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M6A-dependent RNA condensation underlies FUS autoregulation and can be harnessed for ALS therapy development
Get PDFMutations in the FUS gene cause aggressive amyotrophic lateral sclerosis (ALS-FUS). Beyond mRNA, FUS generates partially processed transcripts retaining introns 6 and 7. We demonstrate that these FUSint6&7-RNA molecules form nuclear condensates, scaffolded by the highly structured intron 7 and associated with nuclear speckles. Using hybridization-proximity labeling proteomics, we show that the FUSint6&7-RNA condensates are enriched for splicing factors and the N6-methyladenosine (m6A) reader YTHDC1. These ribonucleoprotein structures facilitate posttranscriptional FUS splicing and depend on m6A/YTHDC1 for integrity. In cells expressing mutant FUS, FUSint6&7-RNAs become hypermethylated, which in turn stimulates their condensation and splicing. We further show that FUS protein is repelled by m6A. Thus, ALS-FUS mutations may cause abnormal activation of FUS posttranscriptional splicing through altered RNA methylation. Notably, ectopic expression of FUS intron 7 sequences dissolves endogenous FUSint6&7-RNA condensates, down-regulating FUS mRNA and protein. Our findings reveal a condensation-dependent mechanism regulating FUS splicing, with possible therapeutic implications for ALS
Interplay between the gut microbiome and typhoid fever: insights from endemic countries and a controlled human infection model
Get PDFBackground
Typhoid fever is a systemic infection caused by Salmonella enterica serovar Typhi (S. Typhi) invasion from the gut lumen. Transmission between people occurs through ingestion of contaminated food and water, particularly in settings with poor water and sanitation infrastructure, resulting in over 10 million illnesses annually. As the pathogen invades via the gastrointestinal tract, it is plausible that the gut microbiome may influence the outcome of S. Typhi exposure. There is some evidence that bacteria producing short-chain fatty acids (SCFAs) may create an environment unfavourable to invasive Salmonella, but data from humans is limited.
Methods
To investigate the association between the gut microbiome and typhoid fever, we analysed samples collected from three all-age cohorts enrolled in a prospective surveillance study conducted across three settings where typhoid fever is endemic (Dhaka, Bangladesh; Blantyre, Malawi; and Kathmandu, Nepal). Cohorts consisted of acute typhoid fever patients (n = 92), asymptomatic household contacts of typhoid fever patients (representing individuals who were likely exposed to S. Typhi but did not develop the disease, n = 97) and asymptomatic serosurvey participants with high Vi antibody titres (representing individuals who were exposed to S. Typhi and may be carriers, n = 69). The stool microbiomes of each cohort were characterised using shotgun metagenomics, and bacterial diversity, composition and function were compared.
Results
We identified 4 bacterial species that were significantly lower in abundance in typhoid fever patients compared with household contacts (i.e. probably exposed), in two of the three participant populations (Bangladesh and Malawi). These bacteria may represent taxa that provide protection against the development of clinical infection upon exposure to S. Typhi and include the inflammation-associated species Prevotella copri clade A and Haemophilus parainfluenzae. Our functional analysis identified 28 specific metabolic gene clusters (MGCs) negatively associated with typhoid fever in Bangladesh and Malawi, including seven MGCs involved in SCFA metabolism. The putative protection provided by microbiome SCFA metabolism was supported by data from a controlled human infection model conducted in a UK population, in which participants who did not develop typhoid fever following ingestion of S. Typhi had a higher abundance of a putative SCFA-metabolising MGC (q-value = 0.22).
Conclusions
This study identified the same protective associations between taxonomic and functional microbiota characteristics and non-susceptibility to typhoid fever across multiple human populations. Future research should explore the potential functional role of SCFAs and inflammation-associated bacteria in resistance to S. Typhi and other enteric infections
Dispute Emergence Mechanisms for a Large Infrastructure Construction Project Using Inductive Thematic Analysis
Get PDFConstruction disputes are widely regarded as detrimental to project delivery. While many studies have explored their causes, most tend to isolate discrete factors and overlook how disputes emerge from an accumulation of interrelated events, decisions, and behaviors over time. Recent scholarship has called for more layered approaches to dispute causation, but empirical research that traces the interaction between proximate, intermediate, and root causes within real project contexts remains limited. This paper addresses that gap by using inductive thematic analysis, facilitated by NVivo software for coding, theme identification, and visualization, to examine the emergence mechanisms of two major disputes in a single-case study of a large hydropower infrastructure project. Drawing on extensive secondary qualitative project data, the study reconstructs the chronological relationships among dispute causal factors and identifies their root causes. The findings reveal that causal factors, broadly categorized under poor contract, poor contract administration and poor contractor performance, were linked to breaches of professional responsibility, competence, and integrity. The study contributes to ongoing discourse on dispute causation by demonstrating how professionalism-related lapses can escalate into disputes. It also highlights the value of inductive thematic analysis in uncovering layered mechanisms of disputes and offers practical insights for dispute avoidance in complex project settings
Geometry-informed material intensity reveals considerable intra-archetype material variability of UK housing
Get PDFBuilding stock modelling underpins energy and environmental assessments of the built environment. Material Intensity (MI), representing material mass per unit dimension, is vital for bottom-up estimation of building material stocks. However, reliance on sparse or uniform MI data can lead to significant inaccuracies due to intra-archetype variability, often stemming from differing building morphologies. This paper develops a geometry-informed MI (GIMI) method to characterise MI variability using machine learning and morphology features, applied to four materials—brick, concrete, mortar, and stone—in Sheffield, UK. Results indicate that GIMI reduces potential material uncertainties by up to 18% compared to conventional unitary MIs. This approach enhances bottom-up building mass accounting, advancing a circular economy and low-carbon building sector
Identification of clonally expanded T-cell receptor sequences in giant cell arteritis
Get PDFBackground
Arterial wall inflammation in giant cell arteritis (GCA) is characterized by T-cell infiltration and granuloma formation. There have been limited studies investigating the diversity of the T-cell receptor (TCR) repertoire in GCA patients. Here we aim to identify disease-relevant TCRs.
Methods
We sequenced the TCRβ repertoires in peripheral blood and biopsies from 72 GCA patients and compared them to repertoires of 60 age-matched controls. Applying K-nearest neighbours classification based on tcrdist3, an established TCR similarity measure, we identified GCA-associated TCRs across multiple model hyperparameters and experimental replicates.
Results
We observed that species richness and Shannon diversity were significantly lower (P = 0.0003 and P = 0.004, respectively) in GCA peripheral blood TCR repertoires compared with age-matched controls. 1526 TCRs were identified that were consistently associated with GCA, 63 TCRs were also detected in TAB repertoires. Identical GCA-associated TCRs were observed in paired blood and tissue samples from 21/30 GCA cases. 57 % of GCA-associated TCRs were fitted into 10 clusters, which displayed distinct TCR sequences and TCR V and J segment usage. TRBV20-1∗01, TRBV4-3∗01, TRBV4-2∗01 and TRBV4-1∗01 segments were over-represented and occurred at least 10 % more often among GCA patients than age-matched controls. Only 27/1526 TCR sequences had matches reported in public databases, reducing the likelihood that these targeted common infectious agents.
Conclusions
Our data provide evidence of circulating T-cell clonal expansions in GCA patients. Certain TCR sequence patterns were over-represented in GCA subjects. As more TCR sequences directed at human antigens become available, further analysis may ultimately reveal whether these TCRs bind a common target antigen
Biodiversity reporting: Comparing listed entities in the United Kingdom and South Africa
Get PDFPurpose: This research conducts an analysis of biodiversity reporting among a sample of companies listed on the stock exchanges of South Africa (SA) and the United Kingdom (UK). The aim is to present empirical evidence on how organisations address and report on biodiversity-related matters to their stakeholders and investors.
Design/methodology/approach: A disclosure schematic is developed and applied to the selected companies using content analysis to analyse their biodiversity-related disclosures and draw comparisons between the two jurisdictions.
Findings/results: Results indicate that South African organisations demonstrate a higher level of visibility in their biodiversity reporting when compared to their UK counterparts. The primary reason for this is because of a higher biodiversity ranking and hosting more biodiversity hotspots, which impact South African organisations. However, UK companies tend to provide more quantitative and valuation-based disclosures because of their advanced management information systems, professional standards network support and access to financial resources. In general, it is observed that biodiversity reporting is still in its nascent stage in both jurisdictions and offers limited insight into the understanding of biodiversity by organisations and their ability to incorporate direct and indirect impacts into their business models, risk assessment and strategy implementation.
Practical implications: The disclosure schematic serves as a valuable tool for evaluating biodiversity reporting in different national contexts and provides a framework for companies developing biodiversity action plans. The findings help stakeholders assess organisations’ progress in achieving biodiversity objectives and integrating biodiversity considerations into business operations.
Originality/value: This study makes two unique contributions to the literature. First, it provides one of the first comparative analyses of biodiversity reporting between a developing and developed economy, offering novel insights into how different jurisdictional contexts influence reporting practices. Second, it develops and applies a comprehensive disclosure schematic that enables evaluation of both symbolic and substantive biodiversity reporting approaches, advancing our understanding of how organisations integrate biodiversity considerations into their reporting and operations
Pore-scale prediction of transport properties in lithium-ion battery cathodes during calendering using DEM and CFD simulations
Get PDFCalendering is a crucial step in the production of lithium-ion batteries (LIBs), due to its significant effect on key parameters of porous electrode structure and resultant performance. This study investigates the influence of calendering degree (compression) on porosity, tortuosity and permeability for different particle configurations. With this motivation, the mechanical behaviour of electrode structures was conducted with Discrete Element Method (DEM), and the electrolyte flow as a continuous phase was described using pore-scale computational fluid dynamics (CFD) simulations. Three different electrode microstructures were generated comprising mono-disperse and polydisperse spherical particles, as well as mono-disperse ellipsoidal particles. The predicted pore-scale properties are used in validated electrochemical–thermal models to correlate calendering process to the overall LIB performance. The results revealed that using the ellipsoidal particles, an anisotropy in tortuosity and permeability appeared with the beginning of the compression process. As the compression degree increased to 30%, the level of anisotropy decreased, and as a consequence, the discrepancy of diagonal components of tortuosity and permeability decreased. The electrochemical–thermal models show that it is best to keep the calendering rate around 20% with smaller particle sizes (for both spherical and ellipsoidal cases)
Polygenic risk discriminates Lewy body dementia from Alzheimer's disease
Get PDFINTRODUCTION
Lewy body dementia (LBD) shares genetic risk factors with Alzheimer's disease (AD), including apolipoprotein E (APOE), but is distinguishable at the genome-wide level. Polygenic risk scores (PRS) may therefore improve diagnostic classification.
METHODS
We assessed diagnostic classification using AD-PRS excluding APOE (AD-PRSnoAPOE), APOE risk score (APOE-RS), and plasma phosphorylated tau 181 (p-tau181), in 83 participants with LBD, 27 with positron emission tomography amyloid beta (Aβ)positive mild cognitive impairment or AD (MCI+/AD), and 57 controls.
RESULTS
Together AD-PRSnoAPOE and APOE-RS performed similarly to p-tau181 in discriminating MCI+/AD from controls (area under the curve 76% vs. 79%) and LBD (71% vs. 72%). In LBD, Aβ positivity was significantly associated with APOE-RS, but not with AD-PRSnoAPOE, or p-tau181. Combining AD-PRSnoAPOE, APOE-RS, and p-tau181 improved the discrimination of MCI+/AD from controls (81%) and LBD (75%), and the detection of Aβ in LBD (82%).
DISCUSSION
Aβ deposition in LBD was associated with APOE, while MCI+/AD was also associated with AD-PRS beyond APOE. AD-PRS explains phenotypic variance not captured by APOE or p-tau181.
Highlights
We investigated Alzheimer's disease (AD) polygenic risk score (PRS), apolipoprotein E (APOE), and plasma phosphorylated tau 181 (p-tau181) to classify AD and Lewy body dementia (LBD).
AD-PRS with APOE achieved similar classification accuracy to p-tau181.
AD-PRS without APOE significantly contributed to discriminating AD from LBD.
Amyloid beta positivity in LBD was associated with APOE but not AD-PRS without APOE or p-tau181.
Combining AD-PRS, APOE, and p-tau181 improved diagnostic classification accuracy
Ionically crosslinked composite gels containing amine-functionalized CoFe2O4 nanoparticles as a bioactive and pH-responsive drug delivery system
No full textComposite gels are a type of soft matter, which contains a continuous three-dimensional crosslinked network and has been embedded with non-gel materials. Compared to pure gels, composite gels show high flexibility and tunability in properties and hence have attracted extensive interest in applications ranging from cancer therapy to tissue engineering. In this study, we incorporated triethylenetetramine (TETA)-functionalized cobalt ferrite nanoparticles (ANPs) into a hydrogel consisting of sodium alginate (SA) and methyl cellulose (MC), and examined the resulting composite gels for controlled drug release. The structural, thermal, and morphological aspects of the composite gels were characterized to confirm successful nanoparticle incorporation. Swelling and degradation data demonstrated the pH-responsiveness and enhanced stability of the composite gels. Along with their controlled drug release profiles and their ROS-generating capacity, our composite gels warrant further development as promising bioactive carriers for pharmaceutical applications
The P3 Explorer:An Open Database of Performance, Portability, and Productivity
Get PDFThis paper introduces a web-based tool designed to organise and present visual representations of performance, portability, and productivity (P3) data from previously published scientific studies. The P3 Explorer operates as both an open repository of application performance data and a data dashboard, providing visual heuristic analyses of performance portability and developer productivity, created using Intel’s P3 Analysis library. The goal of the project is to create a community-led database of P3 studies to better inform application developers of alternative approaches to developing new applications that target high performance on diverse hardware, considering the productivity of the developer. In this paper, we evaluate our tool using a recently published study outlining a performance portable domain-specific language for particle-in-cell applications
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