With the emergence of multidrug-resistant strains of Mycobacterium tuberculosis there is a pressing need for new oral drugs with novel mechanisms of action. Herein, we describe the identification of ...a novel morpholino–thiophenes (MOT) series following phenotypic screening of the Eli Lilly corporate library against M. tuberculosis strain H37Rv. The design, synthesis, and structure–activity relationships of a range of analogues around the confirmed actives are described. Optimized leads with potent whole cell activity against H37Rv, no cytotoxicity flags, and in vivo efficacy in an acute murine model of infection are described. Mode-of-action studies suggest that the novel scaffold targets QcrB, a subunit of the menaquinol cytochrome c oxidoreductase, part of the bc1-aa3-type cytochrome c oxidase complex that is responsible for driving oxygen-dependent respiration.
Stellar feedback is often cited as the biggest uncertainty in galaxy formation models today. This uncertainty stems from a dearth of observational constraints as well as the great dynamic range ...between the small scales (≲1 pc) where the feedback originates and the large scales of galaxies (≳1 kpc) that are shaped by this feedback. To bridge this divide, in this paper we aim to assess observationally the role of stellar feedback at the intermediate scales of H II regions (∼10-100 pc). In particular, we employ multiwavelength data to examine several stellar feedback mechanisms in a sample of 32 H II regions (with ages ∼3-10 Myr) in the Large and Small Magellanic Clouds, respectively. Using optical, infrared, radio, and X-ray images, we measure the pressures exerted on the shells from the direct stellar radiation, the dust-processed radiation, the warm ionized gas, and the hot X-ray-emitting gas. We find that the warm ionized gas dominates over the other terms in all of the sources, although two have comparable dust-processed radiation pressures to their warm gas pressures. The hot gas pressures are comparatively weak, while the direct radiation pressures are one to two orders of magnitude below the other terms. We discuss the implications of these results, particularly highlighting evidence for hot gas leakage from the H II shells and regarding the momentum deposition from the dust-processed radiation to the warm gas. Furthermore, we emphasize that similar observational work should be done on very young H II regions to test whether direct radiation pressure and hot gas can drive the dynamics at early times.
Abstract
We present the ALMA detection of molecular outflowing gas in the central regions of NGC 4945, one of the nearest starbursts and also one of the nearest hosts of an active galactic nucleus ...(AGN). We detect four outflow plumes in CO
J
= 3 − 2 at ∼0.″3 resolution that appear to correspond to molecular gas located near the edges of the known ionized outflow cone and its (unobserved) counterpart behind the disk. The fastest and brightest of these plumes has emission reaching observed line-of-sight projected velocities of over 450 km s
−1
beyond systemic, equivalent to an estimated physical outflow velocity
v
≳ 600 km s
−1
for the fastest emission. Most of these plumes have corresponding emission in HCN or HCO
+
J
= 4 − 3. We discuss a kinematic model for the outflow emission where the molecular gas has the geometry of the ionized gas cone and shares the rotation velocity of the galaxy when ejected. We use this model to explain the velocities we observe, constrain the physical speed of the ejected material, and account for the fraction of outflowing gas that is not detected due to confusion with the galaxy disk. We estimate a total molecular mass outflow rate
M
̇
mol
∼
20
M
⊙
yr
−1
flowing through a surface within 100 pc of the disk midplane, likely driven by a combination of the central starburst and AGN.
Oklahoma's cumulative COVID-19 incidence is higher in rural than urban counties and higher than the overall US incidence. Furthermore, fewer Oklahomans have received at least one COVID-19 vaccine ...compared to the US average. Our goal is to conduct a randomized controlled trial using the multiphase optimization strategy (MOST) to test multiple educational interventions to improve uptake of COVID-19 vaccination among underserved populations in Oklahoma.
Our study uses the preparation and optimization phases of the MOST framework. We conduct focus groups among community partners and community members previously involved in hosting COVID-19 testing events to inform intervention design (preparation). In a randomized clinical trial, we test three interventions to improve vaccination uptake: (1) process improvement (text messages); (2) barrier elicitation and reduction (electronic survey with tailored questions/prompts); and (2) teachable moment messaging (motivational interviewing) in a three-factor fully crossed factorial design (optimization).
Because of Oklahoma's higher COVID-19 impact and lower vaccine uptake, identifying community-driven interventions is critical to address vaccine hesitancy. The MOST framework provides an innovative and timely opportunity to efficiently evaluate multiple educational interventions in a single study.
ClinicalTrials.gov: NCT05236270, First Posted: February 11, 2022, Last Update Posted: August 31, 2022.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
High systolic blood pressure (BP) is the single leading modifiable risk factor for death worldwide. Accurate BP measurement is the cornerstone for screening, diagnosis, and management of ...hypertension. Inaccurate BP measurement is a leading patient safety challenge. A recent World Health Organization report has outlined the technical specifications for automated noninvasive clinical BP measurement with cuff. The report is applicable to ambulatory, home, and office devices used for clinical purposes. The report recommends that for routine clinical purposes, (1) automated devices be used, (2) an upper arm cuff be used, and (3) that only automated devices that have passed accepted international accuracy standards (eg, the International Organization for Standardization 81060-2; 2018 protocol) be used. Accurate measurement also depends on standardized patient preparation and measurement technique and a quiet, comfortable setting. The World Health Organization report provides steps for governments, manufacturers, health care providers, and their organizations that need to be taken to implement the report recommendations and to ensure accurate BP measurement for clinical purposes. Although, health and scientific organizations have had similar recommendations for many years, the World Health Organization as the leading governmental health organization globally provides a potentially synergistic nongovernment government opportunity to enhance the accuracy of clinical BP assessment.
Ewing sarcoma is the second most common pediatric bone and soft tissue tumor presenting with an aggressive behavior and prevalence to metastasize. The diagnostic translocation t(22;11)(q24;12) leads ...to expression of the chimeric oncoprotein EWS-FLI1 which is uniquely expressed in all tumor cells and maintains their survival. Constant EWS-FLI1 protein turnover is regulated by the ubiquitin proteasome system. Here, we now identified ubiquitin specific protease 19 (USP19) as a regulator of EWS-FLI1 stability using an siRNA based screening approach. Depletion of USP19 resulted in diminished EWS-FLI1 protein levels and, vice versa, upregulation of active USP19 stabilized the fusion protein. Importantly, stabilization appears to be specific for the fusion protein as it could not be observed neither for EWSR1 nor for FLI1 wild type proteins even though USP19 binds to the N-terminal EWS region to regulate deubiquitination of both EWS-FLI1 and EWSR1. Further, stable shUSP19 depletion resulted in decreased cell growth and diminished colony forming capacity in vitro, and significantly delayed tumor growth in vivo. Our findings not only provide novel insights into the importance of the N-terminal EWSR1 domain for regulation of fusion protein stability, but also indicate that inhibition of deubiquitinating enzyme(s) might constitute a novel therapeutic strategy in treatment of Ewing sarcoma.
Emerging infectious diseases have caused many species declines, changes in communities and even extinctions. There are also many species that persist following devastating declines due to disease. ...The broad mechanisms that enable host persistence following declines include evolution of resistance or tolerance, changes in immunity and behaviour, compensatory recruitment, pathogen attenuation, environmental refugia, density‐dependent transmission and changes in community composition. Here we examine the case of chytridiomycosis, the most important wildlife disease of the past century. We review the full breadth of mechanisms allowing host persistence, and synthesise research on host, pathogen, environmental and community factors driving persistence following chytridiomycosis‐related declines and overview the current evidence and the information required to support each mechanism. We found that for most species the mechanisms facilitating persistence have not been identified. We illustrate how the mechanisms that drive long‐term host population dynamics determine the most effective conservation management strategies. Therefore, understanding mechanisms of host persistence is important because many species continue to be threatened by disease, some of which will require intervention. The conceptual framework we describe is broadly applicable to other novel disease systems.
We synthesize research on host, pathogen, environmental and community factors and overview the information required to support each mechanism, and current evidence. Using this information, we illustrate how the mechanisms that drive long‐term host population dynamics determine the most effective conservation management strategies.
A Catalog of M-dwarf Flares with ASAS-SN Rodríguez Martínez, Romy; Lopez, Laura A.; Shappee, Benjamin J. ...
The Astrophysical journal,
04/2020, Letnik:
892, Številka:
2
Journal Article
Recenzirano
Odprti dostop
We analyzed the light curves of 1376 early-to-late, nearby M dwarfs to search for white-light flares using photometry from the All-Sky Automated Survey for Supernovae. We identified 480 M dwarfs with ...at least one potential flare employing a simple statistical algorithm that searches for sudden increases in V-band flux. After more detailed evaluation, we identified 62 individual flares on 62 stars. The event amplitudes range from mag. Using classical flare models, we place lower limits on the flare energies and obtain V-band energies spanning erg. The fraction of flaring stars increases with spectral type, and most flaring stars show moderate to strong H emission. Additionally, we find that 14 of the 62 flaring stars are rotational variables, and they have shorter rotation periods and stronger H emission than nonflaring rotational variable M dwarfs.
We present evidence of diffuse, non-thermal X-ray emission from the superbubble 30 Doradus C (30 Dor C) using hard X-ray images and spectra from NuSTAR observations. For this analysis, we utilize ...data from a 200 ks targeted observation of 30 Dor C as well as 2.8 Ms of serendipitous off-axis observations from the monitoring of nearby SN 1987A. The complete shell of 30 Dor C is detected up to 20 keV, and the young supernova remnant MCSNR J0536−6913 in the southeast of 30 Dor C is not detected above 8 keV. Additionally, six point sources identified in previous Chandra and XMM-Newton investigations have hard X-ray emission coincident with their locations. Joint spectral fits to the NuSTAR and XMM-Newton spectra across the 30 Dor C shell confirm the non-thermal nature of the diffuse emission. Given the best-fit rolloff frequencies of the X-ray spectra, we find maximum electron energies of 70-110 TeV (assuming a B-field strength of 4 G), suggesting 30 Dor C is accelerating particles. Particles are either accelerated via diffusive shock acceleration at locations where the shocks have not stalled behind the H shell, or cosmic-rays are accelerated through repeated acceleration of low-energy particles via turbulence and magnetohydrodynamic waves in the bubble's interior.
A wound is the loss of the normal integrity, structure, and functions of the skin due to a physical, chemical, or mechanical agent. Wound repair consists of an orderly and complex process divided ...into four phases: coagulation, inflammation, proliferation, and remodeling. The potential of natural products in the treatment of wounds has been reported in numerous studies, emphasizing those with antioxidant, anti-inflammatory, and antimicrobial properties, e.g., alkaloids, saponins, terpenes, essential oils, and polyphenols from different plant sources, since these compounds can interact in the various stages of the wound healing process. This review addresses the most current in vitro and in vivo studies on the wound healing potential of natural products, as well as the main mechanisms involved in this activity. We observed sufficient evidence of the activity of these compounds in the treatment of wounds; however, we also found that there is no consensus on the effective concentrations in which the natural products exert this activity. For this reason, it is important to work on establishing optimal treatment doses, as well as an appropriate route of administration. In addition, more research should be carried out to discover the possible side effects and the behavior of natural products in clinical trials.
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