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Interfibre bridging in bacterial nanocellulose via co-culture-derived polyhydroxybutyrate and solvent-free blending approaches
No full textBacterial nanocellulose (BNC) is a renewable polymer valued for its strength and purity, but its brittleness and hydrophilicity limit wider application. Incorporating biodegradable polyester polyhydroxybutyrate (PHB) offers a pathway to functional, scalable composites. We establish two complementary routes for producing bacterial nanocellulose-polyhydroxybutyrate composites. In-situ co-cultures of Komagataeibacter rhaeticus (KR) and Cupriavidus necator (CN) were optimised through inoculation timing, medium screening, and pH buffering. 2-(N-morpholino)ethanesulfonic acid (MES) at 50 mM stabilised culture conditions, improved cellulose output, and enabled PHB co-localisation of 4% total wet weight. These natural incorporation levels provided benchmarks for a solvent-free blending strategy, in which powdered PHB was introduced into plasticised sterilised BNC using Gellan gum, Glycerol, PEG400, and CaCl₂ at loadings of 0.1%, 0.3%, 0.7%, and 2.0% (approximately 10%, 30%, 70%, and 200% relative to dry BNC mass) and heat pressed. Blended films reproduced co-culture PHB levels and tolerated up to 0.7% (wet weight) before shrinkage and brittleness were observed. Heat pressing promoted PHB diffusion between cellulose fibrils, enhancing interfibre bonding; in blended films at 0.3 % PHB (heat-pressed), this yielded a 6.3-fold increase in ultimate tensile strength and a 9.5-fold increase in Young's modulus. Co-culturing defined the biological starting point, while blending enabled scalable processing and systematic characterisation, offering complementary routes to manufacture BNC-PHB composites
Advances in engineering and applications of synthetic phase-separated membraneless organelles in biotechnology
No full textMembraneless organelles (MLOs) formed through liquid-liquid phase separation (LLPS) constitute crucial dynamic microenvironments within cells, capable of selectively concentrating specific molecules and regulating biochemical reactions. Based on the working mechanisms of natural MLOs, researchers have designed and constructed various synthetic MLOs. These MLOs have been applied in regulating enzyme activity, optimizing metabolic pathways, regulating gene expression, producing recombinant proteins, and developing functional biomaterials. Here, we systematically summarized the design strategies, characterization techniques, and client protein recruitment methods for synthetic MLOs, and categorically reviewed their application progress in the biotechnology field. We also discussed current challenges faced in the practical applications of synthetic MLOs and future research directions. This review aims to provide theoretical guidance and practical reference for the design and application of LLPS-driven synthetic MLOs, thereby promoting their innovative development in synthetic biology and biotechnology
Symptoms predicting the onset and duration of SARS-CoV-2 infectiousness: a community cohort study
No full textIntroduction
Upper respiratory tract (URT) SARS-CoV-2 viral load (VL) kinetics influence the clinical course of COVID-19, but their relationship to symptoms remains poorly understood. We hypothesised that VL kinetics affect the timing, intensity, and duration of symptoms in community cases.
Methods
Our prospective community cohort provided daily URT swabs for VL quantification for 2 weeks and symptom diaries for 28 days post-recruitment. Symptom data were summarised using a composite Symptom Burden Score (SBS) incorporating symptom presence and severity. Only cases who enrolled sufficiently early post-exposure to discern peak (p)VL were included (n=89). Infectious viral shedding was assessed in a subset (n=37) through quantitative viral culture.
Results
The day of pVL correlated with the day of peak symptom burden score (pSBS) (p170,000,000 RNA copies/ml) was linked to prolonged illness, with a subset experiencing symptoms ≥3 weeks (p<0.001). Cases reported more symptoms, as well as an increase in URT symptom burden, on the first day of virus cultivability compared to the preceding day (p<0.001 and p=0.005, n=31). Peak systemic symptom score, and specifically muscle aches, significantly associated with prolonged infectious viral shedding (p=0.012 and p=0.033, n=34). URT symptoms such as rhinitis, sore throat, and hoarse voice showed the steepest increase at infectiousness onset.
Conclusions
The timing of pSBS aligns with pVL, and pVL above 170,000,000 RNA copies/ml predicts prolonged symptom duration. URT symptom escalation often marks the onset of infectiousness, while systemic symptoms, particularly muscle aches, signal prolonged infectiousness. These findings identify symptom-based markers of infectiousness with implications for testing strategies. They also highlight the importance of collecting early, frequent longitudinal symptom and virological data as a core element of the public health response to novel pathogens and future pandemics
Ultrasound modulates microglial activity and reduces neuroinflammation in a parameter-dependent manner
No full textNeuroinflammation contributes to the progression of many neurological diseases. Here, we explore whether ultrasound can reduce microglia-mediated inflammation in vitro and in vivo. We tested a broad range of ultrasound parameters in a BV2 microglial cell line, treated with lipopolysaccharide (LPS) to induce an inflammatory response. We found that specific combinations of acoustic centre frequency, pressure and treatment duration can significantly lower the levels of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. These effects lasted up to 72 h and were associated with the downregulation of the nuclear factor κB (NF-κB), suggesting a mechanistic link between ultrasound and inflammation. Further investigation in vivo, in LPS-treated mice, revealed a reduction in TNF-α expression in the hippocampus following ultrasound. Overall, our findings showcase the potential of ultrasound as a non-invasive therapeutic strategy to reduce neuroinflammation and restore brain homeostasis
PRICE: direct and robust detection of microRNAs at single-nucleotide resolution
No full textAccurate single-nucleotide discrimination of miRNA is clinically vital because small sequence variations can have significant phenotypic and clinical consequences, yet existing techniques can only detect single nucleotide variations (SNVs) at specific loci. Here, we present a generalized peptide nucleic acid (PNA) mediated CRISPR/Cas13a system (PRICE), enabling detection of SNVs in miRNA sequence without sacrificing the sensitivity. PRICE utilizes PNA blockers fully complementary to non-target miRNAs (e.g., miRNAs containing SNVs at loci of no interest) but not to the target miRNA. These blockers selectively hybridize with and inhibit non-target sequences in samples (serum, cells, or tissues). Only the unhybridized target miRNA then binds to crRNA within the Cas13a complex, activating Cas13a to cleave a fluorescent reporter-quencher linker, generating a detectable signal (~10 fM limit). By designing a panel of PNAs against SNVs, PRICE provides a versatile, amplification-free platform for precise miRNA analysis, advancing cancer diagnosis, prognosis, and biology
Decoding epigenetic adaptation to adjuvant endocrine therapies in hormone-dependent breast cancer
No full textHormone-dependent Breast cancer (HDBC) is the most common cancer type in women. Adjuvant endocrine therapies (ET) disable oestrogen-mediated tumour growth, and they have helped many patients become cancer-free. However, in up to 40% of cases the disease returns, sometimes decades later. This phenomenon stems from cancer cells that can disseminate early from the primary tumour and survive by entering a prolonged life-suspended state called dormancy. Dormant cells can avoid detection and treatment. At an unknown future timepoint, they can awaken and resume proliferation with resistant traits. Understanding the adaptive evolutionary mechanisms behind dormancy entry and exit has become critical to effectively treat HDBC. Instead of defined genetic mutations, previous work in our lab uncovered epigenetic changes specific to dormancy that could explain ET adaptation: a set of repressive histone modifications – H3K27me3, H3K9me2 and H4K20me3 – that decorate DNA in repressive areas of chromatin and contribute to its structure within the nucleus.
This thesis interrogates the epigenomic landscape formed by this set of modifications. First by generating genome-wide histone enrichment maps across the main ET adaptation stages in a lineage-traced, long-term oestrogen-deprivation experiment mimicking ET in vitro. These profiles generated by CUT&Tag, revealed histone-specific patterns of deposition with context-specific consequences in transcription; and together they show dormancy is a convergent but reversible cell state that reprogrammes multiple potential sources of adaptive mechanisms, marking genes of oestrogen receptor (ER) signalling, and developmental pathways. Further generation and analysis of parallel regulatory datasets showed histone remodelling also occurs at DNA damage domains, ER binding sites, and open chromatin regions. Lastly, I investigated three-dimensional chromatin reorganisation associated with dormancy, by imaging H4K20me3-marked domains at the super-resolution scale (STORM), and by profiling all DNA-DNA contacts (HiC), both of which revealed significant structural rewiring. Together this work contributes towards identifying potential adaptive vulnerabilities in ET-induced dormancy.Open Acces
Designing digital mental health interventions for older adults: a scoping review
No full textThis scoping review aimed to explore the technical and health content-related features that digital mental health interventions (DMHIs) for older adults should entail to facilitate their future design, development, and implementation. We included peer-reviewed expert opinion papers, experimental studies and their protocols on digital mental health interventions for older adults. We searched PubMed, Embase, PsycINFO, Web of Science and Google Scholar. A total of 98 studies were included, comprising 81 experimental studies and 17 expert opinion papers. The DMHIs reported in experimental studies and their protocols included mobile apps, online platforms, and videoconferencing tools, targeting depression, anxiety and grief. However, experts highlighted three main challenges faced by older adults: functional limitations, limited digital literacy, and restricted access to technology. This review provides recommendations for the development of future DMHIs, including co-design with older adults, content adaptation, gamification, stakeholder involvement, and privacy and data security. Further research is needed to evaluate these recommendations for real-world settings
Knee osteoarthritis in the intact- and amputation-side knees of UK military personnel and veterans with traumatic unilateral transtibial limb loss 8- and 11-years post-injury: the ADVANCE cohort
No full textObjective: To compare knee osteoarthritis in people with unilateral transtibial (UTT) limb loss (LL) between (i) intact- and amputation-side knees, and (ii) ~8-years and ~11-years post-LL, and report knee osteoarthritis in reference population.
Design: Inception cohort
Setting: UK military
Participants: Volunteers with UTT LL (n=36) and matched controls (n=36).
Interventions: N/a.
Main outcome measures: Kellgren-Lawrence (KL; 0-4 [none-severe]) score and Knee injury and Osteoarthritis Outcome Score (KOOS; 100-0 [no problems-severe problems]) for Pain and Symptoms.
Results: At Baseline, ~8-years after LL, mean age was 32.9±4.2-years. Participants used dynamic–passive prosthetic limbs for daily activities and exercise. At Baseline, KL was not different between intact- and amputation-side knees (p=0.220). At Follow-up, KL was worse on the amputation-side compared to intact-side knee (p=0.021). Rank biserial correlation indicated that, for a randomly chosen pair, the amputation-side knee was 67% more likely to have a higher KL score than the intact-side knee. On both the intact- and amputation-side knees, KL was not different between Baseline and Follow-up (p=0.706 and p=0.138). KOOS Pain and Symptoms were not different between intact- and amputation-side knees at Baseline (Pain: median 100.0 vs. 100.0, p=0.253; Symptoms: median 90.0 vs. 86.5 p=0.573) or Follow-up (Pain: median 94.4 vs. 97.2, p=0.291; Symptoms: median 90.0 vs. 90.0
p=0.247). KOOS Pain (p=0.619 and p=0.557) and Symptoms (p=0.664 and p=0.580) were not different between Baseline and Follow-up for the intact- and amputation-side knees.
Conclusions: For the first time, we have compared osteoarthritis of the intact- and amputation-side knee of people with UTT LL. Contrary to current opinion, radiographic osteoarthritis was worse on the amputation-side knee 11-years post-LL. Modern military populations may be unique in their access to rehabilitation and prosthetic technology, resulting in different patterns of osteoarthritis. Clinical care should focus on the intact- and amputation-side knee of people with UTT LL
Characterisation of sub-resolution porosity in sedimentary rocks by x-ray computed tomography
No full textAccurate porosity characterisation is critical for understanding fluid flow in geological porous media, yet existing methods face significant limitations in capturing multi-scale pore systems in sedimentary rocks. This thesis develops and validates a novel dual-resolution X-ray computed tomography (CT) methodology that integrates medical CT and micro CT imaging to provide three-dimensional porosity quantification across multiple length scales. The dual-resolution approach addresses the fundamental trade-off between spatial resolution and field of view in conventional CT methods. Medical CT provides large-scale effective porosity maps with complete sample coverage, while micro CT resolves individual pore structures at microscale for the same domain. Integration of these complementary datasets enables quantification of effective, resolved, and unresolved porosity components within a unified framework, providing important insight into hierarchical pore system organisation. A key innovation involves using radio-opaque gases, specifically krypton, as saturating fluids for differential imaging. This advancement extends applicability to low permeability samples where conventional liquid saturants cannot penetrate adequately, overcoming a major limitation in tight rock characterisation. The methodology was validated on four representative sedimentary rocks: Bentheimer sandstone, Ketton limestone, Nugget sandstone, and Silurian dolomite, encompassing both simple and complex porosity systems. Validation against established techniques including helium pycnometry, mercury intrusion, and Archimedes methods demonstrates excellent agreement, with porosity values typically within 2-3% of reference measurements. The method successfully generates detailed 3D porosity maps revealing spatial heterogeneity and connectivity patterns. The approach enables enhanced parametrization through sub-resolution porosity mapping in numerical modelling applications, showing important differences in transport behaviours when heterogeneous sub-resolution porosity is applied, representing significant advancement over traditional homogenised approaches. This work addresses critical needs in reservoir characterisation, carbon sequestration, and geothermal applications. The dual resolution methodology provides enhanced tools for characterising complex porous media and establishes new opportunities for porosity quantification in digital rock physics.Open Acces
Mortality and diagnostic practice variation in interstitial lung disease admissions: insights from a multicentre UK cohort study
No full textBackground. Interstitial lung diseases (ILD) are a heterogenous group of often progressive,
unpredictable diseases. They frequently result in hospitalisations secondary to respiratory
decompensation, termed ILD-related admissions. A proportion are due to acute exacerbations
(AEILD). All are associated with high mortality but poorly characterised in real-world populations.
Aim. To evaluate mortality outcomes and associated risk factors following ILD-related hospital
admissions, including AEILD.
Methods. We conducted a multicentre retrospective cohort study of primary ICD10 coded
admissions for ILD between 01.01.2017 and 31.12.2019 across 11 NHS hospitals in the North
West of England. AEILD events were classified using clinical criteria: <30-day respiratory
deterioration not secondary to cardiac failure, pulmonary embolism or pneumothorax. The AEILD
sub-group was divided into those with CT confirmation (definite AEILD) and without CT
confirmation (suspected AEILD). Primary outcome was time from admission to death. Statistical
analyses included Kaplan-Meier and multivariate proportional hazards modelling.
Results. Of 938 ILD-related admissions, 54.5% met study AEILD criteria. Overall 90-day all-cause
mortality was 40.2%. For the AEILD cohort, 90-day all-cause mortality was 47.6%. Median survival
of the AEILD cohort was 107 days (95% CI 87.0 – 141.0 days) and other ILD-related admission
cohort 241.0 days (95% CI 208.0 – 308.0 days), with a statistically significant difference in survival
(p <0.0001). 37.6% (192/511) of AEILD events had CT confirmation. Within the AEILD sub-group,
median survival was higher in the CT group (144 days vs. 100 days, p = 0.027). AEILD was
independently associated with mortality in a multivariate model. Pre-admission oxygen, age and
neutrophilia were associated with mortality in both ILD-admission and AEILD 90-day all-cause
mortality models. 13.9% of admissions had documented palliative care input.
Conclusion. Mortality associated with ILD-related admissions is high, with AEILD events
independently associated with mortality. Findings highlight the need for improved education,
access to palliative care and targeted AEILD research