Cyanide-resistant non-phosphorylating respiration is known in mitochondria from plants, fungi, and microorganisms but is absent in mammals. It results from the activity of an alternative oxidase ...(AOX) that conveys electrons directly from the respiratory chain (RC) ubiquinol pool to oxygen. AOX thus provides a bypath that releases constraints on the cytochrome pathway and prevents the over-reduction of the ubiquinone pool, a major source of superoxide. RC dysfunctions and deleterious superoxide overproduction are recurrent themes in human pathologies, ranging from neurodegenerative diseases to cancer, and may be instrumental in ageing. Thus, preventing RC blockade and excess superoxide production by means of AOX should be of considerable interest. However, because of its energy-dissipating properties, AOX might produce deleterious effects of its own in mammals. Here we show that AOX can be safely expressed in the mouse (MitAOX), with major physiological parameters being unaffected. It neither disrupted the activity of other RC components nor decreased oxidative phosphorylation in isolated mitochondria. It conferred cyanide-resistance to mitochondrial substrate oxidation and decreased reactive oxygen species (ROS) production upon RC blockade. Accordingly, AOX expression was able to support cyanide-resistant respiration by intact organs and to afford prolonged protection against a lethal concentration of gaseous cyanide in whole animals. Taken together, these results indicate that AOX expression in the mouse is innocuous and permits to overcome a RC blockade, while reducing associated oxidative insult. Therefore, the MitAOX mice represent a valuable tool in order to investigate the ability of AOX to counteract the panoply of mitochondrial-inherited diseases originating from oxidative phosphorylation defects.
Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children and causes chronic diarrhea in AIDS patients, but the only approved treatment is ineffective in malnourished ...children and immunocompromised people. We here use a drug repositioning strategy and identify a promising anticryptosporidial drug candidate. Screening a library of benzoxaboroles comprised of analogs to four antiprotozoal chemical scaffolds under pre-clinical development for neglected tropical diseases for Cryptosporidium growth inhibitors identifies the 6-carboxamide benzoxaborole AN7973. AN7973 blocks intracellular parasite development, appears to be parasiticidal, and potently inhibits the two Cryptosporidium species most relevant to human health, C. parvum and C. hominis. It is efficacious in murine models of both acute and established infection, and in a neonatal dairy calf model of cryptosporidiosis. AN7973 also possesses favorable safety, stability, and PK parameters, and therefore, is an exciting drug candidate for treating cryptosporidiosis.
ABSTRACT
In this work we report the discovery and analysis of three new triply eclipsing triple star systems found with the TESS mission during its observations of the northern skies: TICs 193993801, ...388459317, and 52041148. We utilized the TESS precision photometry of the binary eclipses and third-body eclipsing events, ground-based archival and follow-up photometric data, eclipse timing variations, archival spectral energy distributions, as well as theoretical evolution tracks in a joint photodynamical analysis to deduce the system masses and orbital parameters of both the inner and outer orbits. In one case (TIC 193993801) we also obtained radial velocity measurements of all three stars. This enabled us to ‘calibrate’ our analysis approach with and without ‘truth’ (i.e. RV) data. We find that the masses are good to 1–3 per cent accuracy with RV data and 3–10 per cent without the use of RV data. In all three systems we were able to find the outer orbital period before doing any detailed analysis by searching for a longer-term periodicity in the ASAS-SN archival photometry data – just a few thousand ASAS-SN points enabled us to find the outer periods of 49.28 d, 89.86 d, and 177.0 d, respectively. From our full photodynamical analysis we find that all three systems are coplanar to within 1°−3°. The outer eccentricities of the three systems are 0.003, 0.10, and 0.62, respectively (i.e. spanning a factor of 200). The masses of the three stars {Aa, Ab, and B} in the three systems are: {1.31, 1.19, 1.34}, {1.82, 1.73, 2.19}, and {1.62, 1.48, 2.74} M⊙, respectively.
Carboxamide pyrazinyloxy benzoxaboroles were investigated with the goal to identify a molecule with satisfactory antimalarial activity, physicochemical properties, pharmacokinetic profile, in vivo ...efficacy, and safety profile. This optimization effort discovered 46, which met our target candidate profile. Compound 46 had excellent activity against cultured Plasmodium falciparum, and in vivo against P. falciparum and P. berghei in infected mice. It exhibited good PK properties in mice, rats, and dogs. It was highly active against the other 11 P. falciparum strains, which are mostly resistant to chloroquine and pyrimethamine. The rapid parasite in vitro reduction and in vivo parasite clearance profile of 46 were similar to those of artemisinin and chloroquine, two rapid-acting antimalarials. It was nongenotoxic in an Ames assay, an in vitro micronucleus assay, and an in vivo rat micronucleus assay when dosed orally up to 2000 mg/kg. The combined properties of this novel benzoxaborole support its progression to preclinical development.
Changes in the flammability characteristics of a combusting mixture and its 'dilution' levels - characterized, respectively, by the mixture's equivalence ratio and residual gas fraction - can have ...significant impacts on the nature of combustion in internal combustion engines. These combustion changes can manifest as variations in combustion phasing and repeatability, and affect engine efficiency, emissions, and performance.
The current work uses experimental, high-speed, in-cylinder CO
2
concentration data from a single-cylinder, natural gas-fueled engine to track compositional variations in the combusting mixture; and then uses a chemical kinetics solver to isolate the effects of flammability and dilution changes on the mixture's 'reactivity,' which is characterized by its laminar flame speed (LFS) and ignition delay (ID). It is found that LFS changes are driven strongly by the trapped equivalence ratio, while ID changes are driven primarily by dilution and pressure changes. Additionally, the effects of LFS changes on the overall combustion phasing are found to be more pronounced than those from ID changes, as the former influences both the combustion initiation and propagation processes.
The M segment of the 2009 pandemic influenza A virus (IAV) has been implicated in its emergence into human populations. To elucidate the genetic contributions of the M segment to host adaptation, and ...the underlying mechanisms, we examined a panel of isogenic viruses that carry avian- or human-derived M segments. Avian, but not human, M segments restricted viral growth and transmission in mammalian model systems, and the restricted growth correlated with increased expression of M2 relative to M1. M2 overexpression was associated with intracellular accumulation of autophagosomes, which was alleviated by interference of the viral proton channel activity by amantadine treatment. As M1 and M2 are expressed from the M mRNA through alternative splicing, we separated synonymous and non-synonymous changes that differentiate human and avian M segments and found that dysregulation of gene expression leading to M2 overexpression diminished replication, irrespective of amino acid composition of M1 or M2. Moreover, in spite of efficient replication, virus possessing a human M segment that expressed avian M2 protein at low level did not transmit efficiently. We conclude that (i) determinants of transmission reside in the IAV M2 protein, and that (ii) control of M segment gene expression is a critical aspect of IAV host adaptation needed to prevent M2-mediated dysregulation of vesicular homeostasis.
ABSTRACT
In this work, we report the discovery and analysis of six new compact triply eclipsing triple star systems found with the TESS mission: TICs 37743815, 42565581, 54060695, 178010808, ...242132789, and 456194776. All of these exhibit distinct third-body eclipses where the inner eclipsing binary (EB) occults the third (‘tertiary’) star, or vice versa. We utilized the TESS photometry, archival photometric data, and available archival spectral energy distribution curves (SED) to solve for the properties of all three stars, as well as many of the orbital elements. We describe in detail our SED fits, search of the archival data for the outer orbital period, and the final global photodynamical analyses. From these analyses, we find that all six systems are coplanar to within 0°−5°, and are viewed nearly edge on (i.e. within a couple of degrees). The outer orbital periods and eccentricities of the six systems are {Pout (days), e}: {68.7, 0.36}, {123, 0.16}, {60.7, 0.01}, {69.0, 0.29}, {41.5, 0.01}, {93.9, 0.29}, respectively, in the order the sources are listed above. The masses of all 12 EB stars were in the range of 0.7–1.8 M⊙ and were situated near the main sequence. By contrast, the masses and radii of the tertiary stars ranged from 1.5 to 2.3 M⊙ and 2.9 to 12 R⊙, respectively. We use this information to estimate the occurrence rate of compact flat triple systems..
Abstract
We present a strongly interacting quadruple system associated with the K2 target EPIC 220204960. The K2 target itself is a Kp = 12.7-mag star at Teff ≃ 6100 K, which we designate as ‘B-N’ ...(blue northerly image). The host of the quadruple system, however, is a Kp ≃ 17-mag star with a composite M-star spectrum, which we designate as ‘R-S’ (red southerly image). With a 3.2-arcsec separation and similar radial velocities and photometric distances, ‘B-N’ is likely physically associated with ‘R-S’, making this a quintuple system, but that is incidental to our main claim of a strongly interacting quadruple system in ‘R-S’. The two binaries in ‘R-S’ have orbital periods of 13.27 and 14.41 d, respectively, and each has an inclination angle of ≳89°. From our analysis of radial-velocity (RV) measurements, and of the photometric light curve, we conclude that all four stars are very similar with masses close to 0.4 M⊙. Both of the binaries exhibit significant eclipse-timing variations where those of the primary and secondary eclipses ‘diverge’ by 0.05 d over the course of the 80-d observations. Via a systematic set of numerical simulations of quadruple systems consisting of two interacting binaries, we conclude that the outer orbital period is very likely to be between 300 and 500 d. If sufficient time is devoted to RV studies of this faint target, the outer orbit should be measurable within a year.
The COVID-19 pandemic resulted in the implementation of strict public health and social measures (PHSMs) (including mobility restrictions, social distancing, mask-wearing and hand hygiene), ...limitations on non-essential healthcare services, and public fear of COVID-19 infection, all of which potentially affected transmission and healthcare use for other diseases such as lower respiratory tract infections (LRTIs).
To determine changes in LRTI hospital admissions and in-facility mortality in children aged <5 years in the Western Cape Province during the pandemic.
We conducted a retrospective analysis of LRTI admissions and in-facility deaths from January 2019 to November 2021. We estimated changes in rates and trends of LRTI admissions during the pandemic compared with pre-pandemic period using interrupted time series analysis, adjusting for key characteristics.
There were 36 277 children admitted for LRTIs during the study period, of whom 58% were male and 51% were aged 28 days - 1 year. COVID-19 restrictions were associated with a 13% step reduction in LRTI admissions compared with the pre-COVID-19 period (incidence rate ratio (IRR) 0.87, 95% confidence interval (CI)) 0.80 - 0.94). The average LRTI admission trend increased on average by 2% per month during the pandemic (IRR 1.02, 95% CI 1.02 - 1.04).
The COVID-19 surges and their associated measures were linked to declining LRTI admissions and in-facility deaths, likely driven by a combination of reduced infectious disease transmission and reduced use of healthcare services, with effects diminishing over time. These findings may inform future pandemic response policies.
The Random Transiter – EPIC 249706694/HD 139139 Rappaport, S.; Vanderburg, A.; Omohundro, M.R. ...
Monthly Notices of the Royal Astronomical Society,
09/2019, Letnik:
488, Številka:
2
Journal Article
Recenzirano
Odprti dostop
We have identified a star, EPIC 249706694 (HD 139139), that was observed during K2 Campaign 15 with the Kepler extended mission that appears to exhibit 28 transit-like events over the course of the ...87-day observation. The unusual aspect of these dips, all but two of which have depths of 200 ± 80 ppm, is that they exhibit no periodicity, and their arrival times could just as well have been produced by a random number generator. We show that no more than four of the events can be part of a periodic sequence. We have done a number of data quality tests to ascertain that these dips are of astrophysical origin, and while we cannot be absolutely certain that this is so, they have all the hallmarks of astrophysical variability on one of two possible host stars (a likely bound pair) in the photometric aperture. We explore a number of ideas for the origin of these dips, including actual planet transits due to multiple or dust emitting planets, anomalously large TTVs, S- and P-type transits in binary systems, a collection of dust-emitting asteroids, ‘dipper-star’ activity, and short-lived starspots. All transit scenarios that we have been able to conjure up appear to fail, while the intrinsic stellar variability hypothesis would be novel and untested.
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