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Manipulating subcellular protein localization to enhance target protein accumulation in minicells
No full textBackground
Minicells are chromosome-free derivatives of bacteria formed through irregular cell division. Unlike simplified structures, minicells retain all cellular components of the parent cell except for the chromosome. This feature reduces immunogenic responses, making them advantageous for various biotechnological applications, including chemical production and drug delivery. To effectively utilize minicells, it is essential to ensure the accumulation of target proteins within them, enhancing their efficiency as delivery vehicles.
Results
In this study, we engineered Escherichia coli by deleting the minCD genes, generating minicell-producing strains, and investigated strategies to enhance protein accumulation within the minicells. Comparative proteomic analysis revealed that minicells retain most parent-cell proteins but exhibit an asymmetric proteome distribution, leading to selective protein enrichment. We demonstrated that heterologous proteins, such as GFP and RFP, accumulate more abundantly in minicells than in parent cells, regardless of expression levels. To further enhance this accumulation, we manipulated protein localization by fusing target proteins to polar localization signals. While proteins fused with PtsI and Tsr exhibited 2.6-fold and 2.8-fold increases in accumulation, respectively, fusion with the heterologous PopZ protein resulted in a remarkable 15-fold increase in protein concentration under low induction conditions.
Conclusions
These findings highlight the critical role of spatial protein organization in enhancing the cargo-loading capabilities of minicells. By leveraging polar localization signals, this work provides a robust framework for optimizing minicells as efficient carriers for diverse applications, from therapeutic delivery to industrial biomanufacturing
Oral contraceptives and the risk of asthma attacks: a population-based cohort study
No full textBackground
The role that sex hormones play in asthma remains unclear. The oral contraceptive pill (OCP), commonly used by younger women, acutely increases sex hormones providing an opportunity to observe their effect.
Objective
Evaluate the association between OCP and asthma attacks.
Methods
Using the UK's Clinical Practice Research Datalink, linked to hospital admission and mortality data, 2004 to 2020, we observed women with asthma (18–50 years), comparing OCP never-users to new-users; separated into a combined oral contraceptive (COC) cohort and progestogen-only (POP) cohort. We applied inverse-probability of treatment weighting and Cox proportional hazards, accounting for demographics, asthma severity/control and comorbidities. Additionally, we stratified by potential modifiers: age, BMI, blood eosinophils (x109 cells·L−1, normal <0.3, eosinophilia ≥0.3) and corticosteroid use (lower use: ≤3 inhaled corticosteroids prescriptions, higher use: ≥4 inhaled and/or oral corticosteroids).
Results
132 676 and 129 151 were eligible for the COC and POP cohorts, respectively. There was no association between COC, or POP, and asthma attacks (weighted-HR, 95% CI: COC=1.00, 0.89–1.13; POP=1.11, 0.97–1.28). However, POP association was modified by asthma phenotype and corticosteroid use, but not BMI, after accounting for asthma severity/control, demographics and comorbidities. In the POP users, women who were younger than 35 years old (1.39, 1.12–1.72), those with eosinophilia (1.24, 0.97–1.58), or those with lower corticosteroid use (1.20, 1.03–1.40) had an elevated risk of asthma attacks.
Conclusions
Commencing exogenous progesterone without an estrogen component (POP) was associated with increased asthma attacks in asthma phenotypes including in younger women, eosinophilic-asthma, and women with lower corticosteroid use
A computational framework for predicting the effect of surface roughness in fatigue
No full textSurface roughness is a critical factor influencing the fatigue life of structural components. Its effect is commonly quantified using a correction coefficient known as the surface factor. In this paper, a phase field based numerical framework is proposed to estimate the surface factor while accounting for the stochastic nature of surface roughness. The model is validated against existing experimental data. Furthermore, we investigate the influence of key parameters on the fatigue life of rough surfaces, such as surface topology and failure strength. An important effect of surface roughness is observed when the average surface roughness increases and the correlation length of the surface profile decreases. This effect becomes more pronounced with higher failure strengths
Detection of Volatile Organic Compounds as an emerging strategy for Parkinson’s disease diagnosis and monitoring
No full textGrowing evidence suggests that specific volatile organic compound (VOC) profiles may reflect key pathophysiological processes in Parkinson’s disease (PD), including alterations in the microbiome, metabolism, and oxidative stress. Identifying reliable VOC biomarkers could enable non-invasive tests for early diagnosis, disease monitoring, and therapy evaluation. This review examines VOC analysis in biological matrices such as breath, skin, and stool, outlining current research and future applications in PD. We evaluate analytical techniques based on sensitivity, specificity, and clinical applicability. Additionally, we classify VOCs identified in previous studies alongside their proposed biological origins. Special attention is given to short-chain fatty acids, produced by the gut microbiome, a novel target in PD research. Our findings highlight the need for larger cohort studies and standardized protocols to advance VOC-based diagnostics in PD. Understanding the interplay between VOCs and PD may facilitate biomarker discovery, enhancing non-invasive diagnostic strategies and personalized disease management
Socioeconomic and temporal heterogeneity in SARS-CoV-2 exposure and disease in England from May 2020 to February 2023
No full textThe impact of COVID-19 varied significantly by deprivation, ethnicity, and policy measures. We analyzed individual-level data on 12,310,485 first SARS-CoV-2 Pillar 2–PCR-confirmed infections, 439,083 hospitalizations, 107,823 deaths, and vaccination records in England from May 2020 to February 2022. Poisson regression models adjusted for demographic and temporal factors showed higher incidence rate ratios (IRRs) for severe outcomes in the most deprived areas compared to the least. We note higher IRRs for severe outcomes for all non-white relative to white ethnicities. The magnitude of IRRs for both deprivation and ethnicities declined from the wild-type to the omicron periods for severe outcomes. For infections, we observed IRRs above one for non-white ethnicities during the wild-type and alpha periods. Vaccination significantly reduced risks across all groups. For severe outcomes, preexisting health inequalities led to large and persistent disparities. For infections, measures must be structured with ethnicity and deprivation in mind early in a pandemic
An isotach approach for considering the rate-dependent axial loading behaviour of open steel piles driven in chalk
No full textThis paper analyses the effects of loading rate on the axial shaft capacity and stiffness for piles driven in the low-to-medium density chalk, taking advantage of a series of field Maintained Load (ML) tests. As with sands and clays, piles’ axial loading behaviour in chalk is significantly time and rate dependent once a ‘creep-yield’ load is exceeded, which typically corresponds to approximately 1/3rd of the piles’ shaft capacity. An isotach approach was employed to derive families of load-displacement curves for a range of constant displacement rates from the loading and creep stages of ML axial pile tests, while recognising a long-term load-displacement relationship that acts as a lower bound to the field behaviour. A framework was developed for adjusting the load-displacement behaviour to account for rate effects, in which empirical load modifiers are applied that depend on loading levels and pile head displacement rates. Overall, the impact of loading rate amounts to an increase of load of around 7.0% axial shaft resistance per log cycle of displacement rate over the ranges applied in typical tests. These findings aid the assessment of rate effects when analysing site tests on piles driven in chalk and designing the foundations to cope with a wide range of both extreme short-term events and longer-term maintained loading cases
A suppression-modification gene drive for malaria control targeting the ultra-conserved RNA gene mir-184
No full textGene drive technology presents a promising approach to controlling malaria vector populations. Suppression drives are intended to disrupt essential mosquito genes whereas modification drives aim to reduce the individual vectorial capacity of mosquitoes. Here we present a highly efficient homing gene drive in the African malaria vector Anopheles gambiae that targets the microRNA gene mir-184 and combines suppression with modification. Homozygous gene drive (miR-184D) individuals incur significant fitness costs, including high mortality following a blood meal, that curtail their propensity for malaria transmission. We attribute this to a role of miR-184 in regulating solute transport in the mosquito gut. However, females remain fully fertile, and pure-breeding miR-184D populations suitable for large-scale releases can be reared under laboratory conditions. Cage invasion experiments show that miR-184D can spread to fixation thereby reducing population fitness, while being able to propagate a separate antimalarial effector gene at the same time. Modelling indicates that the miR-184D drive integrates aspects of population suppression and population replacement strategies into a candidate strain that should be evaluated further as a tool for malaria eradication
Correction: Environmental impacts of battery electric light-duty vehicles using a dynamic life cycle assessment for qatar’s transport system (2022 to 2050)
No full textIn this article, Table 3 contained a typo: The first row in this table is supposed to say "BEV" but rather it is saying "ICEV." This is the only mistake that needs changing. Basically, where it says "ICEV" in the first row should be replaced with "BEV." The original article has been corrected
Carbon-mineral composite design for microwave-assisted degradation of organic contaminants
No full textMicrowave (MW)-assisted catalytic oxidation with mineral-carbon composites is a potentially promising method for treating organic pollutants, but the underlying mechanisms involving varying mineral/carbon species remain unclear. To address this, we regulated the mineral and carbon speciation in the MW-assisted synthesis of CuFe-biochar composites by varying pyrolysis conditions and evaluated their roles in the MW-assisted generation of reactive oxygen species. The presence of CuFe-biochar composites significantly promoted the generation of •O2− and •OH radicals with H2O2, with an increased removal efficiency of two organic dyes as an example for real-time image visualization in the MW reactor, Acid Orange 7 and Malachite Green (up to 97.8 % and 100 %, respectively). Increasing pyrolysis temperature and/or Fe content promoted graphitization and enhanced MW absorption (absorption broadband from 0.16 GHz to 8.56 GHz). The co-presence of Fe supported the uniform distribution of reactive Cu particles (such as Cu and Cu2O) with smaller sizes (from 45 nm to 1.5 nm), promoting the generation of •O2− radicals for the organic degradation. This study reveals the key speciation of the CuFe-biochar composites that can facilitate the MW-assisted degradation of organic pollutants via radical generation, paving the way for efficient MW-assisted decontamination
Understanding the relationship between adolescents with tuberculosis and health services: an in-depth qualitative study from Cape Town
No full textIntroduction Adolescents’ experiences (10–19 years-old) with tuberculosis (TB) remain poorly understood. Descriptions of adolescent TB experiences, particularly how they interact with the health system, are scarce. We aimed to understand adolescents’ experiences of TB health services in the Western Cape, South Africa. We focused on how TB services were aided or hindered through interactions with healthcare providers and health system processes.
Methods Teen TB, an observational study in Cape Town, enrolled 50 newly diagnosed adolescents with multidrug-resistant and drug-susceptible TB. A subset of 20 was selected for serial qualitative data collection, with 19 completing all tasks between December 2020 and September 2021. 52 interviews were conducted and thematically analysed using a case descriptive process for experiences across the TB care cascade.
Findings Adolescents criticised the difficulties and delays they encountered in obtaining an accurate TB diagnosis. Initial misdiagnoses and delayed TB diagnoses were reported, despite seeking help from multiple healthcare providers at different facilities. Adolescents questioned whether the financial, social and emotional costs of TB care outweighed the costs of delaying treatment initiation and adherence. Adolescents reported that the treatment regimen, adherence support processes and interactions with the health system posed significant challenges to maintaining adherence. Encouragingly, however, most adolescents reported being well treated and cared for by health workers.
Conclusion Our study shows that adolescents experience challenges throughout their TB treatment journeys. More adolescent-focused research is needed to tailor treatment and healthcare processes to their needs