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"Atkinson, C"
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The RelA/SpoT Homolog (RSH) Superfamily: Distribution and Functional Evolution of ppGpp Synthetases and Hydrolases across the Tree of Life
RelA/SpoT Homologue (RSH) proteins, named for their sequence similarity to the RelA and SpoT enzymes of Escherichia coli, comprise a superfamily of enzymes that synthesize and/or hydrolyze the alarmone ppGpp, activator of the \"stringent\" response and regulator of cellular metabolism. The classical \"long\" RSHs Rel, RelA and SpoT with the ppGpp hydrolase, synthetase, TGS and ACT domain architecture have been found across diverse bacteria and plant chloroplasts, while dedicated single domain ppGpp-synthesizing and -hydrolyzing RSHs have also been discovered in disparate bacteria and animals respectively. However, there is considerable confusion in terms of nomenclature and no comprehensive phylogenetic and sequence analyses have previously been carried out to classify RSHs on a genomic scale. We have performed high-throughput sensitive sequence searching of over 1000 genomes from across the tree of life, in combination with phylogenetic analyses to consolidate previous ad hoc identification of diverse RSHs in different organisms and provide a much-needed unifying terminology for the field. We classify RSHs into 30 subgroups comprising three groups: long RSHs, small alarmone synthetases (SASs), and small alarmone hydrolases (SAHs). Members of nineteen previously unidentified RSH subgroups can now be studied experimentally, including previously unknown RSHs in archaea, expanding the \"stringent response\" to this domain of life. We have analyzed possible combinations of RSH proteins and their domains in bacterial genomes and compared RSH content with available RSH knock-out data for various organisms to determine the rules of combining RSHs. Through comparative sequence analysis of long and small RSHs, we find exposed sites limited in conservation to the long RSHs that we propose are involved in transmitting regulatory signals. Such signals may be transmitted via NTD to CTD intra-molecular interactions, or inter-molecular interactions either among individual RSH molecules or among long RSHs and other binding partners such as the ribosome.
Journal Article
Direct activation of a bacterial innate immune system by a viral capsid protein
Bacteria have evolved diverse immunity mechanisms to protect themselves against the constant onslaught of bacteriophages
1
–
3
. Similar to how eukaryotic innate immune systems sense foreign invaders through pathogen-associated molecular patterns
4
(PAMPs), many bacterial immune systems that respond to bacteriophage infection require phage-specific triggers to be activated. However, the identities of such triggers and the sensing mechanisms remain largely unknown. Here we identify and investigate the anti-phage function of CapRel
SJ46
, a fused toxin–antitoxin system that protects
Escherichia coli
against diverse phages. Using genetic, biochemical and structural analyses, we demonstrate that the C-terminal domain of CapRel
SJ46
regulates the toxic N-terminal region, serving as both antitoxin and phage infection sensor. Following infection by certain phages, newly synthesized major capsid protein binds directly to the C-terminal domain of CapRel
SJ46
to relieve autoinhibition, enabling the toxin domain to pyrophosphorylate tRNAs, which blocks translation to restrict viral infection. Collectively, our results reveal the molecular mechanism by which a bacterial immune system directly senses a conserved, essential component of phages, suggesting a PAMP-like sensing model for toxin–antitoxin-mediated innate immunity in bacteria. We provide evidence that CapRels and their phage-encoded triggers are engaged in a ‘Red Queen conflict’
5
, revealing a new front in the intense coevolutionary battle between phages and bacteria. Given that capsid proteins of some eukaryotic viruses are known to stimulate innate immune signalling in mammalian hosts
6
–
10
, our results reveal a deeply conserved facet of immunity.
Genetic, biochemical and structural studies provide insights into the function of
Escherichia coli
CapRel
SJ46
as a fused anti-phage toxin–antitoxin system that binds SECΦ27 Gp57 capsid protein.
Journal Article
Hotspots of human impact on threatened terrestrial vertebrates
Conserving threatened species requires identifying where across their range they are being impacted by threats, yet this remains unresolved across most of Earth. Here, we present a global analysis of cumulative human impacts on threatened species by using a spatial framework that jointly considers the co-occurrence of eight threatening processes and the distribution of 5,457 terrestrial vertebrates. We show that impacts to species are widespread, occurring across 84% of Earth's surface, and identify hotspots of impacted species richness and coolspots of unimpacted species richness. Almost one-quarter of assessed species are impacted across >90% of their distribution, and approximately 7% are impacted across their entire range. These results foreshadow localised extirpations and potential extinctions without conservation action. The spatial framework developed here offers a tool for defining strategies to directly mitigate the threats driving species' declines, providing essential information for future national and global conservation agendas.
Journal Article
Heavy neutrino searches through double-bang events at Super-Kamiokande, DUNE, and Hyper-Kamiokande
A
bstract
A variety of new physics scenarios allows for neutrinos to up-scatter into a heavy neutral lepton state. For a range of couplings and neutrino energies, the heavy neutrino may travel some distance before decaying to visible final states. When both the up-scattering and decay occur within the detector volume, these “double bang” events produce distinctive phenomenology with very low background. In this work, we first consider the current sensitivity at Super-Kamiokande via the atmospheric neutrino flux, and find current data may already provide new constraints. We then examine projected future sensitivity at DUNE and Hyper-Kamiokande, including both atmospheric and beam flux contributions to double-bang signals.
Journal Article
Structural basis for PoxtA-mediated resistance to phenicol and oxazolidinone antibiotics
PoxtA and OptrA are ATP binding cassette (ABC) proteins of the F subtype (ABCF). They confer resistance to oxazolidinone and phenicol antibiotics, such as linezolid and chloramphenicol, which stall translating ribosomes when certain amino acids are present at a defined position in the nascent polypeptide chain. These proteins are often encoded on mobile genetic elements, facilitating their rapid spread amongst Gram-positive bacteria, and are thought to confer resistance by binding to the ribosome and dislodging the bound antibiotic. However, the mechanistic basis of this resistance remains unclear. Here we refine the PoxtA spectrum of action, demonstrate alleviation of linezolid-induced context-dependent translational stalling, and present cryo-electron microscopy structures of PoxtA in complex with the
Enterococcus faecalis
70S ribosome. PoxtA perturbs the CCA-end of the P-site tRNA, causing it to shift by ∼4 Å out of the ribosome, corresponding to a register shift of approximately one amino acid for an attached nascent polypeptide chain. We postulate that the perturbation of the P-site tRNA by PoxtA thereby alters the conformation of the attached nascent chain to disrupt the drug binding site.
PoxtA confers resistance to ribosome-targeting oxazolidinone (linezolid) and chloramphenicol antibiotics. Here, Crowe-McAuliffe et al. provide structural insights into how binding of PoxtA to the ribosome indirectly promotes drug dissociation.
Journal Article
Direct numerical simulation of a self-similar adverse pressure gradient turbulent boundary layer at the verge of separation
The statistical properties are presented for the direct numerical simulation of a self-similar adverse pressure gradient (APG) turbulent boundary layer (TBL) at the verge of separation. The APG TBL has a momentum thickness-based Reynolds number range from
$Re_{\\unicode[STIX]{x1D6FF}_{2}}=570$
to 13 800, with a self-similar region from
$Re_{\\unicode[STIX]{x1D6FF}_{2}}=10\\,000$
to 12 300. Within this domain the average non-dimensional pressure gradient parameter
$\\unicode[STIX]{x1D6FD}=39$
, where for a unit density
$\\unicode[STIX]{x1D6FD}=\\unicode[STIX]{x1D6FF}_{1}P_{\\!e}^{\\prime }/\\unicode[STIX]{x1D70F}_{w}$
, with
$\\unicode[STIX]{x1D6FF}_{1}$
the displacement thickness,
$\\unicode[STIX]{x1D70F}_{w}$
the mean shear stress at the wall and
$P_{\\!e}^{\\prime }$
the far-field pressure gradient. This flow is compared with previous zero pressure gradient and mild APG TBL (
$\\unicode[STIX]{x1D6FD}=1$
) results of similar Reynolds number. All flows are generated via the direct numerical simulation of a TBL on a flat surface with far-field boundary conditions tailored to apply the desired pressure gradient. The conditions for self-similarity, and the appropriate length and velocity scales, are derived. The mean and Reynolds stress profiles are shown to collapse when non-dimensionalised on the basis of these length and velocity scales. As the pressure gradient increases, the extent of the wake region in the mean streamwise velocity profiles increases, whilst the extent of the log-layer and viscous sublayer decreases. The Reynolds stress, production and dissipation profiles of the APG TBL cases exhibit a second outer peak, which becomes more pronounced and more spatially localised with increasing pressure gradient. This outer peak is located at the point of inflection of the mean velocity profiles, and is suggestive of the presence of a shear flow instability. The maximum streamwise velocity variance is located at a wall normal position of
$\\unicode[STIX]{x1D6FF}_{1}$
of spanwise wavelength of
$2\\unicode[STIX]{x1D6FF}_{1}$
. In summary as the pressure gradient increases the flow has properties less like a zero pressure gradient TBL and more akin to a free shear layer.
Journal Article
Cryo-EM analysis of the T3S injectisome reveals the structure of the needle and open secretin
The bacterial type III secretion system, or injectisome, is a syringe shaped nanomachine essential for the virulence of many disease causing Gram-negative bacteria. At the core of the injectisome structure is the needle complex, a continuous channel formed by the highly oligomerized inner and outer membrane hollow rings and a polymerized helical needle filament which spans through and projects into the infected host cell. Here we present the near-atomic resolution structure of a needle complex from the prototypical
Salmonella
Typhimurium SPI-1 type III secretion system, with local masking protocols allowing for model building and refinement of the major membrane spanning components of the needle complex base in addition to an isolated needle filament. This work provides significant insight into injectisome structure and assembly and importantly captures the molecular basis for substrate induced gating in the giant outer membrane secretin portal family.
The bacterial type III secretion system of Gram-negative bacteria uses its core, the needle complex, to penetrate through the infected host cell membrane. Here authors show a near-atomic resolution structure of a needle complex which sheds light on the assembly and function of this nanomachine.
Journal Article
Conservation prioritization can resolve the flagship species conundrum
Conservation strategies based on charismatic flagship species, such as tigers, lions, and elephants, successfully attract funding from individuals and corporate donors. However, critics of this species-focused approach argue it wastes resources and often does not benefit broader biodiversity. If true, then the best way of raising conservation funds excludes the best way of spending it. Here we show that this conundrum can be resolved, and that the flagship species approach does not impede cost-effective conservation. Through a tailored prioritization approach, we identify places containing flagship species while also maximizing global biodiversity representation (based on 19,616 terrestrial and freshwater species). We then compare these results to scenarios that only maximized biodiversity representation, and demonstrate that our flagship-based approach achieves 79−89% of our objective. This provides strong evidence that prudently selected flagships can both raise funds for conservation and help target where these resources are best spent to conserve biodiversity.
Conservation actions focused on flagship species are effective at raising funds and awareness. Here, McGowan et al. show that prioritizing areas for conservation based on the presence of flagship species results in the selection of areas with ~ 79-89% of the total species that would be selected by maximizing biodiversity representation only.
Journal Article
A widespread toxin−antitoxin system exploiting growth control via alarmone signaling
Under stressful conditions, bacterial RelA-SpoT Homolog (RSH) enzymes synthesize the alarmone (p)ppGpp, a nucleotide second messenger. (p)ppGpp rewires bacterial transcription and metabolism to cope with stress, and, at high concentrations, inhibits the process of protein synthesis and bacterial growth to save and redirect resources until conditions improve. Single-domain small alarmone synthetases (SASs) are RSH family members that contain the (p)ppGpp synthesis (SYNTH) domain, but lack the hydrolysis (HD) domain and regulatory C-terminal domains of the long RSHs such as Rel, RelA, and SpoT. We asked whether analysis of the genomic context of SASs can indicate possible functional roles. Indeed, multiple SAS subfamilies are encoded in widespread conserved bicistronic operon architectures that are reminiscent of those typically seen in toxin−antitoxin (TA) operons. We have validated five of these SASs as being toxic (toxSASs), with neutralization by the protein products of six neighboring antitoxin genes. The toxicity of Cellulomonas marina toxSAS FaRel is mediated by the accumulation of alarmones ppGpp and ppApp, and an associated depletion of cellular guanosine triphosphate and adenosine triphosphate pools, and is counteracted by its HD domain-containing antitoxin. Thus, the ToxSAS–antiToxSAS system with its multiple different antitoxins exemplifies how ancient nucleotide-based signaling mechanisms can be repurposed as TA modules during evolution, potentially multiple times independently.
Journal Article