and actin-dependent chloroplast movements. THRUMIN1 bundles filamentous actin in vitro, and it localizes to the plasma membrane and displays light- and phototropin-dependent localization to microfilaments in vivo. These results suggest that phototropin-induced actin bundling via THRUMIN1 is important for chloroplast movement. A mammalian homolog of THRUMIN1, GRXCR1, has been implicated in auditory responses and hair cell stereocilla development as a regulator of actin architecture. Studies of THRUMIN1 will help elucidate the function of this family of eukaryotic proteins.