eIF4GI links nutrient sensing by mTOR to cell proliferation and inhibition of autophagy

Translation initiation factors have complex functions in cells that are not yet understood. We show that depletion of initiation factor eIF4GI only modestly reduces overall protein synthesis in cells, but phenocopies nutrient starvation or inhibition of protein kinase mTOR, a key nutrient sensor. eIF4GI depletion impairs cell proliferation, bioenergetics, and mitochondrial activity, thereby promoting autophagy. Translation of mRNAs involved in cell growth, proliferation, and bioenergetics were selectively inhibited by reduction of eIF4GI, as was the mRNA encoding Skp2 that inhibits p27, whereas catabolic pathway factors were increased. Depletion or overexpression of other eIF4G family members did not recapitulate these results. The majority of mRNAs that were translationally impaired with eIF4GI depletion were excluded from polyribosomes due to the presence of multiple upstream open reading frames and low mRNA abundance. These results suggest that the high levels of eIF4GI observed in many breast cancers might act to specifically increase proliferation, prevent autophagy, and release tumor cells from control by nutrient sensing.     

Over-expression of a zeatin O-glucosylation gene in maize leads to growth retardation and tasselseed formation

To study the effects of cytokinin O-glucosylation in monocots, maize (Zea mays L.) transformants harbouring the ZOG1 gene (encoding a zeatin O-glucosyltransferase from Phaseolus lunatus L.) under the control of the constitutive ubiquitin (Ubi) promoter were generated. The roots and leaves of the transformants had greatly increased levels of zeatin-O-glucoside. The vegetative characteristics of hemizygous and homozygous Ubi:ZOG1 plants resembled those of cytokinin-deficient plants, including shorter stature, thinner stems, narrower leaves, smaller meristems, and increased root mass and branching. Transformant leaves had a higher chlorophyll content and increased levels of active cytokinins compared with those of non-transformed sibs. The Ubi:ZOG1 plants exhibited delayed senescence when grown in the spring/summer. While hemizygous transformants had reduced tassels with fewer spikelets and normal viable pollen, homozygotes had very small tassels and feminized tassel florets, resembling tasselseed phenotypes. Such modifications of the reproductive phase were unexpected and demonstrate a link between cytokinins and sex-specific floral development in monocots.     

The DT40 web site: sampling and connecting the genes of a B cell line

Thousands of new vertebrate genes have been discovered and genetic systems are needed to address their functions at the cellular level. The chicken B cell line DT40 allows efficient gene disruptions due to its high homologous recombination activity. However, cloning the gene of interest is often cumbersome, since relatively few chicken cDNA sequences are present in the public databases. In addition, the accumulation of multiple mutations within the same cell clone is limited by the consumption of one drug-resistance marker for each transfection. Here, we present the DT40 web site (http://genetics.hpi.uni-hamburg.de/dt40.html), which includes a comprehensive database of chicken bursal ESTs to identify disruption candidate genes and recyclable marker cassettes based on the loxP system. These freely available resources greatly facilitate the analysis of genes and genetic networks.     

Relationship of long-term prognosis to MMP and TIMP polymorphisms in patients after ST elevation myocardial infarction

The influence of polymorphisms in the large group of MMP and TIMP genes on clinical outcomes in patients after ST elevation myocardial infarction (STEMI) treated with primary PCI was analysed. In total, 550 consecutive Caucasian patients with STEMI were included in the present study, with a median of 32 months. We analysed 19 polymorphisms in the genes coding MMP and TIMP genes. The MMP-1 -519A/G and -422A/T polymorphisms are associated with combined endpoint after myocardial infarction. The hazard ratio for AT variant of MMP-1 -422A/T was 1.75 (p?<?0.001); the variants with at least one A allele of MMP-1 -519A/G have less risk of combined endpoint. The TT variants of -1562C/T MMP-9 and at least one T allele of +92C/T MMP-13 were considered in a trend to affect disease progression and long-term survival after myocardial infarction. According to reclassification analysis NRI and IDI, long-term risk stratification using MMP-1 -422A/T and -519A/G polymorphisms gives additional information to the commonly used GRACE risk score. Patient stratification after myocardial infraction (MI) according to risk genotypes of MMP-1 polymorphisms could have important clinical implications for identification of patients at risk and therapeutic strategies.     

Tracing the origin of a cryptic invader: phylogeography of the Euwallacea fornicatus (Coleoptera: Curculionidae: Scolytinae) species complex

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Cryptic genetic variation in an inbreeding and cosmopolitan pest,Xylosandrus crassiusculus,revealed using ddRADseq

Each year new exotic species are transported across the world through global commerce, causing considerable economic and ecological damage. An important component of managing invasion pathways is to identify source populations. Some of the most widespread exotic species are haplodiploid ambrosia beetles. The ability to mate with siblings (inbreed) and their transportable food source (symbiotic fungus) have enabled them to colonize most of the world and become pests of plant nurseries, lumber, and forests. One of the fastest spreading ambrosia beetles is Xylosandrus crassiusculus. In order to discover the source populations of this globally invasive species, track its movement around the world, and test biogeographical scenarios, we combined restriction site‐associated DNA sequencing (RADseq) with comprehensive sampling across the species native and introduced range. From 1,365 genotyped SNP loci across 198 individuals, we determined that in its native range, X. crassiusculus is comprised of a population in Southeast Asia that includes mainland China, Thailand, and Taiwan, and a second island population in Japan. North America and Central America were colonized from the island populations, while Africa and Oceania were colonized from the mainland Asia, and Hawaii was colonized by both populations. Populations of X. crassiusculus in North America were genetically diverse and highly structured, suggesting (1) numerous, repeated introductions; (2) introduction of a large founding population; or (3) both scenarios with higher than expected outcrossing. X. crassiusculus, other wood‐boring insects, and indeed many other pests with unusual genetic structure continue to spread around the world. We show that contemporary genetic methods offer a powerful tool for understanding and preventing pathways of future biosecurity threats.     

Data pre-processing in liquid chromatography-mass spectrometry-based proteomics

MOTIVATION: In a liquid chromatography-mass spectrometry (LC-MS)-based expressional proteomics, multiple samples from different groups are analyzed in parallel. It is necessary to develop a data mining system to perform peak quantification, peak alignment and data quality assurance. RESULTS: We have developed an algorithm for spectrum deconvolution. A two-step alignment algorithm is proposed for recognizing peaks generated by the same peptide but detected in different samples. The quality of LC-MS data is evaluated using statistical tests and alignment quality tests. AVAILABILITY: Xalign software is available upon request from the author.     

A new group of monoquaternary reactivators of acetylcholinesterase inhibited by nerve agents

Reactivators of acetylcholinesterase (AChE; EC 3.1.1.7) are able to treat intoxication by organophosphorus compounds, especially with pesticides or nerve agents. Owing to the fact that there exists no universal "broad-spectrum" reactivator of organophosphates-inhibited AChE, many laboratories have synthesized new AChE reactivators. Here, we synthesized five new and three previously known quaternary monopyridinium oximes as potential reactivators of AChE inhibited by nerve agents. Potencies to cleave p-nitrophenyl acetate (PNPA), which is commonly used as a model substrate of nerve agents, were measured. Their cleaving potencies were compared with 4-PAM (4-hydroxyiminomethyl-1-methylpyridinium iodide), which is derived from the structure of the currently used AChE-reactivator 2-PAM (2-hydroxyiminomethyl-1-methylpyridinium iodide). Three newly synthesized oximes achieved similar nucleophilicity at the similar pKa according to 4-PAM, which is very promising for using these derivatives as AChE reactivators.     

Phosphoralaninate pronucleotides of pyrimidine methylenecyclopropane analogues of nucleosides: synthesis and antiviral activity

The Z- and E-thymine and cytosine pronucleotides 3d, 4d, 3e, and 4e of methylenecyclopropane nucleosides analogues were synthesized, evaluated for their antiviral activity against human cytomegalovirus (HCMV), herpes simplex virus 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), human immunodeficiency virus type 1 (HSV-1), and hepatitis B virus (HBV) and their potency was compared with the parent compounds 1d, 2d, 1e, and 2e. Prodrugs 3d and 4d were obtained by phosphorylation of parent analogues 1d or 2d with reagent 8. A similar phosphorylation of N4-benzoylcytosine methylenecyclopropanes 9a and 9b gave intermediates 11a and 11b. Deprotection with hydrazine in pyridine-acetic acid gave pronucleotides 3e and 4e. The Z-cytosine analogue 3e was active against HCMV and EBV The cytosine E-isomer 4e was moderately effective against EBV.