Staphylococcus aureus infection of bone is challenging to treat because it colonizes the osteocyte lacuno-canalicular network (OLCN) of cortical bone. To elucidate factors involved in OLCN invasion ...and identify novel drug targets, we completed a hypothesis-driven screen of 24 S. aureus transposon insertion mutant strains for their ability to propagate through 0.5 μm-sized pores in the Microfluidic Silicon Membrane Canalicular Arrays (μSiM-CA), developed to model S. aureus invasion of the OLCN. This screen identified the uncanonical S. aureus transpeptidase, penicillin binding protein 4 (PBP4), as a necessary gene for S. aureus deformation and propagation through nanopores. In vivo studies revealed that Δpbp4 infected tibiae treated with vancomycin showed a significant 12-fold reduction in bacterial load compared to WT infected tibiae treated with vancomycin (p<0.05). Additionally, Δpbp4 infected tibiae displayed a remarkable decrease in pathogenic bone-loss at the implant site with and without vancomycin therapy. Most importantly, Δpbp4 S. aureus failed to invade and colonize the OLCN despite high bacterial loads on the implant and in adjacent tissues. Together, these results demonstrate that PBP4 is required for S. aureus colonization of the OLCN and suggest that inhibitors may be synergistic with standard of care antibiotics ineffective against bacteria within the OLCN.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Osteomyelitis remains one of the greatest risks in orthopaedic surgery. Although many organisms are linked to skeletal infections, Staphylococcus aureus remains the most prevalent and devastating ...causative pathogen. Important discoveries have uncovered novel mechanisms of S. aureus pathogenesis and persistence within bone tissue, including implant-associated biofilms, abscesses and invasion of the osteocyte lacuno-canalicular network. However, little clinical progress has been made in the prevention and eradication of skeletal infection as treatment algorithms and outcomes have only incrementally changed over the past half century. In this Review, we discuss the mechanisms of persistence and immune evasion in S. aureus infection of the skeletal system as well as features of other osteomyelitis-causing pathogens in implant-associated and native bone infections. We also describe how the host fails to eradicate bacterial bone infections, and how this new information may lead to the development of novel interventions. Finally, we discuss the clinical management of skeletal infection, including osteomyelitis classification and strategies to treat skeletal infections with emerging technologies that could translate to the clinic in the future.
ABSTRACT
We present Galaxy Zoo DECaLS: detailed visual morphological classifications for Dark Energy Camera Legacy Survey images of galaxies within the SDSS DR8 footprint. Deeper DECaLS images (r = ...23.6 versus r = 22.2 from SDSS) reveal spiral arms, weak bars, and tidal features not previously visible in SDSS imaging. To best exploit the greater depth of DECaLS images, volunteers select from a new set of answers designed to improve our sensitivity to mergers and bars. Galaxy Zoo volunteers provide 7.5 million individual classifications over 314 000 galaxies. 140 000 galaxies receive at least 30 classifications, sufficient to accurately measure detailed morphology like bars, and the remainder receive approximately 5. All classifications are used to train an ensemble of Bayesian convolutional neural networks (a state-of-the-art deep learning method) to predict posteriors for the detailed morphology of all 314 000 galaxies. We use active learning to focus our volunteer effort on the galaxies which, if labelled, would be most informative for training our ensemble. When measured against confident volunteer classifications, the trained networks are approximately 99 per cent accurate on every question. Morphology is a fundamental feature of every galaxy; our human and machine classifications are an accurate and detailed resource for understanding how galaxies evolve.
Osteomyelitis is a devastating disease caused by microbial infection of bone. While the frequency of infection following elective orthopedic surgery is low, rates of reinfection are disturbingly ...high.
is responsible for the majority of chronic osteomyelitis cases and is often considered to be incurable due to bacterial persistence deep within bone. Unfortunately, there is no consensus on clinical classifications of osteomyelitis and the ensuing treatment algorithm. Given the high patient morbidity, mortality, and economic burden caused by osteomyelitis, it is important to elucidate mechanisms of bone infection to inform novel strategies for prevention and curative treatment. Recent discoveries in this field have identified three distinct reservoirs of bacterial biofilm including:
abscess communities in the local soft tissue and bone marrow, glycocalyx formation on implant hardware and necrotic tissue, and colonization of the osteocyte-lacuno canalicular network (OLCN) of cortical bone. In contrast,
intracellular persistence in bone cells has not been substantiated in vivo, which challenges this mode of chronic osteomyelitis. There have also been major advances in our understanding of the immune proteome against
, from clinical studies of serum antibodies and media enriched for newly synthesized antibodies (MENSA), which may provide new opportunities for osteomyelitis diagnosis, prognosis, and vaccine development. Finally, novel therapies such as antimicrobial implant coatings and antibiotic impregnated 3D-printed scaffolds represent promising strategies for preventing and managing this devastating disease. Here, we review these recent advances and highlight translational opportunities towards a cure.
Spirals in Galaxies Sellwood, J.A; Masters, Karen L
Annual review of astronomy and astrophysics,
08/2022, Letnik:
60, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Spirals in galaxies have long been thought to be caused by gravitational instability in the stellar component of the disk, but discerning the precise mechanism had proved elusive. Tidal interactions, ...and perhaps bars, may provoke some spiral responses, but spirals in many galaxies must be self-excited. We survey the relevant observational data and aspects of disk dynamical theory. The origin of the recurring spiral patterns in simulations of isolated disk galaxies has recently become clear, and it is likely that the mechanism is the same in real galaxies, although evidence to confirm this supposition is hard to obtain. As transient spiral activity increases random motion, the patterns must fade over time unless the disk also contains a dissipative gas component. Continuing spiral activity alters the structure of the disks in other ways: reducing metallicity gradients and flattening rotation curves are two of the most significant. The overwhelming majority of spirals in galaxies have two- or three-fold rotational symmetry, indicating that the cool, thin disk component is massive. Spirals in simulations of halo-dominated disks instead manifest many arms and, consequently, do not capture the expected full spiral-driven evolution. We conclude by identifying areas where further work is needed.
We use SDSS+GALEX+Galaxy Zoo data to study the quenching of star formation in low-redshift galaxies. We show that the green valley between the blue cloud of star-forming galaxies and the red sequence ...of quiescent galaxies in the colour-mass diagram is not a single transitional state through which most blue galaxies evolve into red galaxies. Rather, an analysis that takes morphology into account makes clear that only a small population of blue early-type galaxies move rapidly across the green valley after the morphologies are transformed from disc to spheroid and star formation is quenched rapidly. In contrast, the majority of blue star-forming galaxies have significant discs, and they retain their late-type morphologies as their star formation rates decline very slowly. We summarize a range of observations that lead to these conclusions, including UV-optical colours and halo masses, which both show a striking dependence on morphological type. We interpret these results in terms of the evolution of cosmic gas supply and gas reservoirs. We conclude that late-type galaxies are consistent with a scenario where the cosmic supply of gas is shut off, perhaps at a critical halo mass, followed by a slow exhaustion of the remaining gas over several Gyr, driven by secular and/or environmental processes. In contrast, early-type galaxies require a scenario where the gas supply and gas reservoir are destroyed virtually instantaneously, with rapid quenching accompanied by a morphological transformation from disc to spheroid. This gas reservoir destruction could be the consequence of a major merger, which in most cases transforms galaxies from disc to elliptical morphology, and mergers could play a role in inducing black hole accretion and possibly active galactic nuclei feedback.
A precise extragalactic test of General Relativity Collett, Thomas E; Oldham, Lindsay J; Smith, Russell J ...
Science (American Association for the Advancement of Science),
06/2018, Letnik:
360, Številka:
6395
Journal Article
Recenzirano
Odprti dostop
Einstein's theory of gravity, General Relativity, has been precisely tested on Solar System scales, but the long-range nature of gravity is still poorly constrained. The nearby strong gravitational ...lens ESO 325-G004 provides a laboratory to probe the weak-field regime of gravity and measure the spatial curvature generated per unit mass, γ. By reconstructing the observed light profile of the lensed arcs and the observed spatially resolved stellar kinematics with a single self-consistent model, we conclude that γ = 0.97 ± 0.09 at 68% confidence. Our result is consistent with the prediction of 1 from General Relativity and provides a strong extragalactic constraint on the weak-field metric of gravity.
Abstract
We present new evidence for AGN feedback in a subset of 69 quenched low-mass galaxies (M⋆ ≲ 5 × 109 M⊙, Mr > −19) selected from the first 2 yr of the Sloan Digital Sky Survey-IV Mapping ...Nearby Galaxies at APO (SDSS-IV MaNGA) survey. The majority (85 per cent) of these quenched galaxies appear to reside in a group environment. We find six galaxies in our sample that appear to have an active AGN that is preventing on-going star formation; this is the first time such a feedback mechanism has been observed in this mass range. Interestingly, five of these six galaxies have an ionized gas component that is kinematically offset from their stellar component, suggesting the gas is either recently accreted or outflowing. We hypothesize these six galaxies are low-mass equivalents to the ‘red geysers’ observed in more massive galaxies. Of the other 63 galaxies in the sample, we find 8 do appear for have some low level, residual star formation, or emission from hot, evolved stars. The remaining galaxies in our sample have no detectable ionized gas emission throughout their structures, consistent with them being quenched. This work shows the potential for understanding the detailed physical properties of dwarf galaxies through spatially resolved spectroscopy.
We present the data release for Galaxy Zoo 2 (GZ2), a citizen science project with more than 16 million morphological classifications of 304 122 galaxies drawn from the Sloan Digital Sky Survey ...(SDSS). Morphology is a powerful probe for quantifying a galaxy's dynamical history; however, automatic classifications of morphology (either by computer analysis of images or by using other physical parameters as proxies) still have drawbacks when compared to visual inspection. The large number of images available in current surveys makes visual inspection of each galaxy impractical for individual astronomers. GZ2 uses classifications from volunteer citizen scientists to measure morphologies for all galaxies in the DR7 Legacy survey with m
r
> 17, in addition to deeper images from SDSS Stripe 82. While the original GZ2 project identified galaxies as early-types, late-types or mergers, GZ2 measures finer morphological features. These include bars, bulges and the shapes of edge-on disks, as well as quantifying the relative strengths of galactic bulges and spiral arms. This paper presents the full public data release for the project, including measures of accuracy and bias. The majority ( 90 per cent) of GZ2 classifications agree with those made by professional astronomers, especially for morphological T-types, strong bars and arm curvature. Both the raw and reduced data products can be obtained in electronic format at http://data.galaxyzoo.org.
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