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PyamilySeq: exposing the fragility of conventional gene (re)clustering and prokaryotic pangenomic inference methods
No full textPangenomics has become a central framework for exploring microbial diversity and evolution, enabling researchers to distinguish genes that define shared biological function from those that drive adaptation. However, this relies on clustering genes by sequence similarity, a process that is far less deterministic than often assumed. This study introduces PyamilySeq, a transparent and flexible toolkit designed to diagnose and quantify hidden biases within gene clustering and pangenome inference methodologies. Using PyamilySeq, we can see how clustering thresholds (often hard-coded and poorly documented) and paralog handling can substantially alter gene family composition. Surprisingly, even parameters unrelated to clustering, such as decimal precision (0.8 versus 0.80), output selection, and even CPU and memory allocation, can alter gene family assignments, challenging the assumption that identical clustering thresholds yield consistent results. Furthermore, tools often fail to report biologically meaningful or representative sequences for gene families, undermining downstream analyses. These findings reveal systematic fragilities in gene clustering and pangenome construction and highlight that pangenomics is not merely a data-driven task but a methodological one, where transparency, reproducibility, and interpretability are as critical as biological insight. This work calls for a re-evaluation of how pangenomes are constructed and compared, and advocates for methodologies that make their assumptions explicit and their results verifiable.<br/
Using Möbius for automated assessment in mathematics: a case study
No full textWe describe a failed pilot that involved using the automated grading software Möbius in place of graduate student markers for three undergraduate courses delivered in the School of Mathematics and Physics in Queen’s University Belfast. We analyze the effects of this change on student engagement and performance. Our evidence suggests that students are more likely to engage with formative assessment activities when they are marked with Möbius. Students also perform better in summative assessments when they have had Möbius assignments to complete—with one module having a stark reduction in failure rate from 32% to 5%. When we surveyed the students who had the opportunity to engage with Möbius, we did not find that they had much enthusiasm for the software. However, we found that students also lacked enthusiasm for the systems for assessment and feedback that Möbius had replaced. Their responses to our survey instead indicating that students may not fully understand the distinction between formative and summative assessment. As we discuss in the conclusion, this project failed because, in spite of this apparent success, we could not drum up the support for Möbius from students and colleagues that justified the expense associated with purchasing software licenses each year. To introduce automated grading in our context we need a system that has zero or negligible associated cost as it will likely only ever be used by a small number of staff.<br/
A Michaelis‐Arbuzov‐Type pathway to a protected 2ʹ‐deoxy‐2ʹ‐selenomethyl‐adenosine‐3ʹ,5ʹ‐phosphoroselenolate guanosine dinucleotide for use in modified m7G cap synthesis
No full textIn this paper, a solution‐phase total synthesis is described of the 5ʹ‐O‐phosphorylated 2ʹ‐deoxy‐2ʹ‐selenomethyl‐adenosine 3ʹ,5ʹ‐phosphoroselenolate guanosine dinucleotide (4) using a rt, 2,6‐lutidine‐mediated, nucleoside 3ʹ‐H‐phosphonate/5ʹ‐selenocyanate Michaelis‐Arbuzov ligative coupling, whose potential mechanism is discussed herein. Our route to 4 is predicated upon the highly efficient new 2ʹ‐O‐triflate selenocyanate anion displacement of 10 in MeCN, to obtain the 2ʹ‐selenocyanate 9, which was allied with an Amosova NaBH4/MeI mediated reductive selenomethylation in MeOH. A novel solid CPR II‐mediated 5ʹ‐O‐phosphitylation of the dinucleotide alcohol 6 and a 70% aqueous t‐BuO2H oxidation successfully installed the 5ʹ‐O‐phosphate moiety within 4 without oxidizing the 2ʹ‐selenomethyl group. It is envisaged that 4 will be of value for a future total synthesis of the m7G cap 1; a molecule of potential utility for therapeutic mRNA manufacture.<br/
Mapping the landscape of mycological organizations in europe: where citizen science meets professional mycology
No full textFungi have been used by humans since prehistoric times. Informal structures or groups for knowledge exchange regarding mushrooms and lichens probably existed for ages. Only recently, mycological activities have been structured in formal organizations. And where until a few centuries ago there were only learned societies and naturalists’ clubs, nowadays also mycological societies and citizen scientists have joined the landscape. However, the history of mycological organizations and activities in Europe is difficult to track. Here, we initiated two surveys to characterize the current landscape of mycological organizations focused on fungal diversity across Europe and to collate citizen science activities mapping fungi. The surveys were shared on social media and sent to mycologists in 49 countries in Europe. Responses of the surveys allowed us to present the history, geographical distribution, and structure of mycological organizations in Europe as well as their types of activities, including the publication of journals and magazines, the organization of meetings and educational initiatives, and citizen science projects. In addition to the surveys, local mycologists presented expert knowledge for a more comprehensive overview. Our data show that the mycological landscape in Europe is diverse and heterogeneous. We discuss ways to overcome economic, cultural, and linguistic barriers towards better integration of mycological communities, activities, and data in Europe. Mycological societies focused on studying fungal diversity can be leveraged towards common goals that include raising public awareness, data integration, uniting academics and non-academics, and developing common standards for research and communication
Female cyclists’ experiences of saddle sores and the effect on cycling
No full textThe aims of this study were to: 1) understand the type, severity and experiences of saddle sores in female cyclists, 2) explore the impact on enjoyment, training and performance, and 3) what prevention or treatment methods female cyclists use, including discussing these issues with their coach, bike fitters and medical staff. Twenty competitive female cyclists (age 35.1 ± 7.7 yrs, cycling for 11.9 ± 7.4 yrs, 3 elite, 7 sub-elite and 10 club cyclists) were interviewed using an open-ended, semi-structured approach. A thematic analysis was conducted. Saddle sores are highly prevalent in female cyclists and most occurred in the vulva region. The causes of saddle sores were suggested to be due to pressure, friction at saddle contact points and sweat or a combination of all three. The biggest reported impact of saddle sores were they reduced the enjoyment of cycling. Participants identified risk factors for developing saddle sores and methods of how they tried to prevent them occurring. To treat and manage saddle sores, participants used treatment creams, modified training, and in severe cases they sought medical treatment or took a break from cycling. Participants reported the process of finding a comfortable saddle and bicycle setup as trial and error which was long and expensive. Saddle sores are thought of as a taboo topic, and many participants had received poor or conflicting advice. These findings highlight the need for improved education on the prevention and treatment of saddle sores, and more research into female specific bicycle setup and saddle design
H&E-based MSI/MMR testing with AI in colorectal cancer: a multi-centred blinded evaluation
No full textMismatch repair (MMR) deficiency occurs in 10-20% of colorectal cancer (CRC) cases, leading to microsatellite instability (MSI). Although MSI/MMR testing is critical for CRC management, high costs and long turnaround times limit testing rates and clinical utility, highlighting the need for more accessible, cost-effective alternatives. PANProfiler Colorectal (PPC) is an artificial intelligence (AI)-based biomarker test that determines MSI/MMR status directly from haematoxylin and eosin (H&E)-stained slides. We conducted a blinded, multi-centred validation to assess PPC's performance against standard testing. The study included 3,576 whole slide images from 1,243 CRC patients across three United Kingdom institutions. PPC produced definitive results for 86.55% of slides, achieving an overall agreement of 93.83%, positive agreement of 92.54%, and negative agreement of 94.02%. PPC accurately determined MSI/MMR status from routine H&E slides, offering a rapid, scalable alternative to conventional diagnostic methods
External evaluation of the Manchester score in a contemporary SCLC cohort
No full textOBJECTIVES: The Manchester Score, a prognostic model developed in 1987, was used to stratify patients with Small Cell Lung Cancer (SCLC) by mortality risk, including stage, performance status, and three blood tests as risk factors. Many tools have since been developed for this purpose, but few have seen clinical use, with lack of robust external validation frequently cited as a barrier. In this study we apply a robust and pragmatic external validation approach to the Manchester Score to understand if it remains valid in an unselected modern patient cohort.METHODS: SCLC patients treated in an academic centre between 2013 and 2022 (N = 1783) were included in the validation cohort. Discrimination was assessed using Kaplan-Meier curves, AUC, and Harrell's C-index for the Manchester score and its underlying Cox model. Three levels of Cox model updating were used to address missing baseline hazard data: recalibration, recalibration with rescaling, and model refitting. Calibration was then evaluated with optimism adjustment at 6-, 12-, and 24-months post-diagnosis.RESULTS: The Manchester score shows good discrimination in the modern patient cohort. There is clear separation between risk groups in the Kaplan-Meier curves, with AUC = 0.75 and C-index = 0.68 for the Manchester Score and (AUC = 0.79, C-index = 0.70) for the underlying Cox model. Median survival in the 'good' prognostic group (meeting < 2/5 risk criteria) has increased compared to that from 1987. All model updating methods reported good calibration, with recalibration alone providing the best observed-to-expected ratio at 6 months (1.012 [0.978,1.045]).CONCLUSION: The original Manchester Score prognostic groups remain discriminative of survival, and when updated can predict survival probability at multiple timepoints.</p
Cholinesterase inhibitors for patients with dementia: Patterns of prescribing and disparities in treatment
No full textBackgroundCholinesterase inhibitors (ChEIs) are cornerstones of the symptomatic treatment of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) and are also prescribed for vascular dementia (VaD). Despite their widespread use, patterns of ChEI prescribing are unclear.ObjectiveOur objective was to examine the prevalence, timing, and types of ChEI prescriptions before and after dementia diagnosis.MethodsWe analyzed electronic health record and claims data for patients diagnosed with AD, DLB, or VaD between October 2015 and August 2022 from a large U.S. healthcare system. ChEI claims (donepezil, rivastigmine, galantamine) were identified in the ±3 years surrounding dementia diagnosis. Repeated measures logistic regression was used to estimate the likelihood of ChEI fills by time-period, dementia type, and time x dementia type interaction to determine if change in prescription patterns significantly differed by diagnosis.ResultsAmong 3166 eligible patients, DLB had the highest prevalence of ChEIs both pre-and post-diagnosis compared to patients with AD and VaD. Post-diagnosis, donepezil was the most common, while galantamine use was sparse. After adjusting for demographics, patients with VaD had lower rates of ChEIs relative to AD (OR: 0.34, 95% CI 0.26–0.45). In the fully adjusted model, females (OR: 0.81, 95% CI: 0.71–0.91) and patients from ethnoracially minoritized populations (OR: 0.74, 95% CI: 0.62–0.88) were less likely to fill ChEI prescriptions.ConclusionsDonepezil was the most frequently filled ChEI across dementias. Patients with DLB had the highest prevalence of ChEIs pre- and post-diagnosis. The potential disparities in treatment we identified should be investigated further
Global cortical thinning predicts slower forward and backward walking in multiple sclerosis
No full textGait impairment and falls are common in multiple sclerosis (MS), yet the neural substrates contributing to mobility decline remain poorly understood. While prior studies have linked regional gray matter atrophy to motor outcomes, the role of diffuse cortical changes in complex gait tasks, such as backward walking, is less clear. This study examined whether diffuse cortical thinning is associated with forward and backward walking speed, and whether these relationships differ between fallers and nonfallers in MS. Forty-three individuals with MS (55 ± 10 years; 65% female) completed forward and backward Timed 25-Foot Walk assessments and high-resolution structural MRI. Cortical thickness and gray matter volume were estimated. Region-specific associations with gait speed were examined using regression with false discovery rate (FDR) correction. Principal component analysis revealed a global cortical thinning component that was associated with slower forward (β = −0.065, adjusted R2 = 0.14) and backward (β = −0.061, adjusted R2 = 0.19) walking speeds. In contrast, volumetric components did not significantly predict gait. Fallers and nonfallers did not differ in gait speed or cortical thinning, but exploratory moderation suggested stronger cortical thinning–gait associations in fallers, although effects did not remain significant after FDR correction. These preliminary findings suggest that diffuse cortical thinning is a consistent neural correlate of gait slowing in MS, with exploratory evidence suggesting that this relationship may be stronger among individuals with recent falls