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result(s) for
"Chrisp, Peter"
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Dinosaur detectives
Describes the achievements of the scientists who have discovered and interpreted the fossils of the dinosaurs.
Book
Whole genome CRISPRi screening identifies druggable vulnerabilities in an isoniazid resistant strain of Mycobacterium tuberculosis
Drug-resistant strains of
Mycobacterium tuberculosis
are a major global health problem. Resistance to the front-line antibiotic isoniazid is often associated with mutations in the
katG
-encoded bifunctional catalase-peroxidase. We hypothesise that perturbed KatG activity would generate collateral vulnerabilities in isoniazid-resistant
katG
mutants, providing potential pathway targets to combat isoniazid resistance. Whole genome CRISPRi screens, transcriptomics, and metabolomics were used to generate a genome-wide map of cellular vulnerabilities in an isoniazid-resistant
katG
mutant strain of
M. tuberculosis
. Here, we show that metabolic and transcriptional remodelling compensates for the loss of KatG but in doing so generates vulnerabilities in respiration, ribosome biogenesis, and nucleotide and amino acid metabolism. Importantly, these vulnerabilities are more sensitive to inhibition in an isoniazid-resistant
katG
mutant and translated to clinical isolates. This work highlights how changes in the physiology of drug-resistant strains generates druggable vulnerabilities that can be exploited to improve clinical outcomes.
In this work, authors utilise genome-wide CRISPRi screening to identify vulnerabilities in isoniazid-resistant strains of
Mycobacterium tuberculosis
.
Journal Article
History year by year
Chronologically traces human history and civilization from prehistoric times to the present day using a detailed timeline, covering key events, people, inventions, and discoveries, and ideas and beliefs.
Book
An argument against the focus on Community Resilience in Public Health
Background
It has been suggested that Public Health professionals focus on community resilience in tackling chronic problems, such as poverty and deprivation; is this approach useful?
Discussion
Resilience is always i) of something ii) to something iii) to an endpoint, as in i) a rubber ball, ii) to a blunt force, iii) to its original shape. “Community resilience” might be: of a neighbourhood, to a flu pandemic, with the endpoint, to return to normality. In these two examples, the endpoint is as-you-were. This is unsuitable for some examples of resilience. A child that is resilient to an abusive upbringing has an endpoint of living a happy life despite that upbringing: this is an as-you-should-be endpoint. Similarly, a chronically deprived community cannot have the endpoint of returning to chronic deprivation: so what is its endpoint? Roughly, it is an as-you-should-be endpoint: to provide an environment for inhabitants to live well. Thus resilient communities will be those that do this in the face of challenges. How can they be identified?
One method uses statistical outliers, neighbourhoods that do better than would be expected on a range of outcomes given a range of stressors. This method tells us
that
a neighbourhood is resilient but not
why
it is. In response, a number of researchers have attributed characteristics to resilient communities; however, these generally fail to distinguish characteristics of a good community from those of a resilient one. Making this distinction is difficult and we have not seen it successfully done; more importantly, it is arguably unnecessary.
There already exist approaches in Public Health to assessing and developing communities faced with chronic problems, typically tied to notions such as Social Capital. Community resilience to chronic problems, if it makes sense at all, is likely to be a property that emerges from the various assets in a community such as human capital, built capital and natural capital.
Summary
Public Health professionals working with deprived neighbourhoods would be better to focus on what neighbourhoods have or could develop as social capital for living well, rather than on the vague and tangential notion of community resilience.
Journal Article
Eyewitness Shakespeare
Explore the life of history's most famous playwright--from his Elizabethan world to the stories that inspired him
Book
The application of CD antigen proteomics to pharmacogenomics
The advent of multiplexing technologies has raised the possibility that disease states can be defined using discrete genomic and proteomic patterns or signatures. However, this emerging area has been limited by the 'content problem , arising from the uncertainty of which molecules to focus on. The human cluster of differentiation (CD) antigens are expressed on cells of the human immune system (leukocytes) and on other cell types. These heterogeneous molecules perform a host of roles essential to immune function and to the physiology of other lineages. The 339 defined CD antigens and their, as yet, undefined counterparts constitute key components of the expressed human cell surface proteome. We propose that CD antigen expression patterns will form the basis of a rational, discrete and generalized diagnostic and prognostic system. Furthermore, disease-specific CD antigen proteomic signatures are likely to be more robust than corresponding genomic signatures and will also help to identify molecular targets for therapeutic intervention.
Journal Article
Power Doppler evaluation of joint effusions: investigation in a rabbit model
To study the power Doppler findings of septic arthritis and noninfectious synovitis in an animal model.
The right knees of 10 rabbits were inoculated with an aqueous suspension of Staphylococcus aureus. The right knees of 5 rabbits were injected with talc suspension. The right knees of 5 rabbits were injected with saline. All 20 left knees were injected with saline. Serial power Doppler images were obtained using constant-imaging parameters. Images were reviewed by blinded observers who assessed for increased power Doppler signal.
All 10 knees inoculated with S. aureus developed septic arthritis. Each infected rabbit knee demonstrated increased signal on power Doppler on at least one examination, ranging from 1-6 days after inoculation. Only 23 of 45 examinations of infected knees were unequivocally positive by power Doppler on examinations performed 1 to 6 days after inoculation. No knee with talc synovitis demonstrated increased power Doppler signal. No control knee demonstrated increased power Doppler signal.
Increased power Doppler signal may be seen with septic arthritis; however, its intensity and timing may vary from subject to subject. A normal power Doppler examination does not exclude septic arthritis.
Journal Article
MRI evaluation of infectious and non-infectious synovitis: preliminary studies in a rabbit model
Literature on magnetic resonance imaging (MR) evaluation of inflammatory joint effusions is sparse.
To describe an animal model for studying infectious and non-infectious joint effusions with magnetic resonance imaging.
Ten rabbit knees with septic arthritis and four with talc synovitis were imaged with MR. Contralateral knees injected with saline served as controls. Fat saturation T2-weighted and gadolinium-enhanced T1-weighted images were assessed for joint effusion, and periarticular and adjacent intraosseous increased signal or enhancement. Each knee was cultured and underwent pathologic examination.
Both Staphylococcus aureus and talc produced effusions in all knees. The degree of periarticular signal and enhancement was greater in infected knees than talc-injected knees. No abnormal enhancement was seen within bone. Pathologic examination showed a greater degree of inflammation and joint destruction in the infected knees, but no evidence of osteomyelitis.
A greater degree of abnormal signal and enhancement seen on MR suggests a more vigorous inflammatory process, as seen with septic arthritis. In spite of advanced septic arthritis, no enhancement was evident within bone, suggesting that enhancement within bone is not an expected finding in isolated septic arthritis and should raise concern for osteomyelitis.
Journal Article