Structural basis for gene regulation by a thiamine pyrophosphate-sensing riboswitch

Riboswitches are metabolite-sensing RNAs, typically located in the non-coding portions of messenger RNAs, that control the synthesis of metabolite-related proteins. Here we describe a 2.05 angstroms crystal structure of a riboswitch domain from the Escherichia coli thiM mRNA that responds to the coenzyme thiamine pyrophosphate (TPP). TPP is an active form of vitamin B1, an essential participant in many protein-catalysed reactions. Organisms from all three domains of life, including bacteria, plants and fungi, use TPP-sensing riboswitches to control genes responsible for importing or synthesizing thiamine and its phosphorylated derivatives, making this riboswitch class the most widely distributed member of the metabolite-sensing RNA regulatory system. The structure reveals a complex folded RNA in which one subdomain forms an intercalation pocket for the 4-amino-5-hydroxymethyl-2-methylpyrimidine moiety of TPP, whereas another subdomain forms a wider pocket that uses bivalent metal ions and water molecules to make bridging contacts to the pyrophosphate moiety of the ligand. The two pockets are positioned to function as a molecular measuring device that recognizes TPP in an extended conformation. The central thiazole moiety is not recognized by the RNA, which explains why the antimicrobial compound pyrithiamine pyrophosphate targets this riboswitch and downregulates the expression of thiamine metabolic genes. Both the natural ligand and its drug-like analogue stabilize secondary and tertiary structure elements that are harnessed by the riboswitch to modulate the synthesis of the proteins coded by the mRNA. In addition, this structure provides insight into how folded RNAs can form precision binding pockets that rival those formed by protein genetic factors.     

Direct cortical input modulates plasticity and spiking in CA1 pyramidal neurons

The hippocampus is necessary for the acquisition and retrieval of declarative memories. The best-characterized sensory input to the hippocampus is the perforant path projection from layer II of entorhinal cortex (EC) to the dentate gyrus. Signals are then processed sequentially in the hippocampal CA fields before returning to the cortex via CA1 pyramidal neuron spikes. There is another EC input-the temporoammonic (TA) pathway-consisting of axons from layer III EC neurons that make synaptic contacts on the distal dendrites of CA1 neurons. Here we show that this pathway modulates both the plasticity and the output of the rat hippocampal formation. Bursts of TA activity can, depending on their timing, either increase or decrease the probability of Schaffer-collateral (SC)-evoked CA1 spikes. TA bursts can also significantly reduce the magnitude of synaptic potentiation at SC-CA1 synapses. The TA-CA1 synapse itself exhibits both long-term depression (LTD) and long-term potentiation (LTP). This capacity for bi-directional plasticity can, in turn, regulate the TA modulation of CA1 activity: LTP or LTD of the TA pathway either enhances or diminishes the gating of CA1 spikes and plasticity inhibition, respectively.     

An asymptotic-giant-branch star in the progenitor system of a type Ia supernova

Stars that explode as supernovae come in two main classes. A type Ia supernova is recognized by the absence of hydrogen and the presence of elements such as silicon and sulphur in its spectrum; this class of supernova is thought to produce the majority of iron-peak elements in the Universe. They are also used as precise 'standard candles' to measure the distances to galaxies. While there is general agreement that a type Ia supernova is produced by an exploding white dwarf star, no progenitor system has ever been directly observed. Significant effort has gone into searching for circumstellar material to help discriminate between the possible kinds of progenitor systems, but no such material has hitherto been found associated with a type Ia supernova. Here we report the presence of strong hydrogen emission associated with the type Ia supernova SN2002ic, indicating the presence of large amounts of circumstellar material. We infer from this that the progenitor system contained a massive asymptotic-giant-branch star that lost several solar masses of hydrogen-rich gas before the supernova explosion.     

A thermosensory pathway controlling flowering time in Arabidopsis thaliana

Onset of flowering is controlled by environmental signals such as light and temperature. Molecular-genetic studies in Arabidopsis thaliana have focused on daily light duration, or photoperiod, and transient exposure to winter-like temperatures, or vernalization. Yet ambient growth temperature, which is strongly affected by current changes in global climate, has been largely ignored. Here, we show that genes of the autonomous pathway, previously thought only to act independently of the environment as regulators of the floral repressor FLC (ref. 1), are centrally involved in mediating the effects of ambient temperature. In contrast to wild-type plants and those mutant in other pathways, autonomous-pathway mutants flower at the same time regardless of ambient temperature. In contrast, the exaggerated temperature response of cryptochrome-2 mutants is caused by temperature-dependent redundancy with the phytochrome A photoreceptor. As with vernalization and photoperiod, ambient temperature ultimately affects expression of the floral pathway integrator FT.     

Post-mating clutch piracy in an amphibian

Female multiple mating and alternative mating systems can decrease the opportunity for sexual selection. Sperm competition is often the outcome of females mating with multiple males and has been observed in many animals, and alternative reproductive systems are widespread among species with external fertilization and parental care. Multiple paternity without associated complex behaviour related to mating or parental care is also seen in simultaneously spawning amphibians and fishes that release gametes into water. Here we report 'clutch piracy' in a montane population of the common frog Rana temporaria, a reproductive behaviour previously unknown in vertebrates with external fertilization. Males of this species clasp the females and the pair deposits one spherical clutch of eggs. No parental care is provided. 'Pirate' males search for freshly laid clutches, clasp them as they would do a female and fertilize the eggs that were left unfertilized by the 'parental' male. This behaviour does not seem to be size-dependent, and some males mate with a female and perform clutch piracy in the same season. Piracy affected 84% of the clutches and in some cases increased the proportion of eggs fertilized, providing direct fitness benefits both for the pirate males and the females. Sexual selection--probably caused by a strong male-biased sex ratio--occurs in this population, as indicated by size-assortative mating; however, clutch piracy may reduce its impact. This provides a good model to explore how alternative mating strategies can affect the intensity of sexual selection.     

Localization to Xq27 of a susceptibility gene for testicular germ-cell tumours

Testicular germ-cell tumours (TGCT) affect 1 in 500 men and are the most common cancer in males aged 15-40 in Western European populations. The incidence of TGCT has risen dramatically over the last century. Known risk factors for TGCT include a history of undescended testis (UDT), testicular dysgenesis, infertility, previously diagnosed TGCT (ref. 7) and a family history of the disease. Brothers of men with TGCT have an 8-10-fold risk of developing TGCT (refs 8,9), whereas the relative risk to fathers and sons is fourfold (ref. 9). This familial relative risk is much higher than that for most other types of cancer. We have collected samples from 134 families with two or more cases of TGCT, 87 of which are affected sibpairs. A genome-wide linkage search yielded a heterogeneity lod (hlod) score of 2.01 on chromosome Xq27 using all families compatible with X inheritance. We obtained a hlod score of 4.7 from families with at least one bilateral case, corresponding to a genome-wide significance level of P=0.034. The proportion of families with UDT linked to this locus was 73% compared with 26% of families without UDT (P=0.03). Our results provide evidence for a TGCT susceptibility gene on chromosome Xq27 that may also predispose to UDT.