Publisher Correction: A planet within the debris disk around the pre-main-sequence star AU Microscopii.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A planet within the debris disk around the pre-main-sequence star AU Microscopii.

AU Microscopii (AU Mic) is the second closest pre-main-sequence star, at a distance of 9.79 parsecs and with an age of 22 million years1. AU Mic possesses a relatively rare2 and spatially resolved3 edge-on debris disk extending from about 35 to 210 astronomical units from the star4, and with clumps exhibiting non-Keplerian motion5-7. Detection of newly formed planets around such a star is challenged by the presence of spots, plage, flares and other manifestations of magnetic 'activity' on the star8,9. Here we report observations of a planet transiting AU Mic. The transiting planet, AU Mic b, has an orbital period of 8.46 days, an orbital distance of 0.07 astronomical units, a radius of 0.4 Jupiter radii, and a mass of less than 0.18 Jupiter masses at 3σ confidence. Our observations of a planet co-existing with a debris disk offer the opportunity to test the predictions of current models of planet formation and evolution.

A sub-Mercury-sized exoplanet.

Since the discovery of the first exoplanets, it has been known that other planetary systems can look quite unlike our own. Until fairly recently, we have been able to probe only the upper range of the planet size distribution, and, since last year, to detect planets that are the size of Earth or somewhat smaller. Hitherto, no planets have been found that are smaller than those we see in the Solar System. Here we report a planet significantly smaller than Mercury. This tiny planet is the innermost of three that orbit the Sun-like host star, which we have designated Kepler-37. Owing to its extremely small size, similar to that of the Moon, and highly irradiated surface, the planet, Kepler-37b, is probably rocky with no atmosphere or water, similar to Mercury.

Alignment of the stellar spin with the orbits of a three-planet system.

The Sun's equator and the planets' orbital planes are nearly aligned, which is presumably a consequence of their formation from a single spinning gaseous disk. For exoplanetary systems this well-aligned configuration is not guaranteed: dynamical interactions may tilt planetary orbits, or stars may be misaligned with the protoplanetary disk through chaotic accretion , magnetic interactions or torques from neighbouring stars. Indeed, isolated 'hot Jupiters' are often misaligned and even orbiting retrograde. Here we report an analysis of transits of planets over starspots on the Sun-like star Kepler-30 (ref. 8), and show that the orbits of its three planets are aligned with the stellar equator. Furthermore, the orbits are aligned with one another to within a few degrees. This configuration is similar to that of our Solar System, and contrasts with the isolated hot Jupiters. The orderly alignment seen in the Kepler-30 system suggests that high obliquities are confined to systems that experienced disruptive dynamical interactions. Should this be corroborated by observations of other coplanar multi-planet systems, then star-disk misalignments would be ruled out as the explanation for the high obliquities of hot Jupiters, and dynamical interactions would be implicated as the origin of hot Jupiters.

Transiting circumbinary planets Kepler-34 b and Kepler-35 b.

Most Sun-like stars in the Galaxy reside in gravitationally bound pairs of stars (binaries). Although long anticipated, the existence of a 'circumbinary planet' orbiting such a pair of normal stars was not definitively established until the discovery of the planet transiting (that is, passing in front of) Kepler-16. Questions remained, however, about the prevalence of circumbinary planets and their range of orbital and physical properties. Here we report two additional transiting circumbinary planets: Kepler-34 (AB)b and Kepler-35 (AB)b, referred to here as Kepler-34 b and Kepler-35 b, respectively. Each is a low-density gas-giant planet on an orbit closely aligned with that of its parent stars. Kepler-34 b orbits two Sun-like stars every 289 days, whereas Kepler-35 b orbits a pair of smaller stars (89% and 81% of the Sun's mass) every 131 days. The planets experience large multi-periodic variations in incident stellar radiation arising from the orbital motion of the stars. The observed rate of circumbinary planets in our sample implies that more than ∼1% of close binary stars have giant planets in nearly coplanar orbits, yielding a Galactic population of at least several million.

Two Earth-sized planets orbiting Kepler-20.

Since the discovery of the first extrasolar giant planets around Sun-like stars, evolving observational capabilities have brought us closer to the detection of true Earth analogues. The size of an exoplanet can be determined when it periodically passes in front of (transits) its parent star, causing a decrease in starlight proportional to its radius. The smallest exoplanet hitherto discovered has a radius 1.42 times that of the Earth's radius (R(⊕)), and hence has 2.9 times its volume. Here we report the discovery of two planets, one Earth-sized (1.03R(⊕)) and the other smaller than the Earth (0.87R(⊕)), orbiting the star Kepler-20, which is already known to host three other, larger, transiting planets. The gravitational pull of the new planets on the parent star is too small to measure with current instrumentation. We apply a statistical method to show that the likelihood of the planetary interpretation of the transit signals is more than three orders of magnitude larger than that of the alternative hypothesis that the signals result from an eclipsing binary star. Theoretical considerations imply that these planets are rocky, with a composition of iron and silicate. The outer planet could have developed a thick water vapour atmosphere.

The polysaccharide inulin is characterized by an extensive series of periodic isoforms with varying biological actions.

In studying the molecular basis for the potent immune activity of previously described gamma and delta inulin particles and to assist in production of inulin adjuvants under Good Manufacturing Practice, we identified five new inulin isoforms, bringing the total to seven plus the amorphous form. These isoforms comprise the step-wise inulin developmental series amorphous → alpha-1 (AI-1) → alpha-2 (AI-2) → gamma (GI) → delta (DI) → zeta (ZI) → epsilon (EI) → omega (OI) in which each higher isoform can be made either by precipitating dissolved inulin or by direct conversion from its precursor, both cases using regularly increasing temperatures. At higher temperatures, the shorter inulin polymer chains are released from the particle and so the key difference between isoforms is that each higher isoform comprises longer polymer chains than its precursor. An increasing trend of degree of polymerization is confirmed by end-group analysis using (1)H nuclear magnetic resonance spectroscopy. Inulin isoforms were characterized by the critical temperatures of abrupt phase-shifts (solubilizations or precipitations) in water suspensions. Such (aqueous) "melting" or "freezing" points are diagnostic and occur in strikingly periodic steps reflecting quantal increases in noncovalent bonding strength and increments in average polymer lengths. The (dry) melting points as measured by modulated differential scanning calorimetry similarly increase in regular steps. We conclude that the isoforms differ in repeated increments of a precisely repeating structural element. Each isoform has a different spectrum of biological activities and we show the higher inulin isoforms to be more potent alternative complement pathway activators.

Chiral self-assembly of designed amphiphiles: influences on aggregate morphology.

A series of novel amphiphiles were designed for self-assembly into chiral morphologies, the amphiphiles consisting of a glutamic acid (Glu) headgroup connected through an 11-carbon alkoxy chain to a diphenyldiazenyl (Azo) group and terminated with a variable length alkyl chain (R-Azo-11-Glu, where R denotes the number of carbons in the distal chain). TEM imaging of amphiphile aggregates self-assembled from heated, methanolic, aqueous solution showed that chiral order, expressed as twisted ribbons, helical ribbons, and helically based nanotubes, increased progressively up to a distal chain length containing eight carbons, and then decreased with further increases in distal chain length. TEM and CD showed that the chiral aggregations of single enantiomers were influenced by the molecular chirality of the headgroup. However, the assembly of D,L-10-Azo-11-Glu into nanotubes demonstrated that chiral symmetry breaking effected by the azo group was also relevant to the chiral organization of the amphiphiles. The chiral order of aggregate morphologies was additionally affected by the temperature and solvent composition of assembly in a manner correlated to the mechanism driving assembly; i.e., D,L-10-Azo-11-Glu was sensitive to the temperature of assembly but less so to solvent composition, while L-14-Azo-11-Glu was sensitive to solvent composition and not to temperature. FTIR and UV-vis spectroscopic investigations into the organization of the head and azo groups, in chiral and achiral structures, illustrated that a balance of the influences of the hydrophilic and hydrophobic components on self-assembly was required for the optimization of the chiral organization of the self-assembled structures.

Chiral self-assembly of designed amphiphiles: optimization for nanotube formation.

Four amphiphiles with L-aspartic acid headgroups (Asp) and a diphenyldiazenyl group (Azo) contained within the hydrophobic tails were designed and synthesized for self-assembly into helically based nanotubes. The amphiphiles of the form R'-{4-[(4-alkylphenyl)diazenyl]phenoxy}alkanoyl-L-aspartic acid (where R' is 10 or 11) varied only in alkyl chain lengths either side of the azo group, having 4, 7, or 10 carbon distal chains and 10 or 11 carbon proximal chains (R-Azo-R'-Asp, where R denotes the number of carbons in the distal chain and R' denotes the number of carbons in the proximal chain). Despite the molecular similarities, distinct differences were identified in the chiral order of the structures self-assembled from hot methanolic aqueous solutions using microscopy and spectroscopic analyses. This was reflected in dominant thermodynamic aggregate morphologies that ranged from amorphous material for 10-Azo-10-Asp, through twisted ribbons (196 ± 49 nm pitch) for 7-Azo-11-Asp, to the desired helically based nanotubes for 4- and 7-Azo-10-Asp (81 ± 11 and 76 ± 6 nm diameters, respectively). Another key variable in the self-assembly of the amphiphiles was the use of a second method to precipitate aggregates from solution at room temperature. This method enabled the isolation of thermodynamically unstable and key transitional structures. Helical ribbons were precursor structures to the nanotubes formed from 4- and 7-Azo-10-Asp as well as the wide, flattened nanotube structures (587 ± 85 nm width) found for 4-Azo-10-Asp. Overall, the results highlighted the interplay of influence of the headgroup and the hydrophobic tail on self-assembly, providing a basis for future rational design of self-assembling amphiphiles.

Influence of Oxidation Degree on the Physicochemical Properties of Oxidized Inulin.

This paper reports the oxidation of inulin using varying ratios of sodium periodate and the characterization of the inulin polyaldehyde. The physicochemical properties of the inulin polyaldehyde (oxidized inulin) were characterized using different techniques including 1D NMR spectroscopy, 13C Nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FTIR), thermal gravimetric analysis (TGA), differential scanning calorimetric (DSC), ultraviolet-visible spectroscopy (UV), and scanning electron microscopy (SEM). The aldehyde peak was not very visible in the FTIR, because the aldehyde functional group exists in a masked form (hemiacetal). The thermal stability of the oxidized inulin decreased with the increasing oxidation degree. The smooth spherical shape of raw inulin was destructed due to the oxidation, as confirmed by the SEM result. The 1HNMR results show some new peaks from 4.8 to 5.0 as well as around 5.63 ppm. However, no aldehyde peak was found around 9.7 ppm. This can be attributed to the hemiacetal. The reaction of oxidized inulin with tert-butyl carbazate produced a carbazone conjugate. There was clear evidence of decreased peak intensity for the proton belonging to the hemiacetal group. This clearly shows that not all of the hemiacetal group can be reverted by carbazate. In conclusion, this work provides vital information as regards changes in the physicochemical properties of the oxidized inulin, which has direct implications when considering the further utilization of this biomaterial.

Review of polysaccharide particle-based functional drug delivery.

This review investigates the significant role polysaccharide particles play in functional drug delivery. The importance of these systems is due to the wide variety of polysaccharides and their natural source meaning that they can provide biocompatible and biodegradable systems with a range of both biological and chemical functionality valuable for drug delivery. This functionality includes protection and presentation of working therapeutics through avoidance of the reticuloendothelial system, stabilization of biomacromolecules and increasing the bioavailability of incorporated small molecule drugs. Transport of the therapeutic is also key to the utility of polysaccharide particles, moving drugs from the site of administration through mucosal binding and transport and using chemistry, size and receptor mediated drug targeting to specific tissues. This review also scrutinizes the methods of synthesizing and constructing functional polysaccharide particle drug delivery systems that maintain and extend the functionality of the natural polysaccharides.

Preparation and Characterization of Oxidized Inulin Hydrogel for Controlled Drug Delivery.

Inulin-based hydrogels are useful carriers for the delivery of drugs in the colon-targeted system and in other biomedical applications. In this project, inulin hydrogels were fabricated by crosslinking oxidized inulin with adipic acid dihydrazide (AAD) without the use of a catalyst or initiator. The physicochemical properties of the obtained hydrogels were further characterized using different techniques, such as swelling experiments, in vitro drug release, degradation, and biocompatibility tests. The crosslinking was confirmed with Fourier transform infrared spectroscopy (FTIR), thermal gravimetric analysis (TGA), and differential scanning calorimetry (DSC). In vitro releases of 5-fluorouracil (5FU) from the various inulin hydrogels was enhanced in acidic conditions (pH 5) compared with physiological pH (pH 7.4). In addition, blank gels did not show any appreciable cytotoxicity, whereas 5FU-loaded hydrogels demonstrated efficacy against HCT116 colon cancer cells, which further confirms the potential use of these delivery platforms for direct targeting of 5-FU to the colon.

Doxorubicin-Loaded Delta Inulin Conjugates for Controlled and Targeted Drug Delivery: Development, Characterization, and In Vitro Evaluation.

Delta inulin, also known as microparticulate inulin (MPI), was modified by covalently attaching doxorubicin to its nanostructured surface for use as a targeted drug delivery vehicle. MPI is readily endocytosed by monocytes, macrophages, and dendritic cells and in this study, we sought to utilize this property to develop a system to target anti-cancer drugs to lymphoid organs. We investigated, therefore, whether MPI could be used as a vehicle to deliver doxorubicin selectively, thereby reducing the toxicity of this antibiotic anthracycline drug. Doxorubicin was covalently attached to the surface of MPI using an acid-labile linkage to enable pH-controlled release. The MPI-doxorubicin conjugate was characterized using FTIR and SEM, confirming covalent attachment and indicating doxorubicin coupling had no obvious impact on the physical nanostructure, integrity, and cellular uptake of the MPI particles. To simulate the stability of the MPI-doxorubicin in vivo, it was stored in artificial lysosomal fluid (ALF, pH 4.5). Although the MPI-doxorubicin particles were still visible after 165 days in ALF, 53% of glycosidic bonds in the inulin particles were hydrolyzed within 12 days in ALF, reflected by the release of free glucose into solution. By contrast, the fructosidic bonds were much more stable. Drug release studies of the MPI-doxorubicin in vitro, demonstrated a successful pH-dependent controlled release effect. Confocal laser scanning microscopy studies and flow cytometric analysis confirmed that when incubated with live cells, MPI-doxorubicin was efficiently internalized by immune cells. An assay of cell metabolic activity demonstrated that the MPI carrier alone had no toxic effects on RAW 264.7 murine monocyte/macrophage-like cells, but exhibited anti-cancer effects against HCT116 human colon cancer cells. MPI-doxorubicin had a greater anti-cancer cell effect than free doxorubicin, particularly when at lower concentrations, suggesting a drug-sparing effect. This study establishes that MPI can be successfully modified with doxorubicin for chemotherapeutic drug delivery.

Synthesis and Characterization of pH-Sensitive Inulin Conjugate of Isoniazid for Monocyte-Targeted Delivery.

The use of particles for monocyte-mediated delivery could be a more efficient strategy and approach to achieve intracellular targeting and delivery of antitubercular drugs to host macrophages. In this study, the potential of inulin microparticles to serve as a drug vehicle in the treatment of chronic tuberculosis using a monocytes-mediated drug targeting approach was evaluated. Isoniazid (INH) was conjugated to inulin via hydrazone linkage in order to obtain a pH-sensitive inulin-INH conjugate. The conjugate was then characterized using proton nuclear magnetic resonance (1HNMR), Fourier transform infrared spectroscopy (FTIR) as well as in vitro, cellular uptake and intracellular Mycobacterium tuberculosis (Mtb) antibacterial efficacy. The acid-labile hydrazone linkage conferred pH sensitivity to the inulin-INH conjugate with ~95, 77 and 65% of the drug released after 5 h at pH 4.5, 5.2, and 6.0 respectively. Cellular uptake studies confirm that RAW 264.7 monocytic cells efficiently internalized the inulin conjugates into endocytic compartments through endocytosis. The intracellular efficacy studies demonstrate that the inulin conjugates possess a dose-dependent targeting effect against Mtb-infected monocytes. This was through efficient internalization and cleavage of the hydrazone bond by the acidic environment of the lysosome, which subsequently released the isoniazid intracellularly to the Mtb reservoir. These results clearly suggest that inulin conjugates can serve as a pH-sensitive intracellular drug delivery system for TB treatment.

Design and Characterization of Inulin Conjugate for Improved Intracellular and Targeted Delivery of Pyrazinoic Acid to Monocytes.

The propensity of monocytes to migrate into sites of mycobacterium tuberculosis (TB) infection and then become infected themselves makes them potential targets for delivery of drugs intracellularly to the tubercle bacilli reservoir. Conventional TB drugs are less effective because of poor intracellular delivery to this bacterial sanctuary. This study highlights the potential of using semicrystalline delta inulin particles that are readily internalised by monocytes for a monocyte-based drug delivery system. Pyrazinoic acid was successfully attached covalently to the delta inulin particles via a labile linker. The formation of new conjugate and amide bond was confirmed using zeta potential, Proton Nuclear Magnetic Resonance (1HNMR) and Fourier transform infrared spectroscopy (FTIR). Scanning electron microscopy (SEM) confirmed that no significant change in size after conjugation which is an important parameter for monocyte targeting. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were used to establish the change in thermal properties. The analysis of in-vitro release demonstrated pH-triggered drug cleavage off the delta inulin particles that followed a first-order kinetic process. The efficient targeting ability of the conjugate for RAW 264.7 monocytic cells was supported by cellular uptake studies. Overall, our finding confirmed that semicrystalline delta inulin particles (MPI) can be modified covalently with drugs and such conjugates allow intracellular drug delivery and uptake into monocytes, making this system potentially useful for the treatment of TB.

PLANETARY CANDIDATES OBSERVED BY Kepler. VIII. A FULLY AUTOMATED CATALOG WITH MEASURED COMPLETENESS AND RELIABILITY BASED ON DATA RELEASE 25.

We present the Kepler Object of Interest (KOI) catalog of transiting exoplanets based on searching four years of Kepler time series photometry (Data Release 25, Q1-Q17). The catalog contains 8054 KOIs of which 4034 are planet candidates with periods between 0.25 and 632 days. Of these candidates, 219 are new in this catalog and include two new candidates in multi-planet systems (KOI-82.06 and KOI-2926.05), and ten new high-reliability, terrestrial-size, habitable zone candidates. This catalog was created using a tool called the Robovetter which automatically vets the DR25 Threshold Crossing Events (TCEs) found by the Kepler Pipeline (Twicken et al. 2016). Because of this automation, we were also able to vet simulated data sets and therefore measure how well the Robovetter separates those TCEs caused by noise from those caused by low signal-to-noise transits. Because of these measurements we fully expect that this catalog can be used to accurately calculate the frequency of planets out to Kepler's detection limit, which includes temperate, super-Earth size planets around GK dwarf stars in our Galaxy. This paper discusses the Robovetter and the metrics it uses to decide which TCEs are called planet candidates in the DR25 KOI catalog. We also discuss the simulated transits, simulated systematic noise, and simulated astrophysical false positives created in order to characterize the properties of the final catalog. For orbital periods less than 100 d the Robovetter completeness (the fraction of simulated transits that are determined to be planet candidates) across all observed stars is greater than 85%. For the same period range, the catalog reliability (the fraction of candidates that are not due to instrumental or stellar noise) is greater than 98%. However, for low signal-to-noise candidates found between 200 and 500 days, our measurements indicate that the Robovetter is 73.5% complete and 37.2% reliable across all searched stars (or 76.7% complete and 50.5% reliable when considering just the FGK dwarf stars). We describe how the measured completeness and reliability varies with period, signal-to-noise, number of transits, and stellar type. Also, we discuss a value called the disposition score which provides an easy way to select a more reliable, albeit less complete, sample of candidates. The entire KOI catalog, the transit fits using Markov chain Monte Carlo methods, and all of the simulated data used to characterize this catalog are available at the NASA Exoplanet Archive.

Investigation of the biodistribution, breakdown and excretion of delta inulin adjuvant.

Insoluble, nanostructured delta inulin particles enhance the immunogenicity of co-administered protein antigens and consequently are used as a vaccine adjuvant (Advax™). To better understand their immunomodulatory properties, the in vitro hydrolysis and in vivo distribution of delta inulin particles were investigated. Delta inulin particle hydrolysis under bio-relevant acidic conditions resulted in no observable change to the bulk morphology using SEM, and HPLC results showed that only 6.1% of the inulin was hydrolysed over 21days. However, 65% of the terminal glucose groups were released, showing that acid hydrolysis relatively rapidly releases surface bound chemistries. This was used to explain in vivo biodistribution results in which delta inulin particles surface-labelled with fluorescein-5-thiosemicabizide were administered to mice using intramuscular (I.M.) or subcutaneous (S.C.) routes. Comparison analysis of the fluorescence of soluble inulin in the supernatants of homogenised tissues maintained at room temperature or heated to 100°C to solubilise particulate inulin was used to distinguish between fluorescent probe on soluble inulin and probe bound to inulin within particles. Following both I.M. and S.C. injection delta inulin exhibited a depot behaviour with local injection site residence for several weeks. Over this time, as injection site inulin reduced, there was measurable transport of intact delta inulin particles by macrophages to secondary lymphoid organs and the liver. Ultimately, the injected delta inulin became solubilised resulting in its detection in the plasma and in the urine. Thus injected delta inulin particles are initially taken up by macrophages at the site of injection, trafficked to secondary lymphoid tissue and the liver, and hydrolysed resulting in their becoming soluble and diffusing into the blood stream, from whence they are glomerularly filtered and excreted into the urine. These results provide important insights into the biodistribution of I.M. or S.C. injected delta inulin particles when used as vaccine adjuvants and their method of excretion.

A Novel Fabrication Approach for Multifunctional Graphene-based Thin Film Nano-composite Membranes with Enhanced Desalination and Antibacterial Characteristics.

A practical fabrication technique is presented to tackle the trade-off between the water flux and salt rejection of thin film composite (TFC) reverse osmosis (RO) membranes through controlled creation of a thinner active selective polyamide (PA) layer. The new thin film nano-composite (TFNC) RO membranes were synthesized with multifunctional poly tannic acid-functionalized graphene oxide nanosheets (pTA-f-GO) embedded in its PA thin active layer, which is produced through interfacial polymerization. The incorporation of pTA-f-GOL into the fabricated TFNC membranes resulted in a thinner PA layer with lower roughness and higher hydrophilicity compared to pristine membrane. These properties enhanced both the membrane water flux (improved by 40%) and salt rejection (increased by 8%) of the TFNC membrane. Furthermore, the incorporation of biocidal pTA-f-GO nanosheets into the PA active layer contributed to improving the antibacterial properties by 80%, compared to pristine membrane. The fabrication of the pTA-f-GO nanosheets embedded in the PA layer presented in this study is a very practical, scalable and generic process that can potentially be applied in different types of separation membranes resulting in less energy consumption, increased cost-efficiency and improved performance.

Single-Step Assembly of Multifunctional Poly(tannic acid)-Graphene Oxide Coating To Reduce Biofouling of Forward Osmosis Membranes.

Graphene oxide (GO) nanosheets have antibacterial properties that have been exploited as a biocidal agent used on desalination membrane surfaces in recent research. Nonetheless, improved strategies for efficient and stable attachment of GO nanosheets onto the membrane surface are still required for this idea to be commercially viable. To address this challenge, we adopted a novel, single-step surface modification approach using tannic acid cross-linked with polyethylene imine as a versatile platform to immobilize GO nanosheets to the surface of polyamide thin film composite forward osmosis (FO) membranes. An experimental design based on Taguchi's statistical method was applied to optimize the FO processing conditions in terms of water and reverse solute fluxes. Modified membranes were analyzed using water contact angle, adenosine triphosphate bioluminescence, total organic carbon, Fourier transform infrared spectroscopy, ζ potential, X-ray photoelectron spectroscopy, transmission electron microscopy, and atomic force microscopy. These results show that membranes were modified with a nanoscale (<10 nm), smooth, hydrophilic coating that, compared to pristine membranes, improved filtration and significantly mitigated biofouling by 33% due to its extraordinary, synergistic antibacterial properties (99.9%).