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Journal articleMugunthan S, Dong Z, Chotirmall SH, et al., 2025,
Stress-induced toxic genomic R-loops support biofilm extracellular matrix formation.
, Nat Commun, Vol: 16Self-aggregation into biofilms is a bacterial stress response that promotes antimicrobial resistance because biofilms comprise viscous extracellular polymeric matrices that impede antimicrobial diffusion. Extracellular DNA (eDNA) is typically a principal component of the biofilm matrix. Here we show that persistent R-loops, which are three-stranded nucleic acid structures consisting of single DNA and a DNA:RNA hybrid, contribute to the viscoelastic behaviour of eDNA in Pseudomonas aeruginosa biofilms. The RNA strands are inserted throughout the genome by the strand exchange protein RecA, at locations in the genome distant from the site of their own transcription i.e. in trans. R-loop formation creates genomic instability in bacterial cells that subsequently die and release R-loops. These events appear to occur as part of a programmed cell death pathway, which is activated by the stringent stress response. The released R-loops become building blocks of the viscoelastic extracellular matrix, for the benefit of the remaining population. Our results indicate that R-loops facilitate the formation of the viscoelastic eDNA matrix in the context of bacterial stress responses, and that interfering with the R-loops may provide a broadly effective strategy for biofilm control.
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Journal articlevan Manen MJG, Wu Z, Molyneaux PL, et al., 2025,
Chronic cough and interstitial lung disease
, Ers Monograph, Vol: 2025-December, Pages: 206-224, ISSN: 2312-508XCough is a common and burdensome symptom in interstitial lung disease (ILD), particularly IPF. It has a profound impact on quality of life and is associated with disease progression and poorer prognosis. This chapter outlines its epidemiology, pathophysiology, assessment and management. Underlying mechanisms include structural distortion, neurogenic inflammation and sensory pathway sensitisation, with comorbidities such as gastro-oesophageal reflux and obstructive sleep apnoea contributing to symptom burden. Evaluation of cough includes both subjective and objective measures. Management focuses on treatable traits, with speech and behavioural therapy showing benefit. Pharmacological options remain limited; however, opioids have demonstrated efficacy and new therapies are emerging. In non-IPF ILD, immunosuppressants may reduce cough, though evidence is mixed. Future research should aim to standardise outcome measures, enrich study populations and clarify whether cough acts as a driver or marker of disease progression.
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Journal articleKim JS, Pugashetti J, Ma S-F, et al., 2025,
Associations of interstitial lung disease subtype and CT pattern with lung function and survival
, Thorax, Vol: 80, Pages: 927-934, ISSN: 0040-6376Background Prior work suggests different interstitial lung diseases (ILDs) that share the radiological usual interstitial pneumonia (UIP) pattern have an overall worse prognosis. However, epidemiological data with longitudinal sampling and replication remains lacking.Methods Data was used from the Pulmonary Fibrosis Foundation Patient Registry (PFF-PR) (n=932) and a meta-cohort of ILD research studies (n=1579). Linear mixed-effects models and Cox proportional hazard models were used to determine forced vital capacity (FVC) slopes and 5-year transplant-free survival, respectively, by ILD diagnosis and UIP radiological pattern. Secondarily, we examined FVC and survival by diagnosis and radiological fibrosis quantified by data-driven texture analysis (DTA) in the PFF-PR. Models were adjusted for age, sex, smoking and antifibrotic and immunosuppression medication use.Results The proportions of idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis (FHP) and connective tissue disease (CTD)-ILD were the following for PFF-PR (70%, 11%, 19%) and meta-cohort (21%, 32%, 47%). In the PFF-PR, CTD-ILD with UIP CT pattern was associated with slower FVC decline (−34.4 mL/year) compared with IPF (−158.4 mL/year) and longer transplant-free survival (HR 0.50, 95% CI 0.29 to 0.85). This was replicated in the meta cohort for FVC (−53.1 vs −185.9 mL/year, p<0.0001) and survival (HR 0.38, 95% CI 0.27 to 0.53). A similar pattern was seen using DTA to objectively categorise patients into higher and lower radiological fibrosis. Between IPF and FHP-UIP, FVC decline was not significantly different in the PFF-PR (−203.4 vs −158.4 mL/year, p=0.58) and meta-cohort (−124.0 vs −185.9 mL/year, p=0.25).Conclusions Even in the presence of a UIP CT pattern, there may still be differences in lung function over time and survival, particularly for CTD-ILD.
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Journal articleLee CT, Ghandi SA, Elmrayed S, et al., 2025,
Inhalational exposures associated with risk of interstitial lung disease: a systematic review and meta-analysis
, Thorax, Vol: 80, Pages: 918-926, ISSN: 0040-6376Rationale: Inhalational exposures are associated with risk of developing interstitial lung disease (ILD), yet the relationship between specific exposures and ILD is poorly characterized. Objective: Identify inhalational exposures associated with ILD and estimate the effects of exposures on ILD risk.Methods: MEDLINE and EMBASE databases were searched from 1990 until 2022 to identify inhalational exposures associated with ILD diagnosis. ILDs where causality is well-established (hypersensitivity pneumonitis, pneumoconiosis) and sarcoidosis were excluded. Two independent reviewers screened abstracts with full-text review and data extraction of eligible studies. Where possible, data were pooled and multi-level meta-analysis was specified using a random effects model. Sources of heterogeneity and risk of bias were assessed. Main Results: Ninety-six studies were included in the systematic review, representing 40,819,116 subjects (295,167 had ILD, 40,523,949 controls). For the meta-analysis, fifty-four studies were included (40,490,793 subjects: 273,899 ILD, 40,216,894 controls). Exposures associated with significantly increased ILD risk included smoking (OR 1.69, 95% CI 1.47-1.94), organic exposures (OR 1.56, 95% CI 1.12-2.16), metals (OR 1.52, 95% CI 1.07-2.16), dust (OR 1.45, 95% CI 1.20-1.76), and asbestos (OR 1.53, 95% CI 1.08-2.15). Silica and fumes had positive associations with ILD that trended toward significance. Conclusions: This systematic review and multilevel meta-analysis is the first to comprehensively assess the effect of inhalational exposures on overall risk of ILD, with multiple putative exposures identified. Future work should investigate novel occupational exposures associated with ILD, characterize the gene-environment interaction, and develop preventative strategies.
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Journal articleSim-Devadas AL, Soon SBS, Lakshmanan EM, et al., 2025,
OPENing the door for patient and public involvement in medical research in Singapore
, Research Involvement and Engagement, Vol: 11Patient and public involvement (PPI) in research in Singapore is developing. In the last 10 years, there has been strong growth in patient advocacy and support groups and increasing interest in contributing to research. In recognition of the positive benefits of PPI to generate high quality research that matters to patients and the community, the Lee Kong Chian School of Medicine launched the Office of Patient Engagement, otherwise known as OPEN. OPEN has developed training workshops and networking opportunities for researchers and patients, developed the Patient Voices community and held its first symposium in November 2024. OPEN is collaborating with the Singapore Clinical Research Institute, healthcare clusters and Universities across Singapore with the aim of expanding training, developing culturally appropriate PPI guidance and undertaking research to understand how to best implement PPI in the Asian setting.
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Journal articleCollins K, Stanley CE, Ouldridge TE, 2025,
Biochemical surface patterning in microfluidic devices
, Current Opinion in Biotechnology, Vol: 96, ISSN: 0958-1669The capacity to pattern biomolecules within microfluidic devices expands the scope of microfluidic technologies. In such patterned systems, surface-bound components remain localized, while the microfluidic network supplies reagents and removes waste products. This approach has enabled continuous protein expression from patterned DNA, chemical synthesis from immobilized enzymes, and cell capture assays. Here, we review methods to pattern surfaces within microfluidic devices. Patterns may be printed before or after the device is assembled; pre-bonding methods are compatible with well-established open-surface patterning protocols but present challenges for device bonding and alignment. Conversely, post-bonding methods are compatible with standard bonding procedures but rely on less established, sequential patterning protocols. Future progress will require consistent reporting of pattern signal and noise relative to controls.
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Journal articleSun M, Zhao Y, Ledesma-Amaro R, et al., 2025,
Engineered membraneless organelles in Corynebacterium glutamicum for enhanced indigoidine biosynthesis and antimicrobial peptide production
, Synthetic and Systems Biotechnology, Vol: 10, Pages: 1331-1340, ISSN: 2405-805XLiquid-liquid phase separation (LLPS)-driven membraneless organelles (MLOs) have been employed to enhance metabolic efficiency in various microbial cell factories. However, their application in the industrial bacterium Corynebacterium glutamicum has not been explored. Here, we report the formation of liquid protein condensates in C. glutamicum using the RGG domain of Caenorhabditis elegans LAF-1. We optimized conditions for condensate formation, including the pre-induction period, inducer concentration, and cultivation temperature. Using the indigoidine biosynthesis pathway as a model, we demonstrated that LLPS-mediated MLOs enhanced indigoidine production. Furthermore, we applied these MLOs to modulate the toxicity of antimicrobial peptides (AMPs) to host cells, facilitating the expression of AMPs, including melittin and lactoferricin B. These findings provide insights into MLOs engineering in C. glutamicum and suggest broader applications of LLPS-mediated systems in industrial biotechnology.
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Journal articleLu M, Hapeta P, Ledesma-Amaro R, 2025,
Alternative protein and microbial food production with<i> Yarrowia</i><i> lipolytica:</i> precision, biomass and traditional fermentation strategies
, Trends in Food Science & Technology, Vol: 166, ISSN: 0924-2244BackgroundWith the rapid growth of the global population, humanity is expected to face significant challenges by 2050, such as food crises, resource shortages, and climate change. The emergence of cellular agriculture not only offers promising solutions to these issues and enhances animal welfare but also provides a sustainable, healthy, and safe approach for the development of future food systems. Precision fermentation, which utilizes microorganisms as cellular factories to produce high-value functional products, plays a pivotal role in the field of cellular agriculture. Additionally, with the increasing demand for high-quality protein-containing food, identifying alternative food sources is essential. Production of alternative proteins via fermentation results in the smallest carbon footprint and generates more stable products, attracting significant interest from both academia and the food industry.Scope and approachThis review discusses the production of alternative proteins in Yarrowia lipolytica via fermentation. It addresses the advantages of using Y. lipolytica as a protein production platform, improvements in production through fermentation strategies, examples of expressed proteins from literature and patents, and the current regulatory aspects and social considerations.Key findings and conclusionsY. lipolytica have a safe usage status, a capacity to utilize various feedstocks, and unique advantages in protein production. Through precision fermentation, specific proteins can be produced, and at scale production can be achieved with appropriate parameter optimization. Additionally, Y. lipolytica is expected to play a critical role in the field of food fermentation due to its rich nutritional profile and desirable organoleptic properties. It not only provides a valuable source of alternative proteins but also improves food flavours, enriches nutritional value, and facilitates the development of new functional foods, thus broadening the scope for future food
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Journal articleLim LHM, Juang YR, Chotirmall SH, et al., 2025,
Economic burden of asthma multimorbidity in Singapore: Shadow costs of steroid use
, World Allergy Organization Journal, Vol: 18Background In some countries including Singapore, biologic therapies are not routinely available. Instead, oral corticosteroid (OCS) is commonly used for severe asthma management, which could lead to substantial adverse health events. Objective To estimate the multimorbidity costs in asthma patients from a multi-ethnic Asian population. Methods We examined national health administrative data (2012–2019) from Singapore. Direct medical costs were summed from costs of hospitalisation, emergency department (ED), specialist care, and public primary care. Prescription data were not available but formed part of public primary care costs. We measured cost per patient-year (PY) in 2023 Singaporean dollars (SGD$1 = US$0.76 = ₤0.60 = €0.69). We performed propensity-score matching on asthma and non-asthma patients, and applied generalised linear models to estimate total and excess costs due to asthma, OCS-related comorbidities, and other comorbidity groups. Results We identified 19,979 paediatric and 48,237 adult asthma patients (48.2% males, 50.4% Chinese, 13.9% Indian, 26.8% Malay), and matched equal number of non-asthma patients. Paediatric and adult asthma patients respectively incurred $816.3/PY (95% CI: $803.0/PY-$829.5/PY) and $1855.9/PY (95% CI: $1845.0/PY-$1871.0/PY) in total costs. The average ($1610.9/PY [95% CI: $1599.5/PY-$1621.3/PY]) was thrice of non-asthma patients’ ($530.4/PY). Excess costs (mean = $927.2/PY) were driven by asthma ($403.0/PY), OCS-related comorbidities ($104.0/PY), other metabolic disease ($116.4/PY), circulatory diseases ($112.9/PY) and non-asthma respiratory conditions ($107.4/PY). All excess cost components increased steadily over the 8-year study period. Conclusion The burden of asthma multimorbidity in Singapore is severe, with a considerable fraction attributable to OCS-related comorbidities. Policies should aim to reduce excess OCS use and enhance integrated multimorbidity management.
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Journal articleMayer-Hamblett N, Kerper NR, Clancy JP, et al., 2025,
Maximising opportunity for therapeutic success: sequential participation in cystic fibrosis nucleic acid-based therapy trials
, LANCET RESPIRATORY MEDICINE, Vol: 13, ISSN: 2213-2600
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