High-fidelity transfers of genetic information in the central dogma can be achieved by a reaction called editing. The crystal structure of an enzyme with editing activity in translation is presented here at 2.5 angstroms resolution. The enzyme, isoleucyl-transfer RNA synthetase, activates not only the cognate substrate L-isoleucine but also the minimally distinct L-valine in the first, aminoacylation step. Then, in a second, "editing" step, the synthetase itself rapidly hydrolyzes only the valylated products. For this two-step substrate selection, a "double-sieve" mechanism has already been proposed. The present crystal structures of the synthetase in complexes with L-isoleucine and L-valine demonstrate that the first sieve is on the aminoacylation domain containing the Rossmann fold, whereas the second, editing sieve exists on a globular beta-barrel domain that protrudes from the aminoacylation domain.

Compared to primordial perturbations on large scales, roughly larger than 1 megaparsec, those on smaller scales are not severely constrained. We revisit the issue of probing small-scale primordial perturbations using gravitational waves (GWs), based on the fact that, when large-amplitude primordial perturbations on small scales exist, GWs with relatively large amplitudes are induced at second order in scalar perturbations, and these induced GWs can be probed by both existing and planned gravitational-wave projects. We use accurate methods to calculate these induced GWs and take into account sensitivities of different experiments to induced GWs carefully, to report existing and expected limits on the small-scale primordial spectrum.

We construct cosmological long-wavelength solutions without symmetry in general gauge conditions which are compatible with the long-wavelength scheme. We then specify the relationship among the solutions in different time slicings. Nonspherical long-wavelength solutions are particularly important for primordial structure formation in the epoch of very soft equations of state. Applying this general framework to spherical symmetry, we show the equivalence between longwavelength solutions in the constant mean curvature slicing with conformally flat spatial coordinates and asymptotic quasihomogeneous solutions in the comoving slicing with the comoving threading. We derive the correspondence relation between these two solutions and compare the results of numerical simulations of primordial black hole (PBH) formation in these two different approaches. To discuss the PBH formation, it is convenient and conventional to useδc, the value which the averaged density perturbation at threshold in the comoving slicing would take at horizon entry in the lowestorder long-wavelength expansion. We numerically find that within (approximately) compensated models, the sharper the transition from the overdense region to the Friedmann-Robertson-Walker universe is, the larger theδc becomes. We suggest that, for the equation of state p = (Γ − 1)ρ, we can apply the analytic formulas for the minimumδc,min ≃ [3Γ/(3Γ+2)] sin 2 π √ Γ − 1/(3Γ − 2) and the maximumδc,max ≃ 3Γ/(3Γ + 2). As for the threshold peak value of the curvature variable ψ0,c, we find that the sharper the transition is, the smaller the ψ0,c becomes. We analytically explain this intriguing feature qualitatively with a compensated top-hat density model. Using simplified models, we also analytically deduce an environmental effect that ψ0,c can be significantly larger (smaller) if the underlying density perturbation of much longer wavelength is positive (negative).

15 pages, 3 figures, accepted in PRDInternational audiencePrimordial black hole (PBH) mergers have been proposed as an explanation for the gravitational wave events detected by the LIGO collaboration. Such PBHs may be formed in the early Universe as a result of the collapse of extremely rare high-sigma peaks of primordial fluctuations on small scales, as long as the amplitude of primordial perturbations on small scales is enhanced significantly relative to the amplitude of perturbations observed on large scales. One consequence of these small-scale perturbations is generation of stochastic gravitational waves that arise at second order in scalar perturbations, mostly before the formation of the PBHs. These induced gravitational waves have been shown, assuming gaussian initial conditions, to be comparable to the current limits from the European Pulsar Timing Array, severely restricting this scenario. We show, however, that models with enhanced fluctuation amplitudes typically involve non-gaussian initial conditions. With such initial conditions, the current limits from pulsar timing can be evaded. The amplitude of the induced gravitational-wave background can be larger or smaller than the stochastic gravitational-wave background from supermassive black hole binaries

An analogue of isoleucyl-adenylate (Ile-AMS) potently inhibits the isoleucyl-tRNA synthetases (IleRSs) from the three primary kingdoms, whereas the antibiotic mupirocin inhibits only the eubacterial and archaeal IleRSs, but not the eukaryotic enzymes, and therefore is clinically used against methicillin-resistant Staphylococcus aureus. We determined the crystal structures of the IleRS from the thermophilic eubacterium, Thermus thermophilus, in complexes with Ile-AMS and mupirocin at 3.0-and 2.5-Å resolutions, respectively. A structural comparison of the IleRS⅐Ile-AMS complex with the adenylate complexes of other aminoacyl-tRNA synthetases revealed the common recognition mode of aminoacyladenylate by the class I aminoacyl-tRNA synthetases. The Ile-AMS and mupirocin, which have significantly different chemical structures, are recognized by many of the same amino acid residues of the IleRS, suggesting that the antibiotic inhibits the enzymatic activity by blocking the binding site of the high energy intermediate, Ile-AMP. In contrast, the two amino acid residues that concomitantly recognize Ile-AMS and mupirocin are different between the eubacterial/archaeal IleRSs and the eukaryotic IleRSs. Mutagenic analyses revealed that the replacement of the two residues significantly changed the sensitivity to mupirocin. Aminoacyl-tRNA synthetases (aaRSs)1 esterify the cognate amino acids with their specific tRNAs via the following twostep reactions: the formation of aminoacyl-adenylate (aa-AMP), an active intermediate, from an amino acid and ATP; and the transfer of the aminoacyl moiety to the 3Ј-terminal adenosine (A 76 ) of tRNA. The aaRSs can be divided into two classes, class I and class II, comprising 10 members each, which have distinct catalytic domain architectures with exclusive signature motifs for the ATP binding (1). The class I aaRSs have a catalytic domain constructed with the Rossmann fold, and display two signature amino acid motifs "HIGH" and "KMSKS." The Rossmann fold has a ␤ 6 ␣ 4 topology and is apparently divided into two symmetrical halves (␤ 3 ␣ 2 topology each), which are believed to have evolved by a genetic event such as gene duplication. The class I aaRSs are further divided into three subclasses (class Ia, Ib, and Ic) on the basis of the sequence homology and the domain architectures (2). The class Ia aaRSs consist of the isoleucyl-, methionyl-, valyl-, leucyl-, cysteinyl-, and arginyl-tRNA synthetases (IleRS, MetRS, ValRS, LeuRS, CysRS, and ArgRS, respectively); the class Ib aaRSs include the glutamyl-and glutaminyl-tRNA synthetases GluRS and GlnRS, respectively, and the class Ic aaRSs are the tyrosyl-and tryptophanyl-tRNA synthetases (TyrRS and TrpRS, respectively).In general, an aa-AMP analogue potently inhibits the corresponding aaRSs from eubacteria, archaea, and eukaryotes. In contrast, some antibiotics inhibit only the eubacterial (and archaeal) aaRSs, but not the eukaryotic enzymes. The best known example is mupirocin, which targets bacterial and archaeal IleRSs (6, 7). Mupirocin (the che...

We study gravitational waves induced from the primordial scalar perturbations at second order around the reheating of the Universe. We consider reheating scenarios in which a transition from an early matter dominated era to the radiation dominated era completes within a timescale much shorter than the Hubble time at that time. We find that an enhanced production of induced gravitational waves occurs just after the reheating transition because of fast oscillations of scalar modes well inside the Hubble horizon. This enhancement mechanism just after an early matterdominated era is much more efficient than a previously known enhancement mechanism during an early matter era, and we show that the induced gravitational waves could be detectable by future observations if the reheating temperature TR is in the range TR 7 × 10 −2 GeV or 20 GeV TR 2 × 10 7 GeV. This is the case even if the scalar perturbations on small scales are not enhanced relative to those on large scales, probed by the observations of the cosmic microwave background.

Supermassive black holes and intermediate mass black holes are believed to exist in the Universe. There is no established astrophysical explanation for their origin and considerations have been made in the literature that those massive black holes (MBHs) may be primordial black holes (PBHs), black holes which are formed in the early universe (well before the matter-radiation equality) due to the direct collapse of primordial overdensities. This paper aims at discussing the possibility of excluding the PBH scenario as the origin of the MBHs. We first revisit the constraints on PBHs obtained from the CMB distortion that the seed density perturbation causes. By adopting a recent computation of the CMB distortion sourced by the seed density perturbation and the stronger constraint on the CMB distortion set by the COBE/FIRAS experiment used in the literature, we find that PBHs in the mass range 6 × 10 4 M ⊙ ∼ 5 × 10 13 M ⊙ are excluded. Since PBHs lighter than 6 × 10 4 M ⊙ are not excluded from the non-observation of the CMB distortion, we propose a new method which can potentially exclude smaller PBHs as well. Based on the observation that large density perturbations required to create PBHs also result in the copious production of ultracompact minihalos (UCMHs), compact dark matter halos formed at around the recombination, we show that weakly interacting massive particles (WIMPs) as dark matter annihilate efficiently inside UCMHs to yield cosmic rays far exceeding the observed flux. Our bound gives severe restriction on the compatibility between the particle physics models for WIMPs and the PBH scenario as the explanation of MBHs.2

Primordial black holes (PBHs) are an important tool in cosmology to probe the primordial spectrum of small-scale curvature perturbations that reenter the cosmological horizon during radiation domination epoch. We numerically solve the evolution of spherically symmetric highly perturbed configurations to clarify the criteria of PBHs formation using an extremely wide class of curvature profiles characterized by five parameters, (in contrast to only two parameters used in all previous papers) which specify the curvature profiles not only at the central region but also at the outer boundary of configurations. It is shown that formation or non-formation of PBHs is determined essentialy by only two master parameters one of which can be presented as an integral of curvature over initial configurations and the other is presented in terms of the position of the boundary and the edge of the core. PACS numbers: