Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
478
result(s) for
"Reid, Jack"
Sort by:
Targeted homology-directed repair in blood stem and progenitor cells with CRISPR nanoformulations
Ex vivo CRISPR gene editing in haematopoietic stem and progenitor cells has opened potential treatment modalities for numerous diseases. The current process uses electroporation, sometimes followed by virus transduction. While this complex manipulation has resulted in high levels of gene editing at some genetic loci, cellular toxicity was observed. We have developed a CRISPR nanoformulation based on colloidal gold nanoparticles with a unique loading design capable of cellular entry without the need for electroporation or viruses. This highly monodispersed nanoformulation avoids lysosomal entrapment and localizes to the nucleus in primary human blood progenitors without toxicity. Nanoformulation-mediated gene editing is efficient and sustained with different CRISPR nucleases at multiple loci of therapeutic interest. The engraftment kinetics of nanoformulation-treated primary cells in humanized mice are better relative to those of non-treated cells, with no differences in differentiation. Here we demonstrate non-toxic delivery of the entire CRISPR payload into primary human blood progenitors.Gold nanoparticles that passively deliver CRISPR machinery to blood repopulating cells have been developed and are shown to be capable of precise editing of multiple genetic loci of therapeutic interest without cytotoxicity or reduced fitness.
Journal Article
Gaps in mangrove forest valuation limit understanding of socioeconomic benefits
Mangrove forests face disproportionately higher deforestation rates that exceed those of tropical rainforests, and accurately estimating their economic value is essential for informing conservation policies. However, existing valuation studies produce highly variable estimates, limiting their relevance for decision-making. In this study, we develop a set of method-specific evaluation criteria to assess the quality of mangrove valuation research. We systematically review recent estimates of mangrove ecosystem services and compare value ranges before and after applying these criteria. Our curated estimates provide a more realistic and policy-relevant value range by eliminating studies likely to under- or over-estimate direct and indirect use, non-use, or option values. We find average per hectare value estimates for direct uses increase by 14%, while average estimates for indirect use and total economic value decline extensively after the curation. We also identify opportunities to strengthen future valuation efforts, including methodological improvements, integration of new remote sensing products, estimation of marginal value changes, and better accounting for regulating services under increasing climate risks.
Journal Article
Self-Consistent Heating of the Magnetically Closed Solar Corona: Generation of Nanoflares, Thermodynamic Response of the Plasma and Observational Signatures
The energy that heats the magnetically closed solar corona originates in the complex motions of the massive photosphere. Turbulent photospheric convection slowly displaces the footpoints of coronal field lines, causing them to become twisted and tangled. Magnetic stresses gradually build until reaching a breaking point when the field reconnects and releases a sudden burst of energy. We simulate this basic picture of nanoflares using a high-fidelity, three-dimensional, multistranded magnetohydrodynamic simulation that starts with a fully stratified atmosphere. This simulation includes the effects of field-aligned thermal conduction and optically thin radiation and uses the state-of-the-art Transition Region Adaptive Conduction (TRAC) method to capture the response of the plasma to the nanoflare heating. We find that our physical model supports a unified explanation for both the diffuse emission observed in active regions and the bright coronal loops. Specifically, our results suggest that the diffuse emission originates from spatially and temporally uncorrelated nanoflares, whereas coherent clusters of nanoflares—nanoflare storms—are responsible for the formation of bright coronal loops. Quantitative comparisons between the simulated emission and observed characteristics of coronal loops show that key observed properties—such as loop widths, lifetimes, and cross sections—are reasonably well reproduced by the model. The idea that avalanche spread naturally leads to circular cross sections in coronal loops is strongly supported. Our results also suggest that phase differences in heating and cooling events across neighboring magnetic flux strands are a plausible explanation for the anomalous cross-field motions of coronal loops that were recently reported in high-resolution observations.
Journal Article
Expansion of the HSV-2–specific T cell repertoire in skin after immunotherapeutic HSV-2 vaccine
The skin at the site of HSV-2 reactivation is enriched for HSV-2–specific T cells. To evaluate whether an immunotherapeutic vaccine could elicit skin-based memory T cells, we studied skin biopsies and HSV-2–reactive CD4 + T cells from PBMCs by T cell receptor (TCR) β chain ( TRB ) sequencing before and after vaccination with a replication-incompetent whole-virus HSV-2 vaccine candidate (HSV529). The representation of HSV-2–reactive CD4 + TRB sequences from PBMCs in the skin TRB repertoire increased after the first vaccine dose. We found sustained expansion after vaccination of unique, skin-based T cell clonotypes that were not detected in HSV-2–reactive CD4 + T cells isolated from PBMCs. In one participant, a switch in immunodominance occurred with the emergence of a TCR αβ pair after vaccination that was not detected in blood. This TCRαβ was shown to be HSV-2 reactive by expression of a synthetic TCR in a Jurkat-based NR4A1 reporter system. The skin in areas of HSV-2 reactivation possessed an oligoclonal TRB repertoire that was distinct from the circulation. Defining the influence of therapeutic vaccination on the HSV-2–specific TRB repertoire requires tissue-based evaluation.
Journal Article
COMPARISON OF WASTE DUE TO IRRADIATED STEELS IN THE ESFR AND DEMO
For either nuclear fusion or generation IV fission reactors to be viable as a commercial energy source the decommissioning and waste disposal solutions must be considered during the design. A multi-step simulation process combining Monte Carlo Neutron Transport simulations with inventory simulations have been performed to estimate the activation of steels in key reactor components of the European Sodium-cooled fast Reactor (ESFR). Waste classifications based on UK waste disposal regulations have been applied to the key components to estimate the expected masses of low level and intermediate level waste. The use of reduced activation steels, EUROFER and F82H, in reactor components external to the core results in a factor of 10 reduction in the percentage of waste classified as Intermediate Level Waste (ILW). Waste estimates are compared to existing waste estimates for the European Demonstration fusion reactor (DEMO). The ESFR has a lower percentage of ILW per total reactor mass due to irradiated steels compared to DEMO. However, there is no Higher Activity Waste (HAW) associated with DEMO, compared with arisings from the ESFR spent fission fuel.
Journal Article
192 Pooled T cell receptor screening (POTS) provides unbiased, high-throughput method for TCR discovery
BackgroundT Cell Receptor (TCR)-T cell therapies have shown some promising results in cancer clinical trials, however the efficacy of treatment remains suboptimal. Outcomes could potentially be improved by utilizing highly functional TCRs for future trials. Current TCR discovery methods are relatively low throughput and rely on synthesis and screening of individual TCRs based on tetramer binding and peptide specificity, which is costly and labor intensive. We have developed and validated a pooled approach relying on directly cloned TCRs transduced into a fluorescent Jurkat reporter system (figure 1). This approach provides an unbiased, high-throughput method for TCR discovery.MethodsAs a model for POTS, T cells specific for a peptide derived adenovirus structural protein were sorted on tetramer and subjected to 10x single cell VDJ analysis. Pools of randomly paired TCR alpha and beta chains were cloned from the 10x cDNA into a lentiviral vector and transduced into a Jurkat reporter cells. Consecutive stimulations with cognate antigen followed by cell sorts were performed to enrich for functional TCRs. Full length TCRab pools were sequenced by Oxford Nanopore Technologies (ONT) and compared to a 10x dataset to find naturally paired TCRs.ResultsComparison between the ex vivo single cell VDJ sequencing and ONT sequencing of the transduced antigen specific TCRs showed more than 99% of the TCR pairs found in reporter positive Jurkat cells were naturally paired TCRs. The functionality of 8 TCR clonotypes discovered using POTS were compared and clone #2 showed the strongest response. Of the selected clonotypes, clone #2 showed a low frequency of 0.9% in the ex vivo single cell VDJ sequencing. After the first round of stimulation and sequencing, clone #2 takes up of 5% of all reporter-positive clones. The abundance of clone #2 further increased to 17% after another round of stimulation, sorting and sequencing, suggesting this method can retrieve and enrich for highly functional antigen specific TCRs.Abstract 192 Figure 1Outline of the POTS workflow.ConclusionsPOTS provides a high-throughput method for discovery of naturally paired, high-avidity T cell receptors. This method mitigates bias introduced by T cell differentiation state by screening TCRs in a clonal reporter system. Additionally, POTS allows for screening of low abundance clones when compared with traditional TCR discovery techniques. Pooled TCRs could also be screened in vivo with primary T cells in a mouse model to screen for the most functional and physiologically fit TCR for cancer treatment.
Journal Article
Risk of infection associated with intravenous iron preparations: protocol for updating a systematic review
IntroductionThe benefits and risk of intravenous iron have been documented in previous systematic reviews and continue to be the subject of randomised controlled trials (RCTs). An ongoing issue that continues to be raised is the relationship between administering iron and developing infection. This is supported by biological plausibility from animal models. We propose an update of a previously published systematic review and meta-analysis with the primary focus being infection.Methods and analysisWe will include RCTs and non-randomised studies (NRS) in this review update. We will search the relevant electronic databases. Two reviewers will independently extract data. Risk of bias for RCTs and NRS will be assessed using the relevant tools recommended by The Cochrane Collaboration. Data extracted from RCTs and NRS will be analysed and reported separately. Pooled data from RCTs will be analysed using a random effects model. We will also conduct subgroup analyses to identify any patient populations that may be at increased risk of developing infection. We will provide a narrative synthesis on the definitions, sources and responsible pathogens for infection in the included studies. Overall quality of evidence on the safety outcomes of mortality and infection will be assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach.Ethics and disseminationThis systematic review will only investigate published studies and therefore ethical approval is not required. The results will be broadly distributed through conference presentations and peer-reviewed publications.Trial registration numberPROSPERO (CRD42018096023).
Journal Article
What is the effect of perioperative intravenous iron therapy in patients undergoing non-elective surgery? A systematic review with meta-analysis and trial sequential analysis
Background
Guidelines to treat anaemia with intravenous (IV) iron have focused on elective surgical patients with little attention paid to those undergoing non-elective/emergency surgery. Whilst these patients may experience poor outcomes because of their presenting illness, observational data suggests that untreated anaemia may also be a contributing factor to poor outcomes. We conducted a systematic review to investigate the safety and efficacy of IV iron in patients undergoing non-elective surgery.
Methods
We followed a pre-defined review protocol and included randomised controlled trials (RCTs) in patients undergoing non-elective surgery who received IV iron. Primary outcomes were all-cause infection and mean difference in haemoglobin (Hb) at follow-up. Secondary outcomes included transfusion requirements, hospital length of stay (LOS), health-related quality of life (HRQoL), mortality and adverse events.
Results
Three RCTs (605 participants) were included in this systematic review of which two, in both hip fracture (HF) patients, provided data for meta-analysis. Both of these RCTs were at low risk of bias. We found no evidence of a difference in the risk of infection (RR 0.99, 95% CI 0.55 to 1.80,
I
2
= 9%) or in the Hb concentration at ‘short-term’ (≤ 7 days) follow-up (mean difference − 0.32 g/L, 95% CI − 3.28 to 2.64,
I
2
= 37%). IV iron did not reduce the risk of requiring a blood transfusion (RR 0.90, 95% CI 0.73 to 1.11,
p
= 0.46,
I
2
= 0%), and we observed no difference in mortality, LOS or adverse events. One RCT reported on HRQoL and found no difference between treatment arms.
Conclusion
We found no conclusive evidence of an effect of IV iron on clinically important outcomes in patients undergoing non-elective surgery. Further adequately powered trials to evaluate its benefit in emergency surgical specialties with a high burden of anaemia are warranted.
Trial registration
This systematic review was registered on PROSPERO (
CRD42018096288
)
Journal Article
