Shouting from far away: three poems about living with speechlessness.

We present three poems written from personal experience of living with primary progressive non-fluent aphasia (primary progressive apraxia of speech). The poems provide a window on this illness 'from the inside', and vividly illustrate how intellect and inner life may survive strikingly intact, even after speech is lost.

Increased Sensitivity of Plasmodium falciparum to Artesunate/Amodiaquine Despite 14 Years as First-Line Malaria Treatment, Zanzibar.

Artemisinin-based combination therapies (ACTs) are first-line treatments for uncomplicated Plasmodium falciparum malaria. ACT resistance is spreading in Asia but not yet in Africa. Reduced effects of ACT partner drugs have been reported but with little information regarding widely used artesunate/amodiaquine (ASAQ). We studied its efficacy in Zanzibar after 14 years as first-line treatment directly by an in vivo, single-armed trial and indirectly by prevalences of different genotypes in the P. falciparum chloroquine-resistance transporter, multidrug-resistance 1, and Kelch 13 propeller domain genes. In vivo efficacy was higher during 2017 (100%; 95% CI 97.4%-100%) than during 2002-2005 (94.7%; 95% CI 91.9%-96.7%) (p = 0.003). Molecular findings showed no artemisinin resistance-associated genotypes and major increases in genotypes associated with high sensitivity/efficacy for amodiaquine than before ASAQ was introduced. Thus, the efficacy of ASAQ is maintained and appears to be increased after long-term use in contrast to what is observed for other ACTs used in Africa.

Parasite clearance, cure rate, post-treatment prophylaxis and safety of standard 3-day versus an extended 6-day treatment of artemether-lumefantrine and a single low-dose primaquine for uncomplicated Plasmodium falciparum malaria in Bagamoyo district, Tanzania: a randomized controlled trial.

BACKGROUND: Artemisinin-based combination therapy (ACT) resistant Plasmodium falciparum represents an increasing threat to Africa. Extended ACT regimens from standard 3 to 6 days may represent a means to prevent its development and potential spread in Africa. METHODS: Standard 3-day treatment with artemether-lumefantrine (control) was compared to extended 6-day treatment and single low-dose primaquine (intervention); in a randomized controlled, parallel group, superiority clinical trial of patients aged 1-65 years with microscopy confirmed uncomplicated P. falciparum malaria, enrolled in Bagamoyo district, Tanzania. The study evaluated parasite clearance, including proportion of PCR detectable P. falciparum on days 5 and 7 (primary endpoint), cure rate, post-treatment prophylaxis, safety and tolerability. Clinical, and laboratory assessments, including ECG were conducted during 42 days of follow-up. Blood samples were collected for parasite detection (by microscopy and PCR), molecular genotyping and pharmacokinetic analyses. Kaplan-Meier survival analyses were done for both parasite clearance and recurrence. RESULTS: A total of 280 patients were enrolled, 141 and 139 in the control and intervention arm, respectively, of whom 121 completed 42 days follow-up in each arm. There was no difference in proportion of PCR positivity across the arms at day 5 (80/130 (61.5%) vs 89/134 (66.4%), p = 0.44), or day 7 (71/129 (55.0%) vs 70/134 (52.2%), p = 0.71). Day 42 microscopy determined cure rates (PCR adjusted) were 97.4% (100/103) and 98.3% (110/112), p = 0.65, in the control and intervention arm, respectively. Microscopy determined crude recurrent parasitaemia during follow-up was 21/121 (17.4%) in the control and 14/121 (11.6%) in the intervention arm, p = 0.20, and it took 34 days and 42 days in the respective arms for 90% of the patients to remain without recurrent parasitaemia. Lumefantrine exposure was significantly higher in intervention arm from D3 to D42, but cardiac, biochemical and haematological safety was high and similar in both arms. CONCLUSION: Extended 6-day artemether-lumefantrine treatment and a single low-dose of primaquine was not superior to standard 3-day treatment for ACT sensitive P. falciparum infections but, importantly, equally efficacious and safe. Thus, extended artemether-lumefantrine treatment may be considered as a future treatment regimen for ACT resistant P. falciparum, to prolong the therapeutic lifespan of ACT in Africa. Trial registration ClinicalTrials.gov, NCT03241901. Registered July 27, 2017 https://clinicaltrials.gov/show/NCT03241901.

Habitability of extrasolar planets and tidal spin evolution.

Stellar radiation has conservatively been used as the key constraint to planetary habitability. We review here the effects of tides, exerted by the host star on the planet, on the evolution of the planetary spin. Tides initially drive the rotation period and the orientation of the rotation axis into an equilibrium state but do not necessarily lead to synchronous rotation. As tides also circularize the orbit, eventually the rotation period does equal the orbital period and one hemisphere will be permanently irradiated by the star. Furthermore, the rotational axis will become perpendicular to the orbit, i.e. the planetary surface will not experience seasonal variations of the insolation. We illustrate here how tides alter the spins of planets in the traditional habitable zone. As an example, we show that, neglecting perturbations due to other companions, the Super-Earth Gl581d performs two rotations per orbit and that any primordial obliquity has been eroded.

Magma Ocean Evolution of the TRAPPIST-1 Planets.

Recent observations of the potentially habitable planets TRAPPIST-1 e, f, and g suggest that they possess large water mass fractions of possibly several tens of weight percent of water, even though the host star's activity should drive rapid atmospheric escape. These processes can photolyze water, generating free oxygen and possibly desiccating the planet. After the planets formed, their mantles were likely completely molten with volatiles dissolving and exsolving from the melt. To understand these planets and prepare for future observations, the magma ocean phase of these worlds must be understood. To simulate these planets, we have combined existing models of stellar evolution, atmospheric escape, tidal heating, radiogenic heating, magma-ocean cooling, planetary radiation, and water-oxygen-iron geochemistry. We present MagmOc, a versatile magma-ocean evolution model, validated against the rocky super-Earth GJ 1132b and early Earth. We simulate the coupled magma-ocean atmospheric evolution of TRAPPIST-1 e, f, and g for a range of tidal and radiogenic heating rates, as well as initial water contents between 1 and 100 Earth oceans. We also reanalyze the structures of these planets and find they have water mass fractions of 0-0.23, 0.01-0.21, and 0.11-0.24 for planets e, f, and g, respectively. Our model does not make a strong prediction about the water and oxygen content of the atmosphere of TRAPPIST-1 e at the time of mantle solidification. In contrast, the model predicts that TRAPPIST-1 f and g would have a thick steam atmosphere with a small amount of oxygen at that stage. For all planets that we investigated, we find that only 3-5% of the initial water will be locked in the mantle after the magma ocean solidified.

Pharmacological characterisation of GSK3335103, an oral αvß6 integrin small molecule RGD-mimetic inhibitor for the treatment of fibrotic disease.

Fibrosis is the formation of scar tissue due to injury or long-term inflammation and is a leading cause of morbidity and mortality. Activation of the pro-fibrotic cytokine transforming growth factor-ß (TGFß) via the alpha-V beta-6 (αvß6) integrin has been identified as playing a key role in the development of fibrosis. Therefore, a drug discovery programme to identify an orally bioavailable small molecule αvß6 arginyl-glycinyl-aspartic acid (RGD)-mimetic was initiated. As part of a medicinal chemistry programme GSK3335103 was identified and profiled in a range of pre-clinical in vitro and in vivo systems. GSK3335103 was shown to bind to the αvß6 with high affinity and demonstrated fast binding kinetics. In primary human lung epithelial cells, GSK3335103-induced concentration- and time-dependent internalisation of αvß6 with a rapid return of integrin to the cell surface observed after washout. Following sustained engagement of the αvß6 integrin in vitro, lysosomal degradation was induced by GSK3335103. GSK3335103 was shown to engage with the αvß6 integrin and inhibit the activation of TGFß in both ex vivo IPF tissue and in a murine model of bleomycin-induced lung fibrosis, as measured by αvß6 engagement, TGFß signalling and collagen deposition, with a prolonged duration of action observed in vivo. In summary, GSK3335103 is a potent αvß6 inhibitor that attenuates TGFß signalling in vitro and in vivo with a well-defined pharmacokinetic/pharmacodynamic relationship. This translates to a significant reduction of collagen deposition in vivo and therefore GSK3335103 represents a potential novel oral therapy for fibrotic disorders.

Translational pharmacology of an inhaled small molecule αvß6 integrin inhibitor for idiopathic pulmonary fibrosis.

The αvß6 integrin plays a key role in the activation of transforming growth factor-ß (TGFß), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvß6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvß6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFß signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvß6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvß6, induces prolonged inhibition of TGFß signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.

The Habitability of Proxima Centauri b: Environmental States and Observational Discriminants.

Proxima Centauri b provides an unprecedented opportunity to understand the evolution and nature of terrestrial planets orbiting M dwarfs. Although Proxima Cen b orbits within its star's habitable zone, multiple plausible evolutionary paths could have generated different environments that may or may not be habitable. Here, we use 1-D coupled climate-photochemical models to generate self-consistent atmospheres for several evolutionary scenarios, including high-O2, high-CO2, and more Earth-like atmospheres, with both oxic and anoxic compositions. We show that these modeled environments can be habitable or uninhabitable at Proxima Cen b's position in the habitable zone. We use radiative transfer models to generate synthetic spectra and thermal phase curves for these simulated environments, and use instrument models to explore our ability to discriminate between possible planetary states. These results are applicable not only to Proxima Cen b but to other terrestrial planets orbiting M dwarfs. Thermal phase curves may provide the first constraint on the existence of an atmosphere. We find that James Webb Space Telescope (JWST) observations longward of 10 µm could characterize atmospheric heat transport and molecular composition. Detection of ocean glint is unlikely with JWST but may be within the reach of larger-aperture telescopes. Direct imaging spectra may detect O4 absorption, which is diagnostic of massive water loss and O2 retention, rather than a photosynthetic biosphere. Similarly, strong CO2 and CO bands at wavelengths shortward of 2.5 µm would indicate a CO2-dominated atmosphere. If the planet is habitable and volatile-rich, direct imaging will be the best means of detecting habitability. Earth-like planets with microbial biospheres may be identified by the presence of CH4-which has a longer atmospheric lifetime under Proxima Centauri's incident UV-and either photosynthetically produced O2 or a hydrocarbon haze layer. Key Words: Planetary habitability and biosignatures-Planetary atmospheres-Exoplanets-Spectroscopic biosignatures-Planetary science-Proxima Centauri b. Astrobiology 18, 133-189.

The Effect of Orbital Configuration on the Possible Climates and Habitability of Kepler-62f.

UNLABELLED: As lower-mass stars often host multiple rocky planets, gravitational interactions among planets can have significant effects on climate and habitability over long timescales. Here we explore a specific case, Kepler-62f (Borucki et al., 2013 ), a potentially habitable planet in a five-planet system with a K2V host star. N-body integrations reveal the stable range of initial eccentricities for Kepler-62f is 0.00 ≤ e ≤ 0.32, absent the effect of additional, undetected planets. We simulate the tidal evolution of Kepler-62f in this range and find that, for certain assumptions, the planet can be locked in a synchronous rotation state. Simulations using the 3-D Laboratoire de Météorologie Dynamique (LMD) Generic global climate model (GCM) indicate that the surface habitability of this planet is sensitive to orbital configuration. With 3 bar of CO2 in its atmosphere, we find that Kepler-62f would only be warm enough for surface liquid water at the upper limit of this eccentricity range, providing it has a high planetary obliquity (between 60° and 90°). A climate similar to that of modern-day Earth is possible for the entire range of stable eccentricities if atmospheric CO2 is increased to 5 bar levels. In a low-CO2 case (Earth-like levels), simulations with version 4 of the Community Climate System Model (CCSM4) GCM and LMD Generic GCM indicate that increases in planetary obliquity and orbital eccentricity coupled with an orbital configuration that places the summer solstice at or near pericenter permit regions of the planet with above-freezing surface temperatures. This may melt ice sheets formed during colder seasons. If Kepler-62f is synchronously rotating and has an ocean, CO2 levels above 3 bar would be required to distribute enough heat to the nightside of the planet to avoid atmospheric freeze-out and permit a large enough region of open water at the planet's substellar point to remain stable. Overall, we find multiple plausible combinations of orbital and atmospheric properties that permit surface liquid water on Kepler-62f. KEY WORDS: Extrasolar planets-Habitability-Planetary environments. Astrobiology 16, 443-464.

IDENTIFYING PLANETARY BIOSIGNATURE IMPOSTORS: SPECTRAL FEATURES OF CO AND O4 RESULTING FROM ABIOTIC O2/O3 PRODUCTION.

O2 and O3 have been long considered the most robust individual biosignature gases in a planetary atmosphere, yet multiple mechanisms that may produce them in the absence of life have been described. However, these abiotic planetary mechanisms modify the environment in potentially identifiable ways. Here we briefly discuss two of the most detectable spectral discriminants for abiotic O2/O3: CO and O4. We produce the first explicit self-consistent simulations of these spectral discriminants as they may be seen by James Webb Space Telescope (JWST). If JWST-NIRISS and/or NIRSpec observe CO (2.35, 4.6 µm) in conjunction with CO2 (1.6, 2.0, 4.3 µm) in the transmission spectrum of a terrestrial planet it could indicate robust CO2 photolysis and suggest that a future detection of O2 or O3 might not be biogenic. Strong O4 bands seen in transmission at 1.06 and 1.27 µm could be diagnostic of a post-runaway O2-dominated atmosphere from massive H-escape. We find that for these false positive scenarios, CO at 2.35 µm, CO2 at 2.0 and 4.3 µm, and O4 at 1.27 µm are all stronger features in transmission than O2/O3 and could be detected with S/Ns ≳ 3 for an Earth-size planet orbiting a nearby M dwarf star with as few as 10 transits, assuming photon-limited noise. O4 bands could also be sought in UV/VIS/NIR reflected light (at 0.345, 0.36, 0.38, 0.445, 0.475, 0.53, 0.57, 0.63, 1.06, and 1.27 µm) by a next generation direct-imaging telescope such as LUVOIR/HDST or HabEx and would indicate an oxygen atmosphere too massive to be biologically produced.

Formation, habitability, and detection of extrasolar moons.

The diversity and quantity of moons in the Solar System suggest a manifold population of natural satellites exist around extrasolar planets. Of peculiar interest from an astrobiological perspective, the number of sizable moons in the stellar habitable zones may outnumber planets in these circumstellar regions. With technological and theoretical methods now allowing for the detection of sub-Earth-sized extrasolar planets, the first detection of an extrasolar moon appears feasible. In this review, we summarize formation channels of massive exomoons that are potentially detectable with current or near-future instruments. We discuss the orbital effects that govern exomoon evolution, we present a framework to characterize an exomoon's stellar plus planetary illumination as well as its tidal heating, and we address the techniques that have been proposed to search for exomoons. Most notably, we show that natural satellites in the range of 0.1-0.5 Earth mass (i) are potentially habitable, (ii) can form within the circumplanetary debris and gas disk or via capture from a binary, and (iii) are detectable with current technology.

Astrobiological stoichiometry.

Chemical composition affects virtually all aspects of astrobiology, from stellar astrophysics to molecular biology. We present a synopsis of the research results presented at the "Stellar Stoichiometry" Workshop Without Walls hosted at Arizona State University April 11-12, 2013, under the auspices of the NASA Astrobiology Institute. The results focus on the measurement of chemical abundances and the effects of composition on processes from stellar to planetary scales. Of particular interest were the scientific connections between processes in these normally disparate fields. Measuring the abundances of elements in stars and giant and terrestrial planets poses substantial difficulties in technique and interpretation. One of the motivations for this conference was the fact that determinations of the abundance of a given element in a single star by different groups can differ by more than their quoted errors. The problems affecting the reliability of abundance estimations and their inherent limitations are discussed. When these problems are taken into consideration, self-consistent surveys of stellar abundances show that there is still substantial variation (factors of ∼ 2) in the ratios of common elements (e.g., C, O, Na, Al, Mg, Si, Ca) important in rock-forming minerals, atmospheres, and biology. We consider how abundance variations arise through injection of supernova nucleosynthesis products into star-forming material and through photoevaporation of protoplanetary disks. The effects of composition on stellar evolution are substantial, and coupled with planetary atmosphere models can result in predicted habitable zone extents that vary by many tens of percent. Variations in the bulk composition of planets can affect rates of radiogenic heating and substantially change the mineralogy of planetary interiors, affecting properties such as convection and energy transport.

Exomoon habitability constrained by illumination and tidal heating.

The detection of moons orbiting extrasolar planets ("exomoons") has now become feasible. Once they are discovered in the circumstellar habitable zone, questions about their habitability will emerge. Exomoons are likely to be tidally locked to their planet and hence experience days much shorter than their orbital period around the star and have seasons, all of which works in favor of habitability. These satellites can receive more illumination per area than their host planets, as the planet reflects stellar light and emits thermal photons. On the contrary, eclipses can significantly alter local climates on exomoons by reducing stellar illumination. In addition to radiative heating, tidal heating can be very large on exomoons, possibly even large enough for sterilization. We identify combinations of physical and orbital parameters for which radiative and tidal heating are strong enough to trigger a runaway greenhouse. By analogy with the circumstellar habitable zone, these constraints define a circumplanetary "habitable edge." We apply our model to hypothetical moons around the recently discovered exoplanet Kepler-22b and the giant planet candidate KOI211.01 and describe, for the first time, the orbits of habitable exomoons. If either planet hosted a satellite at a distance greater than 10 planetary radii, then this could indicate the presence of a habitable moon.

Habitable planets around white and brown dwarfs: the perils of a cooling primary.

White and brown dwarfs are astrophysical objects that are bright enough to support an insolation habitable zone (IHZ). Unlike hydrogen-burning stars, they cool and become less luminous with time; hence their IHZ moves in with time. The inner edge of the IHZ is defined as the orbital radius at which a planet may enter a moist or runaway greenhouse, phenomena that can remove a planet's surface water forever. Thus, as the IHZ moves in, planets that enter it may no longer have any water and are still uninhabitable. Additionally, the close proximity of the IHZ to the primary leads to concern that tidal heating may also be strong enough to trigger a runaway greenhouse, even for orbital eccentricities as small as 10(-6). Water loss occurs due to photolyzation by UV photons in the planetary stratosphere, followed by hydrogen escape. Young white dwarfs emit a large amount of these photons, as their surface temperatures are over 10(4) K. The situation is less clear for brown dwarfs, as observational data do not constrain their early activity and UV emission very well. Nonetheless, both types of planets are at risk of never achieving habitable conditions, but planets orbiting white dwarfs may be less likely to sustain life than those orbiting brown dwarfs. We consider the future habitability of the planet candidates KOI 55.01 and 55.02 in these terms and find they are unlikely to become habitable.

Tidal Venuses: triggering a climate catastrophe via tidal heating.

Traditionally, stellar radiation has been the only heat source considered capable of determining global climate on long timescales. Here, we show that terrestrial exoplanets orbiting low-mass stars may be tidally heated at high-enough levels to induce a runaway greenhouse for a long-enough duration for all the hydrogen to escape. Without hydrogen, the planet no longer has water and cannot support life. We call these planets "Tidal Venuses" and the phenomenon a "tidal greenhouse." Tidal effects also circularize the orbit, which decreases tidal heating. Hence, some planets may form with large eccentricity, with its accompanying large tidal heating, and lose their water, but eventually settle into nearly circular orbits (i.e., with negligible tidal heating) in the habitable zone (HZ). However, these planets are not habitable, as past tidal heating desiccated them, and hence should not be ranked highly for detailed follow-up observations aimed at detecting biosignatures. We simulated the evolution of hypothetical planetary systems in a quasi-continuous parameter distribution and found that we could constrain the history of the system by statistical arguments. Planets orbiting stars with masses<0.3 MSun may be in danger of desiccation via tidal heating. We have applied these concepts to Gl 667C c, a ∼4.5 MEarth planet orbiting a 0.3 MSun star at 0.12 AU. We found that it probably did not lose its water via tidal heating, as orbital stability is unlikely for the high eccentricities required for the tidal greenhouse. As the inner edge of the HZ is defined by the onset of a runaway or moist greenhouse powered by radiation, our results represent a fundamental revision to the HZ for noncircular orbits. In the appendices we review (a) the moist and runaway greenhouses, (b) hydrogen escape, (c) stellar mass-radius and mass-luminosity relations, (d) terrestrial planet mass-radius relations, and (e) linear tidal theories.

Tides and the evolution of planetary habitability.

Tides raised on a planet by the gravity of its host star can reduce the planet's orbital semi-major axis and eccentricity. This effect is only relevant for planets orbiting very close to their host stars. The habitable zones of low-mass stars are also close in, and tides can alter the orbits of planets in these locations. We calculate the tidal evolution of hypothetical terrestrial planets around low-mass stars and show that tides can evolve planets past the inner edge of the habitable zone, sometimes in less than 1 billion years. This migration requires large eccentricities (>0.5) and low-mass stars ( less or similar to 0.35 M(circle)). Such migration may have important implications for the evolution of the atmosphere, internal heating, and the Gaia hypothesis. Similarly, a planet that is detected interior to the habitable zone could have been habitable in the past. We consider the past habitability of the recently discovered, approximately 5 M(circle) planet, Gliese 581 c. We find that it could have been habitable for reasonable choices of orbital and physical properties as recently as 2 Gyr ago. However, when constraints derived from the additional companions are included, most parameter choices that indicate past habitability require the two inner planets of the system to have crossed their mutual 3:1 mean motion resonance. As this crossing would likely have resulted in resonance capture, which is not observed, we conclude that Gl 581 c was probably never habitable.