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"Hamilton, Thomas"
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Efficient inter-species conjugative transfer of a CRISPR nuclease for targeted bacterial killing
The selective regulation of bacteria in complex microbial populations is key to controlling pathogenic bacteria. CRISPR nucleases can be programmed to kill bacteria, but require an efficient and broad-host range delivery system to be effective. Here, using an
Escherichia coli
and
Salmonella enterica
co-culture system, we show that plasmids based on the IncP RK2 conjugative system can be used as delivery vectors for a TevSpCas9 dual nuclease. Notably, a
cis
-acting plasmid that encodes the conjugation and CRISPR machinery conjugates from
E
.
coli
to
S
.
enterica
with high frequency compared to a
trans
system that separates conjugation and CRISPR machinery. In culture conditions that enhance cell-to-cell contact, conjugation rates approach 100% with the
cis
-acting plasmid. Targeting of single or multiplexed sgRNAs to non-essential genes results in high
S
.
enterica
killing efficiencies. Our data highlight the potential of
cis
-acting conjugative plasmids as a delivery system for CRISPR nucleases or other microbial-altering agents for targeted bacterial killing.
CRISPR nucleases can be programmed to cleave sequences in specific bacteria to induce cell death. Here, Hamilton et al. present an optimized method for conjugative delivery of CRISPR nucleases, consisting of a single plasmid that encodes both the conjugative machinery and the nuclease.
Journal Article
Animation
With an introduction by John Lasseter-- and very little else in the way of words-- this second book in The Artist Series lavishly showcases the most brilliant animation created by such luminaries as Ub Iwerks, Norm Ferguson, Ben Sharpsteen, Hamilton Luske, Dick Huemer, Grim Natwick, Art Babbitt, Fred Moore, Bill Tytla, Frank Thomas, Ollie Johnston, Milt Kahl, Marc Davis, John Lounsbery, Ward Kimball, Eric Larson, Les Clark, Wolfgang Reitherman, John Sibley, Bill Justice, Clyde Geronimi, Ted Berman, Glen Keane, Andreas Deja, Eric Goldberg, Mark Henn and Tony Bancroft. The artwork-- much of which has never before been published-- offers the opportunity to marvel at the those magical lines of pencil that brought life to so many unforgettable Disney characters. Animation represents a rare opportunity to enjoy a glimpse into the truly spectacular trove of treasures from the Walt Disney Animation Research Library.
Book
Myeloid Colony-Stimulating Factors as Regulators of Macrophage Polarization
The scope of functional heterogeneity in macrophages has been defined by two polarized end states known as M1 and M2, which exhibit the proinflammatory activities necessary for host defense and the tissue repair activities required for restoration of homeostasis, respectively. Macrophage populations in different tissue locations exist in distinct phenotypic states across this M1/M2 spectrum and the development and abundance of individual subsets result from the local and systemic action of myeloid colony-stimulating factors (CSFs) including M-CSF and GM-CSF. These factors have relatively non-overlapping roles in the differentiation and maintenance of specific macrophage subsets. Furthermore, there is now evidence that CSFs may also regulate macrophage phenotype during challenge. Cell culture studies from multiple laboratories demonstrate that macrophages developed in the presence of GM-CSF exhibit amplified response to M1 polarizing stimuli while M-CSF potentiates responses to M2 stimuli. As a consequence, these factors can be important determinants of the magnitude and duration of both acute and chronic inflammatory pathology and may, therefore, be potential targets for therapeutic manipulation in specific human disease settings.
Journal Article
IL-17-receptor-associated adaptor Act1 directly stabilizes mRNAs to mediate IL-17 inflammatory signaling
Mechanisms that degrade inflammatory mRNAs are well known; however, stabilizing mechanisms are poorly understood. Here, we show that Act1, an interleukin-17 (IL-17)-receptor-complex adaptor, binds and stabilizes mRNAs encoding key inflammatory proteins. The Act1 SEFIR domain binds a stem-loop structure, the SEFIR-binding element (SBE), in the 3′ untranslated region (UTR) of
Cxcl1
mRNA, encoding an inflammatory chemokine. mRNA-bound Act1 directs formation of three compartmentally distinct RNA–protein complexes (RNPs) that regulate three disparate events in inflammatory-mRNA metabolism: preventing mRNA decay in the nucleus, inhibiting mRNA decapping in P bodies and promoting translation. SBE RNA aptamers decreased IL-17-mediated mRNA stabilization in vitro, IL-17-induced skin inflammation and airway inflammation in a mouse asthma model, thus providing a therapeutic strategy for autoimmune diseases. These results reveal a network in which Act1 assembles RNPs on the 3′ UTRs of select mRNAs and consequently controls receptor-mediated mRNA stabilization and translation during inflammation.
Act1 is an adaptor protein that associates with the IL-17 receptor at the cell membrane. Li and colleagues show that Act1 also exhibits unexpected RNA-binding activity and directly stabilizes select mRNAs encoding inflammatory cytokines and chemokines.
Journal Article
Ten-year patient-reported outcomes following total and minimally invasive unicompartmental knee arthroplasty: a propensity score-matched cohort analysis
Purpose
For patients with medial compartment arthritis who have failed non-operative treatment, either a total knee arthroplasty (TKA) or a unicompartmental knee arthroplasty (UKA) can be undertaken. This analysis considers how the choice between UKA and TKA affects long-term patient-reported outcome measures (PROMs).
Methods
The Knee Arthroplasty Trial (KAT) and a cohort of patients who received a minimally invasive UKA provided data. Propensity score matching was used to identify comparable patients. Oxford Knee Score (OKS), its pain and function components, and the EuroQol 5 Domain (EQ-5D) index, estimated on the basis of OKS responses, were then compared over 10 years following surgery. Mixed-effects regressions for repeated measures were used to estimate the effect of patient characteristics and type of surgery on PROMs.
Results
Five-hundred and ninety UKAs were matched to the same number of TKAs. Receiving UKA rather than TKA was found to be associated with better scores for OKS, including both its pain and function components, and EQ-5D, with the differences expected to grow over time. UKA was also associated with an increased likelihood of patients achieving a successful outcome, with an increased chance of attaining minimally clinically important improvements in both OKS and EQ-5D, and an ‘excellent’ OKS. In addition, for both procedures, patients aged between 60 and 70 and better pre-operative scores were associated with better post-operative outcomes.
Conclusion
Minimally invasive UKAs performed on patients with the appropriate indications led to better patient-reported pain and function scores than TKAs performed on comparable patients. UKA can lead to better long-term quality of life than TKA and this should be considered alongside risk of revision when choosing between the procedures.
Level of evidence
II.
Journal Article
Pharmacological inhibition of BACE1 suppresses glioblastoma growth by stimulating macrophage phagocytosis of tumor cells
Glioblastoma (GBM) contains abundant tumor-associated macrophages (TAMs). The majority of TAMs are tumor-promoting macrophages (pTAMs), while tumor-suppressive macrophages (sTAMs) are the minority. Thus, reprogramming pTAMs into sTAMs represents an attractive therapeutic strategy. By screening a collection of small-molecule compounds, we find that inhibiting β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) with MK-8931 potently reprograms pTAMs into sTAMs and promotes macrophage phagocytosis of glioma cells; moreover, low-dose radiation markedly enhances TAM infiltration and synergizes with MK-8931 treatment to suppress malignant growth. BACE1 is preferentially expressed by pTAMs in human GBMs and is required to maintain pTAM polarization through trans-interleukin 6 (IL-6)-soluble IL-6 receptor (sIL-6R)-signal transducer and activator of transcription 3 (STAT3) signaling. Because MK-8931 and other BACE1 inhibitors have been developed for Alzheimer's disease and have been shown to be safe for humans in clinical trials, these inhibitors could potentially be streamlined for cancer therapy. Collectively, this study offers a promising therapeutic approach to enhance macrophage-based therapy for malignant tumors.
Journal Article
The effect of obesity on revision rate in unicompartmental knee arthroplasty: a systematic review and meta-analysis
The number of patients with knee osteoarthritis, the proportion that is obese and the number undergoing unicompartmental knee arthroplasty (UKA) are all increasing. The primary aim of this systematic review was to determine the effects of obesity on outcomes in UKA. A systematic review was performed using PRISMA guidelines and the primary outcome was revision rate per 100 observed component years, with a BMI of ≥ 30 used to define obesity. The MINORS criteria and OCEBM criteria were used to assess risk of bias and level of evidence, respectively. 9 studies were included in the analysis. In total there were 4621 knees that underwent UKA. The mean age in included studies was reported to be 63 years (mean range 59.5–72 years old)) and range of follow up was 2–18 years. Four studies were OCEBM level 2b and the average MINORS score was 13. The mean revision rate in obese patients (BMI > 30) was 0.33% pa (95% CI − 3.16 to 2.5) higher than in non-obese patients, however this was not statistically significant (
p
= 0.82). This meta-analysis concludes that there is no significant difference in outcomes between obese and non-obese patients undergoing UKA. There is currently no evidence that obesity should be considered a definite contraindication to UKA. Further studies are needed to increase the numbers in meta-analysis to explore activity levels, surgeon’s operative data, implant design and perioperative complications and revision in more depth.
Level of evidence
Level III.
Journal Article
Indications and techniques for non-articulating spacers in massive bone loss following prosthetic knee joint infection: a scoping review
IntroductionProsthetic joint infection (PJI) is a destructive complication of knee replacement surgery (KR). In two-stage revision a spacer is required to maintain limb length and alignment and provide a stable limb on which to mobilise. Spacers may be articulating or static with the gold standard spacer yet to be defined. The aims of this scoping review were to summarise the types of static spacer used to treat PJI after KR, their indications for use and early complication rates.MethodsWe conducted a scoping review based on the Joanna Briggs Institute’s “JBI Manual for Evidence Synthesis” Scoping review reported following Preferred Reporting Items for Systematic Review and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist. MEDLINE, EMBASE and CINAHL were searched from 2005 to 2022 for studies on the use of static spacers for PJI after KR.Results41 studies (1230 patients/knees) were identified describing 42 static spacer constructs. Twenty-three (23/42 [54.2%]) incorporated cement augmented with metalwork, while nineteen (19/42, [45.9%]) were made of cement alone. Spacers were most frequently anchored in the diaphysis (22/42, [53.3%]), particularly in the setting of extensive bone loss (mean AORI Type = F3/T3; 11/15 studies 78.3% diaphyseal anchoring). 7.1% (79 of 1117 knees) of static spacers had a complication requiring further surgery prior to planned second stage with the most common complication being infection (86.1%).ConclusionsThis study has summarised the large variety in static spacer constructs used for staged revision KR for PJI. Static spacers were associated with a high risk of complications and further work in this area is required to improve the quality of care in this vulnerable group.
Journal Article
Cost-effectiveness of unicompartmental compared with total knee replacement: a population-based study using data from the National Joint Registry for England and Wales
ObjectivesTo assess the value for money of unicompartmental knee replacement (UKR) compared with total knee replacement (TKR).DesignA lifetime Markov model provided the framework for the analysis.SettingData from the National Joint Registry (NJR) for England and Wales primarily informed the analysis.ParticipantsPropensity score matched patients in the NJR who received either a UKR or TKR.InterventionsUKR is a less invasive alternative to TKR, where only the compartment affected by osteoarthritis is replaced.Primary outcome measuresIncremental quality-adjusted life years (QALYs) and healthcare system costs.ResultsThe provision of UKR is expected to lead to a gain in QALYs compared with TKR for all age and gender subgroups (male: <60 years: 0.12, 60–75 years: 0.20, 75+ years: 0.19; female: <60 years: 0.10, 60–75 years: 0.28, 75+ years: 0.44) and a reduction in costs (male: <60: £−1223, 60–75 years: £−1355, 75+ years: £−2005; female: <60 years: £−601, 60–75 years: £−935, 75+ years: £−1102 per patient over the lifetime). UKR is expected to lead to a reduction in QALYs compared with TKR when performed by surgeons with low UKR utilisation but an increase among those with high utilisation (<10%, median 6%: −0.04, ≥10%, median 27%: 0.26). Regardless of surgeon usage, costs associated with UKR are expected to be lower than those of TKR (<10%: £−127, ≥10%: £−758).ConclusionsUKR can be expected to generate better health outcomes and lower lifetime costs than TKR. Surgeon usage of UKR does, however, have a significant impact on the cost-effectiveness of the procedure. To achieve the best results, surgeons need to perform a sufficient proportion of knee replacements as UKR. Low usage surgeons may therefore need to broaden their indications for UKR.
Journal Article