A distance to the Large Magellanic Cloud that is precise to one per cent.

In the era of precision cosmology, it is essential to determine the Hubble constant empirically with an accuracy of one per cent or better1. At present, the uncertainty on this constant is dominated by the uncertainty in the calibration of the Cepheid period-luminosity relationship2,3 (also known as the Leavitt law). The Large Magellanic Cloud has traditionally served as the best galaxy with which to calibrate Cepheid period-luminosity relations, and as a result has become the best anchor point for the cosmic distance scale4,5. Eclipsing binary systems composed of late-type stars offer the most precise and accurate way to measure the distance to the Large Magellanic Cloud. Currently the limit of the precision attainable with this technique is about two per cent, and is set by the precision of the existing calibrations of the surface brightness-colour relation5,6. Here we report a calibration of the surface brightness-colour relation with a precision of 0.8 per cent. We use this calibration to determine a geometrical distance to the Large Magellanic Cloud that is precise to 1 per cent based on 20 eclipsing binary systems. The final distance is 49.59 ± 0.09 (statistical) ± 0.54 (systematic) kiloparsecs.

The frequency of snowline-region planets from four-years of OGLE-MOA-Wise second-generation microlensing.

We present a statistical analysis of the first four seasons from a "second-generation" microlensing survey for extrasolar planets, consisting of near-continuous time coverage of 8 deg2 of the Galactic bulge by the OGLE, MOA, and Wise microlensing surveys. During this period, 224 microlensing events were observed by all three groups. Over 12% of the events showed a deviation from single-lens microlensing, and for ~1/3 of those the anomaly is likely caused by a planetary companion. For each of the 224 events we have performed numerical ray-tracing simulations to calculate the detection efficiency of possible companions as a function of companion-to-host mass ratio and separation. Accounting for the detection efficiency, we find that 55 - 22 + 34 % of microlensed stars host a snowline planet. Moreover, we find that Neptunes-mass planets are ~ 10 times more common than Jupiter-mass planets. The companion-to-host mass ratio distribution shows a deficit at q ~ 10-2, separating the distribution into two companion populations, analogous to the stellar-companion and planet populations, seen in radial-velocity surveys around solar-like stars. Our survey, however, which probes mainly lower-mass stars, suggests a minimum in the distribution in the super-Jupiter mass range, and a relatively high occurrence of brown-dwarf companions.

Extremely metal-poor stars from the cosmic dawn in the bulge of the Milky Way.

The first stars are predicted to have formed within 200 million years after the Big Bang, initiating the cosmic dawn. A true first star has not yet been discovered, although stars with tiny amounts of elements heavier than helium ('metals') have been found in the outer regions ('halo') of the Milky Way. The first stars and their immediate successors should, however, preferentially be found today in the central regions ('bulges') of galaxies, because they formed in the largest over-densities that grew gravitationally with time. The Milky Way bulge underwent a rapid chemical enrichment during the first 1-2 billion years, leading to a dearth of early, metal-poor stars. Here we report observations of extremely metal-poor stars in the Milky Way bulge, including one star with an iron abundance about 10,000 times lower than the solar value without noticeable carbon enhancement. We confirm that most of the metal-poor bulge stars are on tight orbits around the Galactic Centre, rather than being halo stars passing through the bulge, as expected for stars formed at redshifts greater than 15. Their chemical compositions are in general similar to typical halo stars of the same metallicity although intriguing differences exist, including lower abundances of carbon.

A mass of less than 15 solar masses for the black hole in an ultraluminous X-ray source.

Most ultraluminous X-ray sources have a typical set of properties not seen in Galactic stellar-mass black holes. They have luminosities of more than 3 × 10(39) ergs per second, unusually soft X-ray components (with a typical temperature of less than about 0.3 kiloelectronvolts) and a characteristic downturn in their spectra above about 5 kiloelectronvolts. Such puzzling properties have been interpreted either as evidence of intermediate-mass black holes or as emission from stellar-mass black holes accreting above their Eddington limit, analogous to some Galactic black holes at peak luminosity. Recently, a very soft X-ray spectrum was observed in a rare and transient stellar-mass black hole. Here we report that the X-ray source P13 in the galaxy NGC 7793 is in a binary system with a period of about 64 days and exhibits all three canonical properties of ultraluminous sources. By modelling the strong optical and ultraviolet modulations arising from X-ray heating of the B9Ia donor star, we constrain the black hole mass to be less than 15 solar masses. Our results demonstrate that in P13, soft thermal emission and spectral curvature are indeed signatures of supercritical accretion. By analogy, ultraluminous X-ray sources with similar X-ray spectra and luminosities of up to a few times 10(40) ergs per second can be explained by supercritical accretion onto massive stellar-mass black holes.

Exoplanet detection. A terrestrial planet in a ~1-AU orbit around one member of a ~15-AU binary.

Using gravitational microlensing, we detected a cold terrestrial planet orbiting one member of a binary star system. The planet has low mass (twice Earth's) and lies projected at ~0.8 astronomical units (AU) from its host star, about the distance between Earth and the Sun. However, the planet's temperature is much lower, <60 Kelvin, because the host star is only 0.10 to 0.15 solar masses and therefore more than 400 times less luminous than the Sun. The host itself orbits a slightly more massive companion with projected separation of 10 to 15 AU. This detection is consistent with such systems being very common. Straightforward modification of current microlensing search strategies could increase sensitivity to planets in binary systems. With more detections, such binary-star planetary systems could constrain models of planet formation and evolution.

An eclipsing-binary distance to the Large Magellanic Cloud accurate to two per cent.

In the era of precision cosmology, it is essential to determine the Hubble constant to an accuracy of three per cent or better. At present, its uncertainty is dominated by the uncertainty in the distance to the Large Magellanic Cloud (LMC), which, being our second-closest galaxy, serves as the best anchor point for the cosmic distance scale. Observations of eclipsing binaries offer a unique opportunity to measure stellar parameters and distances precisely and accurately. The eclipsing-binary method was previously applied to the LMC, but the accuracy of the distance results was lessened by the need to model the bright, early-type systems used in those studies. Here we report determinations of the distances to eight long-period, late-type eclipsing systems in the LMC, composed of cool, giant stars. For these systems, we can accurately measure both the linear and the angular sizes of their components and avoid the most important problems related to the hot, early-type systems. The LMC distance that we derive from these systems (49.97 ± 0.19 (statistical) ± 1.11 (systematic) kiloparsecs) is accurate to 2.2 per cent and provides a firm base for a 3-per-cent determination of the Hubble constant, with prospects for improvement to 2 per cent in the future.

RR-Lyrae-type pulsations from a 0.26-solar-mass star in a binary system.

RR Lyrae pulsating stars have been extensively used as tracers of old stellar populations for the purpose of determining the ages of galaxies, and as tools to measure distances to nearby galaxies. There was accordingly considerable interest when the RR Lyrae star OGLE-BLG-RRLYR-02792 (referred to here as RRLYR-02792) was found to be a member of an eclipsing binary system, because the mass of the pulsator (hitherto constrained only by models) could be unambiguously determined. Here we report that RRLYR-02792 has a mass of 0.26 solar masses M[symbol see text] and therefore cannot be a classical RR Lyrae star. Using models, we find that its properties are best explained by the evolution of a close binary system that started with M[symbol see text] and 0.8M[symbol see text]stars orbiting each other with an initial period of 2.9 days. Mass exchange over 5.4 billion years produced the observed system, which is now in a very short-lived phase where the physical properties of the pulsator happen to place it in the same instability strip of the Hertzsprung-Russell diagram as that occupied by RR Lyrae stars. We estimate that only 0.2 per cent of RR Lyrae stars may be contaminated by systems similar to this one, which implies that distances measured with RR Lyrae stars should not be significantly affected by these binary interlopers.

One or more bound planets per Milky Way star from microlensing observations.

Most known extrasolar planets (exoplanets) have been discovered using the radial velocity or transit methods. Both are biased towards planets that are relatively close to their parent stars, and studies find that around 17-30% (refs 4, 5) of solar-like stars host a planet. Gravitational microlensing, on the other hand, probes planets that are further away from their stars. Recently, a population of planets that are unbound or very far from their stars was discovered by microlensing. These planets are at least as numerous as the stars in the Milky Way. Here we report a statistical analysis of microlensing data (gathered in 2002-07) that reveals the fraction of bound planets 0.5-10 AU (Sun-Earth distance) from their stars. We find that 17(+6)(-9)% of stars host Jupiter-mass planets (0.3-10 M(J), where M(J) = 318 M(⊕) and M(⊕) is Earth's mass). Cool Neptunes (10-30 M(⊕)) and super-Earths (5-10 M(⊕)) are even more common: their respective abundances per star are 52(+22)(-29)% and 62(+35)(-37)%. We conclude that stars are orbited by planets as a rule, rather than the exception.

The dynamical mass of a classical Cepheid variable star in an eclipsing binary system.

Stellar pulsation theory provides a means of determining the masses of pulsating classical Cepheid supergiants-it is the pulsation that causes their luminosity to vary. Such pulsational masses are found to be smaller than the masses derived from stellar evolution theory: this is the Cepheid mass discrepancy problem, for which a solution is missing. An independent, accurate dynamical mass determination for a classical Cepheid variable star (as opposed to type-II Cepheids, low-mass stars with a very different evolutionary history) in a binary system is needed in order to determine which is correct. The accuracy of previous efforts to establish a dynamical Cepheid mass from Galactic single-lined non-eclipsing binaries was typically about 15-30% (refs 6, 7), which is not good enough to resolve the mass discrepancy problem. In spite of many observational efforts, no firm detection of a classical Cepheid in an eclipsing double-lined binary has hitherto been reported. Here we report the discovery of a classical Cepheid in a well detached, double-lined eclipsing binary in the Large Magellanic Cloud. We determine the mass to a precision of 1% and show that it agrees with its pulsation mass, providing strong evidence that pulsation theory correctly and precisely predicts the masses of classical Cepheids.

Discovery of a Jupiter/Saturn analog with gravitational microlensing.

Searches for extrasolar planets have uncovered an astonishing diversity of planetary systems, yet the frequency of solar system analogs remains unknown. The gravitational microlensing planet search method is potentially sensitive to multiple-planet systems containing analogs of all the solar system planets except Mercury. We report the detection of a multiple-planet system with microlensing. We identify two planets with masses of approximately 0.71 and approximately 0.27 times the mass of Jupiter and orbital separations of approximately 2.3 and approximately 4.6 astronomical units orbiting a primary star of mass approximately 0.50 solar mass at a distance of approximately 1.5 kiloparsecs. This system resembles a scaled version of our solar system in that the mass ratio, separation ratio, and equilibrium temperatures of the planets are similar to those of Jupiter and Saturn. These planets could not have been detected with other techniques; their discovery from only six confirmed microlensing planet detections suggests that solar system analogs may be common.

Discovery of a cool planet of 5.5 Earth masses through gravitational microlensing.

In the favoured core-accretion model of formation of planetary systems, solid planetesimals accumulate to build up planetary cores, which then accrete nebular gas if they are sufficiently massive. Around M-dwarf stars (the most common stars in our Galaxy), this model favours the formation of Earth-mass (M(o)) to Neptune-mass planets with orbital radii of 1 to 10 astronomical units (au), which is consistent with the small number of gas giant planets known to orbit M-dwarf host stars. More than 170 extrasolar planets have been discovered with a wide range of masses and orbital periods, but planets of Neptune's mass or less have not hitherto been detected at separations of more than 0.15 au from normal stars. Here we report the discovery of a 5.5(+5.5)(-2.7) M(o) planetary companion at a separation of 2.6+1.5-0.6 au from a 0.22+0.21-0.11 M(o) M-dwarf star, where M(o) refers to a solar mass. (We propose to name it OGLE-2005-BLG-390Lb, indicating a planetary mass companion to the lens star of the microlensing event.) The mass is lower than that of GJ876d (ref. 5), although the error bars overlap. Our detection suggests that such cool, sub-Neptune-mass planets may be more common than gas giant planets, as predicted by the core accretion theory.

Search for low-mass exoplanets by gravitational microlensing at high magnification.

Observations of the gravitational microlensing event MOA 2003-BLG-32/OGLE 2003-BLG-219 are presented, for which the peak magnification was over 500, the highest yet reported. Continuous observations around the peak enabled a sensitive search for planets orbiting the lens star. No planets were detected. Planets 1.3 times heavier than Earth were excluded from more than 50% of the projected annular region from approximately 2.3 to 3.6 astronomical units surrounding the lens star, Uranus-mass planets were excluded from 0.9 to 8.7 astronomical units, and planets 1.3 times heavier than Saturn were excluded from 0.2 to 60 astronomical units. These are the largest regions of sensitivity yet achieved in searches for extrasolar planets orbiting any star.

Combinatorial approaches to formulation development.

This review describes the use of combinatorial methods for the development of drug formulations. Combinatorial methods are applied to find solutions to various formulation problems, including drug solubilization, controlled release, oral drug administration, and others. Various methods are described, including the synthesis of carrier libraries, high-throughput screening and computational analysis, which are used during the formulation development process, starting from initial assays through the optimization of formulation composition, to the optimization of the manufacturing process. This review also describes an integrated approach to drug formulation development using libraries of block copolymers as the drug carriers.

Block copolymeric biotransport carriers as versatile vehicles for drug delivery.

This review describes block copolymer-based systems that are used in drug formulation development. The use of amphiphilic block copolymers to modify pharmacological performance of various classes of drugs attracts more and more attention. This is largely attributable to the high tendency of block copolymer-based drug formulations to self-assemble, as well as flexibility of block copolymer chemistry, which allows precise tailoring of the carrier to virtually any chemical entity. Combination of these features allows adjustment of block copolymer-based drug formulations to achieve the most beneficial balance in drug biological interactions with the systems that control its circulation in and removal from the body and its therapeutic activity. The following major aspects are considered: 1) physical properties of formulations and the methods used to adjust these properties towards the highest pharmacological performance of the product; 2) combinatorial methods for optimisation of block copolymer-based formulations; 3) biological response modifying properties of block copolymer-based formulations.

Substrate specificity of the streptococcal cysteine protease.

The streptococcal pyrogenic exotoxin B (SpeB) is an important factor in mediating Streptococcus pyogenes infections. SpeB is the zymogen of the streptococcal cysteine protease (SCP), of which relatively little is known regarding substrate specificity. To investigate this aspect of SCP function, a series of internally quenched fluorescent substrates was designed based on the cleavage sites identified in the autocatalytic processing of SpeB to mature SCP. The best substrates for SCP contain three amino acids in the nonprimed position (i.e. AIK in P(3)-P(2)-P(1)). Varying the length of the substrate on the primed side of the scissile bond has a relatively lower effect on activity. The highest activity (k(cat)/K(M) = 2.8 +/- 0.6 (10(5) x m(-1)s(-1)) is observed for the pentamer 3-aminobenzoic acid-AIKAG-3-nitrotyrosine, which spans subsites S(3) to S(2)' on the enzyme. High pressure liquid chromatography and mass spectrometry analyses show that the substrates are cleaved at the site predicted from the autoprocessing experiments. These results show that SCP can display an important level of endopeptidase activity. Substitutions at position P(2) of the substrate clearly indicate that the S(2) subsite of SCP can readily accommodate substrates containing a hydrophobic residue at that position and that some topological preference exists for that subsite. Substitutions in positions P(3), P(1), and P(1)' had little or no effect on SCP activity. The substrate specificity outlined in this work further supports the similarity between SCP and the cysteine proteases of the papain family. From the data regarding the identified or proposed natural substrates for SCP, it appears that this substrate specificity profile may also apply to the processing of mammalian and streptococcal protein targets by SCP.

Conformational investigation of alpha,beta-dehydropeptides. IX. N-Acetyl-(E)-alpha,beta-methylamide: stereoelectronic properties from infrared and theoretical studies.

The Fourier transform infrared spectra of Ac-(E)-deltaAbu-NHMe were analyzed to determine the predominant solution conformation(s) of this (E)-alpha,beta-dehydropeptide-related compound and the electron density perturbation in its amide groups. The measurements were performed in dichloromethane and acetonitrile in the region of mode vs (N-H), amide I, amide II and vs (C(alpha)=Cbeta). The equilibrium geometrical parameters, calculated by a method based on the density functional theory with the B3LYP functional and the 6-31G* basis set, were used to support spectroscopic interpretation and gain some deeper insight into the molecule. The experimental and theoretical data were compared with those of three previously described molecules: isomeric Ac-(Z)-deltaAbu-NHMe, Ac-deltaAla-NHMe, which is deprived of any beta-substituent, and saturated species Ac-Abu-NHMe. The titled compound assumes two conformational states in equilibrium in the DCM solution. One conformer is extended almost fully and like Ac-deltaAla-NHMe is C5 hydrogen-bonded. The other adopts a warped C5 structure similar to that of Ac-(Z)-deltaAbu-NHMe. The C5 hydrogen bond, unlike the H-bond in Ac-deltaAla-NHMe, is disrupted by acetonitrile. The resonance within the N-terminal amide groups in either of the (E)-deltaAbu conformers is not as well developed as the resonance in Ac-Abu-NHMe. However, these N-terminal groups, compared with the other unsaturated compounds, constitute better resonance systems in each conformationally related couple: the C5 hydrogen-bonded Ac-(E)-deltaAbu-NHMe/Ac-deltaAla-NHMe and the warped C5 Ac-(E)-deltaAbu-NHMe/Ac-(Z)-deltaAbu-NHMe. The resonance within the C-terminal groups of the latter couple apparently is similar, but less developed than the resonance in Ac-Abu-NHMe. The electron distribution within the C-terminal group of the hydrogen-bonded C5 (E)-deltaAbu conformer apparently is determined mainly by the electron influx from the C(alpha)=Cbeta double bond.

Conformational investigation of alpha,beta-dehydropeptides. VII. Conformation of Ac-Pro-deltaAla-NHCH3 and Ac-Pro-(E)-deltaAbu-NHCH3: comparison with (Z)-substituted alpha,beta-dehydropeptides.

The crystal structure and solution conformation of Ac-Pro-deltaAla-NHCH3 and the solution conformation of Ac-Pro-(E)-deltaAbu-NHCH3 were investigated by X-ray diffraction method and NMR, FTIR and CD spectroscopies. Ac-Pro-deltaAla-NHCH3 adopts an extended-coil conformation in the crystalline state, with all-trans peptide bonds and the deltaAla residue being in a C5 form, phi(1)=-71.4(4), psi(1)=-16.8(4), phi(2)= -178.4(3) and psi(2)= 172.4(3) degrees. In inert solvents the peptide also assumes the C5 conformation, but a gamma-turn on the Pro residue cannot be ruled out. In these solvents Ac-Pro-(E)-deltaAbu-NHCH3 accommodates a beta(II)-turn, but a minor conformer with a nearly planar disposition of the CO-NH and C=C bonds (phi(2) approximately 0 degrees) is also present. Previous spectroscopic studies of the (Z)-substituted dehydropeptides Ac-Pro-(Z)-deltaAbu-NHCH3 and Ac-Pro-deltaVal-NHCH3 reveal that both peptides prefer a beta(II)-turn in solution. Comparison of conformations in the family of four Ac-Pro-deltaXaa-NHCH3 peptides let us formulate the following order of their tendency to adopt a beta-turn in solution: (Z)-deltaAbu > (E)-deltaAbu > deltaVal; deltaAla does not. None of the folded structures formed by the four compounds is stable in strongly solvating media.

Conformational investigation of alpha, beta-dehydropeptides. V*. Stability of reverse turns in saturated and alpha, beta-unsaturated peptides Ac-Pro-Xaa-NHCH3: CD studies in various solvents.

Conformations of three series of model peptides: homochiral Ac-Pro-L-Xaa-NHCH3 and heterochiral Ac-Pro-D-Xaa-NHCH3 (Xaa = Phe, Val, Leu, Abu, Ala) as well as alpha, beta-dehydro Ac-Pro-delta Xaa-NHCH3 [delta Xaa = (Z)-delta Phe, delta Val,(Z)-delta Leu,(Z)-delta Abu] were investigated by CD spectroscopy in 2% dichloromethane-cyclohexane, trifluoroethanol, water, and occasionally in other solvents. The spectra of homochiral peptides show a significant solvent dependence. Folded structures are present in 2% dichloromethane-cyclohexane and unordered ones occur in water. The folded conformers are of the inverse gamma-turn type for all the peptides but Ac-Pro-L-Phe-NHCH3 for which the type-I beta-turn is preferred. The changes in the spectra of the heterochiral peptides are limited. The compounds adopt the type-II beta-turn in 2% dichloromethane-cyclohexane, represented by class B spectra, and retain this conformation in water as well as in fluorinated alcohols but not always to a full extent. The CD spectra of the unsaturated peptides in 2% dichloromethane-cyclohexane, although they cannot be assigned to any common spectral class, must be attributed to the beta II-turn conformation as determined for these compounds by NMR and IR spectroscopy. The CD spectra of dehydropeptides exhibit a considerable solvent dependence and suggest unordered structures in water.

Conformational investigation of alpha,beta-dehydropeptides. Part. IV. Beta-turn in saturated and alpha,beta-unsaturated peptides Ac-Pro-Xaa-NHCH3: NMR and IR studies.

Solution conformations of three series of model peptides, homochiral Ac-Pro-L-Xaa-NHCH3 and heterochiral Ac-Pro-D-Xaa-NHCH3 (Xaa = Val, Phe, Leu, Abu, Ala) as well as alpha,beta-unsaturated Ac-Pro-delta Xaa-NHCH3 [delta Xaa = delta Val, (Z)-delta Phe, (Z)-delta Leu, (Z)-delta Abu] were investigated in CDCl3 and CH2Cl2 by 1H-, 13C-NMR, and FTIR spectroscopy. NH stretching absorption spectra, solvent shifts delta delta for NH (Xaa) and NHCH3 on going from CDCl3 to (CD3)2SO, diagnostic interresidue proton NOEs, and trans-cis isomer ratios were examined. These studies performed showed the essential difference in conformational propensities between homochiral peptides (L-Xaa) on the one hand and heterochiral (D-Xaa) and alpha,beta-dehydropeptides (delta Xaa) on the other. Former compounds are conformationally flexible with an inverse gamma-bend, a beta-turn, and open forms in an equilibrium depending on the nature of the Xaa side chain. Conformational preferences of heterochiral and alpha,beta-dehydropeptides are very similar, with the type-II beta-turn as the dominating structure. There is no apparent correlation between conformational properties and the nature of the Xaa side chain within the two groups. The beta-turn formation propensity seems to be somewhat greater in alpha,beta-unsaturated than in heterochiral peptides, but an estimation of beta-folded conformers is risky.

Conformational investigation of alpha, beta-dehydropeptides. Part III. Molecular and crystal structure of acetyl-L-prolyl-alpha, beta-dehydrovaline methylamide.

The crystal structure of Ac-Pro-delta Val-NHCH3 was examined to determine the influence of the alpha,beta-dehydrovaline residue on the nature of peptide conformation. The peptide crystallizes from methanol-diethyl ether solution at 4 degrees in needle-shaped form in orthorhombic space group P2(1)2(1)2(1) with a = 11.384(2) A, b = 13.277(2) A, c = 9.942(1) A, V = 1502.7(4) A3, Z = 4, Dm = 1.17 g.cm-3 and Dc = 1.18 g.cm-3. The structure was solved by direct methods using SHELXS-86 and refined to an R value of 0.057 for 1922 observed reflections. The peptide is found to adopt a beta-bend between the type I and the type III conformation with phi 1 = -68.3(4) degrees, psi 1 = -20.1(4) degrees, phi 2 = -73.5(4) degrees and psi 2 = -14.1(4) degrees. An intramolecular hydrogen bond between the carbonyl oxygen of ith residue and the NH of (i + 3)th residue stabilizes the beta-bend. An additional intermolecular N...O hydrogen bond joins molecules into infinite chains. In the literature described crystal structures of peptides having a single alpha,beta-dehydroamino acid residue in the (i + 2) position and forming a beta-bend reveal a type II conformation.