Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2, the causative agent of COVID-19. Here, we show ...that the ribonucleoside analog β-d-N
-hydroxycytidine (NHC; EIDD-1931) has broad-spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c bat-CoVs, as well as increased potency against a CoV bearing resistance mutations to the nucleoside analog inhibitor remdesivir. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC prodrug (β-d-N
-hydroxycytidine-5'-isopropyl ester), improved pulmonary function and reduced virus titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were associated with increased transition mutation frequency in viral, but not host cell RNA, supporting a mechanism of lethal mutagenesis in CoV. The potency of NHC/EIDD-2801 against multiple CoVs and oral bioavailability highlights its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic CoVs.
Abstract
Mutagenic ribonucleosides can act as broad-based antiviral agents. They are metabolized to the active ribonucleoside triphosphate form and concentrate in genomes of RNA viruses during viral ...replication. β-d-N4-hydroxycytidine (NHC, initial metabolite of molnupiravir) is >100-fold more active than ribavirin or favipiravir against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with antiviral activity correlated to the level of mutagenesis in virion RNA. However, NHC also displays host mutational activity in an animal cell culture assay, consistent with RNA and DNA precursors sharing a common intermediate of a ribonucleoside diphosphate. These results indicate highly active mutagenic ribonucleosides may hold risk for the host.
•Ocean color algorithms for obtaining marine inherent optical properties are reviewed.•Known uncertainties associated with each approach and knowledge gaps are discussed.•Common performance metrics ...used to evaluate the satellite retrievals are provided.•Recommendations for future investment for upcoming satellite missions are presented.
Ocean color measured from satellites provides daily global, synoptic views of spectral water-leaving reflectances that can be used to generate estimates of marine inherent optical properties (IOPs). These reflectances, namely the ratio of spectral upwelled radiances to spectral downwelled irradiances, describe the light exiting a water mass that defines its color. IOPs are the spectral absorption and scattering characteristics of ocean water and its dissolved and particulate constituents. Because of their dependence on the concentration and composition of marine constituents, IOPs can be used to describe the contents of the upper ocean mixed layer. This information is critical to further our scientific understanding of biogeochemical oceanic processes, such as organic carbon production and export, phytoplankton dynamics, and responses to climatic disturbances. Given their importance, the international ocean color community has invested significant effort in improving the quality of satellite-derived IOP products, both regionally and globally. Recognizing the current influx of data products into the community and the need to improve current algorithms in anticipation of new satellite instruments (e.g., the global, hyperspectral spectroradiometer of the NASA Plankton, Aerosol, Cloud, ocean Ecosystem (PACE) mission), we present a synopsis of the current state of the art in the retrieval of these core optical properties. Contemporary approaches for obtaining IOPs from satellite ocean color are reviewed and, for clarity, separated based their inversion methodology or the type of IOPs sought. Summaries of known uncertainties associated with each approach are provided, as well as common performance metrics used to evaluate them. We discuss current knowledge gaps and make recommendations for future investment for upcoming missions whose instrument characteristics diverge sufficiently from heritage and existing sensors to warrant reassessing current approaches.
Context: .Scatter around the relationship between central black hole masses in active galactic nuclei (AGNs) obtained by reverberation-mapping methods and host-galaxy bulge velocity dispersion ...indicates that the masses are uncertain typically by a factor of about three. Aims: .In this paper, we try to identify the sources and systematics of this uncertainty. Methods: .We characterize the broad Hbeta emission-line profiles by the ratio of their full-width at half maximum (FWHM) to their line dispersion, i.e., the second moment of the line profile. We use this parameter to separate the reverberation-mapped AGNs into two populations, the first with narrower Hbeta lines that tend to have relatively extended wings, and the second with broader lines that are relatively flat-topped. The first population is characterized by higher Eddington ratios than the second. Within each population, we calibrate the black-hole mass scale by comparison of the reverberation-based mass with that predicted by the bulge velocity dispersion. We also use the distribution of ratios of the reverberation-based mass to the velocity-dispersion mass prediction in a comparison with a "generalized thick disk" model in order to see if inclination can plausibly account for the observed distribution. Results: .We find that the line dispersion is a less biased parameter in general than FWHM for black hole mass estimation, although we show that it is possible to empirically correct for the bias introduced by using FWHM to characterize the emission-line width. We also argue that inclination effects are apparent only in some small subset of the reverberation-based mass measurements; it is primarily the objects with the narrowest emission lines that seem to be most strongly affected. Conclusions: .Our principal conclusion is that the Hbeta profile is sensitive primarily to Eddington ratio, but that inclination effects play a role in some cases.
This article compares two asymmetric Gaussian likelihood models and their corresponding estimators. Recently, there has been confusion in the literature regarding these models and (1) whether they ...are the same, or (2) whether both of them can be used to estimate expectiles. After the comparison, it becomes clear that they are not the same and only one of these models is appropriate for that purpose. The similarity between these models is purely superficial. The historical origin of expectiles has also been disputed: some degree of credit can be shared between two papers.
Flexible bronchoscopy under anesthesia is a mainstay diagnostic tool for evaluating respiratory disorders in pediatric patients. While flexible bronchoscopy is generally regarded as a safe procedure ...with low risk for major complications, it does entail additional risks associated with the use of general anesthesia. The use of diagnostic awake flexible bronchoscopy in children is not well documented in current literature.
The objective of this case series is to investigate the feasibility and potential utility of awake flexible bronchoscopy in pediatric patients and to highlight important precautions and complications.
This was a consecutive case series of patients who underwent an awake flexible bronchoscopy over a two year period at a tertiary children's hospital. Data collection included demographics, indications, number of attempts, scope findings, and complications. Successful attempts of flexible bronchoscopy were defined by visualization of the trachea and mainstem bronchi while failed attempts include if the scope entered the esophagus or if cough, vocal fold adduction, or movement prevented the scope from entering the trachea.
11 patients were involved in this study (mean age 20 months, age range 0d to 5y 1m, 72 % male). Common indications for bronchoscopy were suspicion of foreign body (5, 45.4 %), chronic cough (4, 36.4 %), and stridor (4, 36.4 %). The mean number of attempts until successful was 1.72 (range 1–3). One patient experienced a 30-s episode of gagging with mucinous emesis. There were no other complications. One patient ultimately underwent another flexible bronchoscopy under general anesthesia to confirm the findings and to evaluate the tertiary bronchioles and another patient underwent a surgical resection of an oral mass under general anesthesia after awake flexible bronchoscopy.
Awake flexible bronchoscopy was well tolerated in this study and could serve as a useful diagnostic tool without necessitating anesthetic. However, further study is needed to compare awake flexible bronchoscopy with flexible bronchoscopy under general anesthesia. Additionally, the patients selected for this study were limited to those with minimal risk, such as patients without cardiac disease. Limitations of this technique include suboptimal visualization of subglottic region and limited diagnostic utility for sleep related airway pathologies and cases where therapeutic intervention is needed.
Rich fossil deposits of the late Quaternary help us understand responses of biodiversity to global change and thus predict the future of ecosystems. Studies from the late Quaternary, however, are ...often limited taxonomically, geographically (often one site), and by their use of largely taxon‐based metrics that do not inform about ecosystem‐level consequences of biodiversity change. Here, we compare change in functional composition of small mammal communities at El Mirón Cave (Spain) and Samwell Cave (California, USA) across the last 22 000 years, and examine their relationships with climate and vegetation. We find opposing temporal trends between the two locations. European small mammal communities occupied increasingly greater trait space, driven by increases in arboreal granivory and frugivory as ground‐dwelling herbivory declined toward the late Holocene. North American communities occupied smaller trait space as ground‐level foraging and insectivory increased and arboreal herbivory and mean body mass declined. Our results point to the importance of the interaction between climate change and vegetation shifts for explaining changes in small mammal functional diversity, through their synergistic impacts on individual traits. Specifically, increasing temperature across both continents likely led to increases in nocturnal activity and declines in assemblage mean body mass, while transition to mixed forest (El Mirón) or open woodland (Samwell) resulted in increasing structural complexity of vegetation that potentially supported more diverse community‐level dietary characteristics. These results demonstrate the ability of a trait‐based approach to identify how environmental variables correlate with changes in community functional composition through time and gain insight into the potential consequences of environmental change for ecosystem functioning.
•MSiO4 phases crystallize from the reaction of Hf/ZrO2 with acidic silicate melts.•Reactive crystallization is more favorable in HfO2 relative to ZrO2 based systems.•YO1.5 addition degrades MSiO4 ...formation in favor of non-equilibrium (M,Y)O2.•A secondary phase can constrain grain growth, preventing microcracking in HfO2.•Dissolution and diffusion kinetics of Hf4+ and Zr4+ are quantified and compared.
Hafnia is of interest in thermal and environmental barrier coatings, but little is known about its response to molten silicate attack. This article investigates that response using two model silicate melts, compares it with pure ZrO2 and examines the effect of YO1.5 additions. HfO2 was found to form HfSiO4 with acidic melts but undergoes grain boundary penetration in basic melts, which do not exhibit reactive crystallization. The latter can be exacerbated by microcracking resulting from the thermal expansion anisotropy of monoclinic HfO2. Y additions generally degrade the ability to form hafnon (and zircon), and exacerbate grain boundary penetration, especially in HfO2 where Y is present as a fluorite second phase. The fluorite controls grain growth in monoclinic HfO2 and suppresses microcracking, but dissolves faster, especially in basic melts. The results are presented in the context of the relevant thermodynamics and kinetics. The implications for coating applications are discussed.
Transcranial focused ultrasound (tFUS) is a promising approach for the treatment of neurological disorders. It has proven useful in several clinical applications, with promising outcomes reported in ...the recent literature. Furthermore, it is currently being investigated in a range of neuromodulation (NM) and ablative applications, including epilepsy. In this application, tFUS access through the temporal window is the key to optimizing the treatment safety and efficacy. Traditional approaches have utilized transducers with low operating frequencies for tFUS applications. Modern array transducers and driving systems allow for more intelligent use of the temporal window by exploiting the spatio-spectral transmission bandwidth to a specified target or targets within the brain. To demonstrate the feasibility of this approach, we have investigated the ultrasound reflection and transmission characteristics for different access points within the temporal window of human skull samples ex vivo . Different transmit-receive (Rx) configurations are used for characterization of the spatio-spectral variability in reflection and transmission through the temporal window. In this article, we show results from a dual-piston transducer set up in the frequency range of 2-7 MHz. Broadband pulses as well as synthesized orthogonal frequency division multiplexed (OFDM) waveforms were used. The latter was used to improve the magnitude and phase measurements in 100-kHz subbands within the 2-7 MHz spectral window. A temperature-controlled water bath was used to characterize the change in reflection and transmission characteristics with temperature in the 25°C-43°C range. The measured values of the complex reflection and transmission coefficients exhibited significant variations with space, frequency, and temperature. On the other hand, the measured transmission phase varied more with location and frequency, with smaller sensitivity to temperature. A measurement-based hybrid angular spectrum (HAS) simulation through the human temporal bone was used to demonstrate the dependence of focusing gain on the skull profile and spatial distribution of change of speed of sound (SOS) at different skull temperatures.
PDF
