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Journal articleHernández-García J, Serrano-Mislata A, Lozano-Quiles M, et al., 2024,
DELLA proteins recruit the Mediator complex subunit MED15 to coactivate transcription in land plants
, Proceedings of the National Academy of Sciences of USA, Vol: 121, ISSN: 0027-8424DELLA proteins are negative regulators of the gibberellin response pathway in angiosperms, acting as central hubs that interact with hundreds of transcription factors (TFs) and regulators to modulate their activities. While the mechanism of TF sequestration by DELLAs to prevent DNA binding to downstream targets has been extensively documented, the mechanism that allows them to act as coactivators remains to be understood. Here, we demonstrate that DELLAs directly recruit the Mediator complex to specific loci in Arabidopsis, facilitating transcription. This recruitment involves DELLA amino-terminal domain and the conserved MED15 KIX domain. Accordingly, partial loss of MED15 function mainly disrupted processes known to rely on DELLA coactivation capacity, including cytokinin-dependent regulation of meristem function and skotomorphogenic response, gibberellin metabolism feedback, and flavonol production. We have also found that the single DELLA protein in the liverwort Marchantia polymorpha is capable of recruiting MpMED15 subunits, contributing to transcriptional coactivation. The conservation of Mediator-dependent transcriptional coactivation by DELLA between Arabidopsis and Marchantia implies that this mechanism is intrinsic to the emergence of DELLA in the last common ancestor of land plants.
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Journal articleDarawshy F, Molyneaux PL, Segal LN, 2024,
Looking Beyond the Lower Airways for Microbes Affecting Pulmonary Fibrosis
, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 209, Pages: 1054-1056, ISSN: 1073-449X -
Journal articleWu Z, Smith DJF, Yazbeck L, et al., 2024,
Cough Severity Visual Analog Scale Assesses Cough Burden and Predicts Survival in Idiopathic Pulmonary Fibrosis
, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 209, Pages: 1165-1167, ISSN: 1073-449X -
Journal articleHassan S, Syun-Ichi U, Shabeer S, et al., 2024,
Molecular and biological characterization of a novel partitivirus from Talaromyces pinophilus
, Virus Research, Vol: 343, ISSN: 0168-1702Talaromyces spp. have a worldwide distribution, are ecologically diverse and have been isolated from numerous different substrates. Talaromyces spp. are considered biotechnologically important due to their ability to produce a range of enzymes and pigments. Talaromyces pinophilus, belonging to genus Talaromyces and family Trichocomaceae, is known for producing several important bioactive metabolites. Here we report the isolation and characterisation of a partitivirus from T. pinophilus which we have nominated Talaromyces pinophilus partitivirus-1 (TpPV-1). TpPV-1 possesses a genome consisting of three double stranded (ds) RNA segments i.e., dsRNAs1-3, 1824 bp, 1638 bp and 1451 bp respectively, which are encapsidated in icosahedral particles 35 nm in diameter. Both dsRNA1 and dsRNA2 contain a single open reading frame (ORF) encoding respectively a 572 amino acid (aa) protein of 65 kDa and a 504 aa protein of 50 kDa. The third segment (dsRNA3) is potentially a satellite RNA. Phylogenetic analysis revealed that the TpPV-1 belongs to the family Partitiviridae in the proposed genus Zetapartitivirus. TpPV-1 infection decreases the mycelial growth rate of the host fungus and alters pigmentation as indicated by time course experiments performed on a range of different solid media comparing virus-infected and virus-free isogenic lines. This is the first report of mycovirus infection in T. pinophilus and may provide insights into understanding the effect of the mycovirus on the production of enzymes and pigments by the host fungus.
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Journal articleMcNally P, Singh A, McColley SA, et al., 2024,
Safety and efficacy of ivacaftor in infants aged 1 to less than 4 months with cystic fibrosis
, Journal of Cystic Fibrosis, Vol: 23, Pages: 429-435, ISSN: 1569-1993BACKGROUND: Ivacaftor (IVA) has been shown to be safe and efficacious in children aged ≥4 months with cystic fibrosis (CF) and CFTR gating variants. We evaluated safety, pharmacokinetics (PK), and efficacy of IVA in a small cohort of infants aged 1 to <4 months with CF. METHODS: In this phase 3, open-label study, infants 1 to <4 months with CF and an IVA-responsive CFTR variant received an initial low dose of IVA based on age and weight. Because IVA is a sensitive CYP3A substrate and CYP3A maturation is uncertain in infants, doses were adjusted at day 15 to better match median adult exposures based on individual PK measurements taken on day 4. Primary endpoints were safety and PK measurements. RESULTS: Seven infants (residual function CFTR variants [n=5]; minimal function CFTR variants [n=2]) received ≥1 dose of IVA. Six infants had doses adjusted at day 15 and one infant did not require dose adjustment; subsequent PK analyses showed mean trough concentrations for IVA and metabolites were within range of prior clinical experience. Four infants (57.1%) had adverse events (AEs); no serious AEs were noted. One infant discontinued study drug due to a non-serious AE of elevated alanine aminotransferase >8x the upper limit of normal. Mean sweat chloride concentration decreased (-40.3 mmol/L [SD: 29.2]) through week 24. Improvements in biomarkers of pancreatic function and intestinal inflammation, as well as growth parameters, were observed. CONCLUSIONS: In this small, open-label study, IVA dosing in infants achieved exposures previously shown to be safe and efficacious. Because PK was predictable, a dosing regimen based on age and weight is proposed. IVA was generally safe and well tolerated, and led to improvements in CFTR function, markers of pancreatic function and intestinal inflammation, and growth parameters, supporting use in infants as young as 1 month of age.
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Journal articleMainz JG, Lester K, Elnazir B, et al., 2024,
Reduction in abdominal symptoms (CFAbd-Score), faecal M2-pyruvate-kinase and Calprotectin over one year of treatment with Elexacaftor-Tezacaftor-Ivacaftor in people with CF aged ≥12 years - The RECOVER study.
, J Cyst Fibros, Vol: 23, Pages: 474-480BACKGROUND: RECOVER is a multicentre post-approval study of Elexacaftor/Tezacaftor/Ivacaftor (ETI) in pwCF in Ireland and the UK. The CFAbd-Score is the first validated CF-specific patient reported outcome measure (PROM) focusing on gastrointestinal symptoms; it comprises 28 items in 5 domains. In a preliminary study, we previously reported reductions in abdominal symptoms (AS) in pwCF after 26 weeks of ETI-therapy using the CFAbd-Score. AIM: to assess changes in AS in a second, large cohort and explore novel GI-biomarkers of gut inflammation and cell-proliferation in pwCF over one year of ETI-therapy. METHODS: Participants were recruited as part of the RECOVER study at 8 sites (Ireland&UK). The CFAbd-Score was administered prior to ETI-initiation, and subsequently at 1,2,6 and 12 months on treatment. Faecal M2-pyruvate kinase (M2-PK) and calprotectin (FC) were quantified in samples collected at baseline, 1 and 6 months. RESULTS: 108 CFAbd-Scores and 73 stool samples were collected at baseline. After 12 months of ETI-therapy, total CFAbd-Scores had significantly declined (15.0±1.4→9.8±1.2pts/p<0.001), and so had all its five domains of "pain" (16.9±2.0pts→9.9±1.8pts/p<0.01), "GERD" (14.4±1.8→9.9±1.6/p<0.05), "disorders of bowel movements" (19.2±1.4→14.1±1.5/p<0.01), "appetite" (7.0±1.1→4.6±1.2/p<0.01) and "impaired-QoL" (13.3±1.9→7.5±1.5/p<0.001). Levels of M2-PK and FC significantly decreased during ETI-therapy. DISCUSSION: In-depth analysis of AS with the CFAbd-Score reveals a statistically significant, clinically relevant and sustained improvement with ETI. We attribute this to high sensitivity of the implemented CF-specific PROM, developed and validated following FDA-guidelines. Furthermore, for the first time during ETI-therapy a significant decline in faecal M2-PK, a marker of
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Journal articleBarnes H, Elmrayed S, Barber CM, et al., 2024,
Scoping review of exposure questionnaires and surveys in interstitial lung disease
, BMJ OPEN RESPIRATORY RESEARCH, Vol: 11 -
Journal articleMerckx VSFT, Gomes SIF, Wang D, et al., 2024,
Mycoheterotrophy in the wood-wide web
, Nature Plants, Vol: 10, Pages: 710-718, ISSN: 2055-026XThe prevalence and potential functions of common mycorrhizal networks, or the 'wood-wide web', resulting from the simultaneous interaction of mycorrhizal fungi and roots of different neighbouring plants have been increasingly capturing the interest of science and society, sometimes leading to hyperbole and misinterpretation. Several recent reviews conclude that popular claims regarding the widespread nature of these networks in forests and their role in the transfer of resources and information between plants lack evidence. Here we argue that mycoheterotrophic plants associated with ectomycorrhizal or arbuscular mycorrhizal fungi require resource transfer through common mycorrhizal networks and thus are natural evidence for the occurrence and function of these networks, offering a largely overlooked window into this methodologically challenging underground phenomenon. The wide evolutionary and geographic distribution of mycoheterotrophs and their interactions with a broad phylogenetic range of mycorrhizal fungi indicate that common mycorrhizal networks are prevalent, particularly in forests, and result in net carbon transfer among diverse plants through shared mycorrhizal fungi. On the basis of the available scientific evidence, we propose a continuum of carbon transfer options within common mycorrhizal networks, and we discuss how knowledge on the biology of mycoheterotrophic plants can be instrumental for the study of mycorrhizal-mediated transfers between plants.
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Journal articleMohammed A, Mohammed C, Mautner A, et al., 2024,
On the performance of Sargassum-derived calcium alginate ion exchange resins for Pb2+ adsorption: batch and packed bed applications.
, Environ Sci Pollut Res Int, Vol: 31, Pages: 31224-31239Driven by climate change and human activity, Sargassum blooming rates have intensified, producing copious amount of the invasive, pelagic seaweed across the Caribbean and Latin America. Battery recycling and lead-smelter wastes have heavily polluted the environment and resulted in acute lead poisoning in children through widespread heavy metal contamination particular in East Trinidad. Our study details a comprehensive investigation into the use of Sargassum (S. natans), as a potential resource-circular feedstock for the synthesis of calcium alginate beads utilized in heavy metal adsorption, both in batch and column experiments. Here, ionic cross-linking of extracted sodium alginate with calcium chloride was utilized to create functional ion-exchange beads. Given the low quality of alginates extracted from Sargassum which produce poor morphological beads, composite beads in conjunction with graphene oxide and acrylamide were used to improve fabrication. Stand-alone calcium alginate beads exhibited superior Pb2+ adsorption, with a capacity of 213 mg g-1 at 20 °C and pH 3.5, surpassing composite and commercial resins. Additives like acrylamide and graphene oxide in composite alginate resins led to a 21-40% decrease in Pb2+ adsorption due to reduced active sites. Column operations confirmed Alginate systems' practicality, with 20-24% longer operating times, 15 times lower adsorbent mass on scale-up and 206% smaller column diameters compared to commercial counterparts. Ultimately, this study advocates for Sargassum-based Alginate ion-exchange beads as a bio-based alternative in Trinidad and developing nations for dealing with heavy metal ion waste, offering superior heavy metal adsorption performance and supporting resource circularity.
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Journal articleGramegna A, Addy C, Allen L, et al., 2024,
Standards for the care of people with cystic fibrosis (CF); Planning for a longer life.
, J Cyst Fibros, Vol: 23, Pages: 375-387This is the final of four papers updating standards for the care of people with CF. That this paper "Planning a longer life" was considered necessary, highlights how much CF care has progressed over the past decade. Several factors underpin this progress, notably increased numbers of people with CF with access to CFTR modulator therapy. As the landscape for CF changes, so do the hopes and aspirations of people with CF and their families. This paper reflects the need to consider people with CF not as a "problem" to be solved, but as a success, a potential and a voice to be heard. People with CF and the wider CF community have driven this approach, reflecting many of the topics in this paper. This exercise involved wide stakeholder engagement. People with CF are keen to contribute to research priorities and be involved in all stages of research. People with CF want healthcare professionals to respect them as individuals and consider the impact of our actions on the world around us. Navigating life presents challenges to all, but for people with CF these challenges are heightened and complex. In this paper we highlight the concerns and life moments that impact people with CF, and events that the CF team should aim to support, including the challenges around having a family. People with CF and their care teams must embrace the updated standards outlined in these four papers to enjoy the full potential for a healthier life.
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