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Predicting pyrazinamide resistance in Mycobacterium tuberculosis using a graph convolutional network
Get PDFBackgroundPyrazinamide is an important first-line antibiotic for treating tuberculosis, with resistance primarily driven by mutations in the pncA gene. Traditional machine learning models are able to predict pyrazinamide resistance with some success but are limited in their ability to incorporate 3-dimensional protein structural information. Graph neural networks offer the potential to integrate protein structure and residue-level features to better predict the impact of mutations on drug resistance.ResultsWe trained a graph convolutional network on PncA variants containing missense mutations and evaluated its ability to classify resistance to pyrazinamide. Each PncA variant was represented as an amino acid-level graph, with edges calculated from 3-dimensional spatial proximity, and node features derived from chemical properties and mutation meta-predictors. We used AlphaFold2 to generate predicted structures of the PncA variants, which we used to create the protein graphs. The predicted structures of resistant PncA variants showed greater deviation from the wild-type structure compared to susceptible variants. Our model achieved an F1 score of 81.6%, sensitivity of 81.6% and specificity of 80.4% on the test set and either matched or exceeded the performance of a published set of traditional machine learning models. We show that both structural graph connectivity and node features contribute significantly to model performance. Furthermore, we employ additional train/test dataset splits to demonstrate the GCN’s ability to generalise and predict resistance in samples with mutations in unseen positions and structural regions.ConclusionsOur study demonstrates that graph-based deep learning can leverage protein structure and biochemical features to accurately predict antimicrobial resistance, despite being trained on a small dataset with little variation. We present this as a proof-of-concept for these methods to be applied to resistance phenotype prediction in more genetically diverse pathogens to predict the more complex observed patterns of antimicrobial resistance
Comprehensive repertoire of the chromosomal alteration and mutational signatures across 16 cancer types
Get PDFWhole-genome sequencing (WGS) enables exploration of the full spectrum of oncogenic processes that generate characteristic patterns of mutations. Mutational signatures provide clues to tumor etiology and highlight potentially targetable pathway defects. Here alongside single-base substitution, doublet-base substitution, small insertion and deletion and copy number aberration signatures previously covered by the Catalogue of Somatic Mutations in Cancer (COSMIC), we report signatures from an additional mutation type, structural variations (SVs), extracted de novo from WGS in 10,983 patients across 16 tumor types recruited to the 100,000 Genomes Project. Across the five mutation classes, we report 134 signatures, 26 of which are new to COSMIC, including an SV signature reference set. By relating signatures to genomic features and clinical phenotypes, we provide further insights into mutagenic processes and the application of signature analysis to precision oncology
Simulated natural daylight and twilight modulate activity and light sampling behaviour in mice
Get PDFBackground: In the wild, mice are subject to changes in light intensity and spectrum (colour) across the solar day. In addition, mice are able to self-modulate their light exposure – a concept termed light sampling behaviour, which results in intermittent patterns of light exposure. These complexities are poorly considered in most laboratory animal housing. As such, our understanding of the role of intermittent exposure to naturally-occurring changes in intensity and spectrum in circadian behaviour are limited. To address these issues we simulated both daylight and twilight in the laboratory, and provided a dark nestbox to enable behavioural regulation of light exposure. Results: The results show that gradual changes in light intensity are a key driver of crepuscular light sampling in mice, whilst demonstrating for the first time that spectral cues at twilight modulate the timing of behaviour – advancing locomotor activity by 0.5h and light sampling behaviour by 1.1h. Conclusions: Collectively, our results demonstrate the significance of changes in intensity and spectrum across twilight for regulating mouse behaviour. These findings highlight important differences in mouse behaviour under naturalistic environments compared to normal laboratory conditions
Hierarchies of minion tests for PCSPs through tensors
No full textWe provide a unified framework to study hierarchies of relaxations for Constraint Satisfaction Problems and their Promise variant. The idea is to split the description of a hierarchy into an algebraic part, depending on a minion capturing the “base level”, and a geometric part – which we call tensorisation – inspired by multilinear algebra. We exploit the structure of the tensor spaces arising from our construction to prove general properties of hierarchies. We identify certain classes of minions, which we call linear and conic, whose corresponding hierarchies have particularly fine features. We establish that the (combinatorial) bounded width, Sherali–Adams LP, affine IP, Sum-of-Squares SDP, and combined “LP + affine IP” hierarchies are all captured by this framework. In particular, in order to analyse the Sum-of-Squares SDP hierarchy, we also characterise the solvability of the standard SDP relaxation through a new minion
Pluralism under asymmetry: China’s international research collaboration in economics and education
Get PDFScientific activities can be largely conceptualised into two interlocking levels—the national and the global systems. International collaboration as a distinctive practice in this dual system is shaped by materiality (infrastructures, regulations, funding), epistemology (disciplinary logics and methods), and values and imaginaries (norms of openness, merit, and techno-nationalist imperatives). Researchers in international collaboration seek to build trust and negotiate relations of power through various strategies regarding agendas, authorship, data, and leadership. This study investigates social science collaborations between on one hand researchers from China, on the other hand researchers from Western countries (the United States and France), the East Asian region (South Korea) and the global South (Pakistan). Collaborations in two disciplines are explored: Economics and Education. The central question of the study is: what do these researchers’ cross-country collaborative experiences suggest about the global and national research systems? To address the question, this study used an exploratory emergent design that applied primarily semi-structured interviews (N=43, including 11 cross-country dyads on the same projects) complemented with bibliometric analysis. In the experiences of these researchers, global standards travel through unequal infrastructures and nationally inflected imaginaries, producing patterned yet negotiable asymmetries whose outcomes hinge on how partners organise relations of power, translate epistemic repertoires, and sustain reciprocity. In this sense, global science is neither a flat, stateless network nor a fixed centre–periphery order. It is a layered system in motion in which structural inequalities are consequential yet never fully determining; collaboration is made workable—and sometimes innovative—through situated practices that reorder relations of power and render epistemic difference intelligible
Diagnosis and management of fracture-related infections in a low-income country: a prospective study comparing current practice to international consensus guidelines
Get PDFData on the implementation of international consensus guidelines for fracture-related infection (FRI) in low- and middle-income countries (LMICs) are scarce. This study assessed whether FRI diagnosis and management in an LMIC align with these recommendations. Methods: We conducted a prospective multicenter study across four tertiary hospitals in Yaoundé, Cameroon (September 2022-July 2025). All consecutive patients with a working FRI diagnosis were included. Confirmatory/suggestive diagnostic criteria and treatment strategies were assessed against consensus guidelines. Results: A total of 169 patients were included (mean age 39.4 ± 15.4 years; 72.7 % male). In 34.3 % of cases, FRI occurred without prior surgery, limiting applicability of the Willenegger and Roth classification. Clinical confirmatory criteria were present in 97 % of cases. Microbiological standards were seldom achieved: none fulfilled sampling quantity, and only 46.6 % met sampling method recommendations. A microbiological confirmatory criterion was documented in 36 patients (21.3 %); histopathology was rarely performed (1.2 %), and nuclear imaging was not used. Most patients (81.1 %) were on antibiotics before admission or surgery. The most common treatment strategies were suppressive antibiotic therapy (44.4 %); one-stage (11.2 %) or two-stage (10.7 %) debridement, antibiotics, and implant exchange (DAIEX); and debridement, antibiotics, and implant retention (DAIR; 9.5 %). Overall, 62.7 % of treatments deviated from consensus guidelines. Conclusion: Nearly two-thirds of FRIs in this LMIC setting were managed outside international consensus guidelines. While the consensus definition is applicable, diagnostic capacity remains limited and microbiological standards are often impractical. Context-adapted, evidence-based guidelines are urgently needed to improve outcomes where the burden is highest
Barriers to immediate corticosteroid treatment in suspected giant cell arteritis with visual symptoms: insights from a tertiary eye care unit
Get PDFBackground: Visual symptoms in Giant cell arteritis (GCA) represent a sight-threatening condition; immediate treatment with systemic corticosteroids is important. Treatment delays may occur due to several issues such as diagnostic uncertainty, unfamiliarity with managing the condition or logistical medication issues. Current literature has not assessed local factors that might impact timely management of suspected GCA patients with visual features; we explored this and created an innovative infographic to enhance current practice. Methods: Following an index case, we formed a multi-disciplinary working group to improve current practice. We started with an online questionnaire assessing the confidence and practice of our emergency eye care (EEC) team managing suspected GCA patients presenting with visual symptoms. Responses were collected over 4 weeks. Results: We obtained valid responses from 41 out of 53 EEC staff. Most respondents felt confident taking a history (mean self-rating 4.3/5, CI: 4.0-4.6) and knowing investigations for GCA with visual loss (mean 4.0/5, CI: 3.7–4.3). However, participants were less confident liaising with rheumatology colleagues out of hours (mean 2.7/5, CI: 2.2–3.2). While 37.5% (n = 15) of respondents thought they knew the pharmacy team’s working hours, only one person was able to specify these correctly. We used information from the survey to design a novel GCA infographic, incorporating British Society of Rheumatology (BSR) 2020 and European Alliance of Associations for Rheumatology (EULAR) 2018 guidelines. We displayed the infographic in EEC and provided teaching to EEC staff to address the issues that we found. Conclusions: This novel study has identified local factors that negatively impact immediate management of suspected GCA patients in EEC and designed an infographic to support clinical decision-making. Data from other centres and further evaluation of this approach is needed to assess its impact on practice
Extending the frontier of spatially resolved supermassive black hole mass measurements to at 1 ≲ z ≲ 2: simulations with ELT/MICADO high-resolution mass models and HARMONI integral-field stellar kinematics
Get PDFCurrent spatially resolved kinematic measurements of supermassive black hole (SMBH) masses are largely confined to the local Universe (distances Mpc). We investigate the potential of the Extremely Large Telescope’s (ELT) first-light instruments, MICADO and HARMONI, to extend these dynamical measurements to galaxies at redshift . We select a sample of five bright, massive, quiescent galaxies at these redshifts, adopting their Sérsic profiles, from HST photometry, as their intrinsic surface brightness distributions. Based on these intrinsic models, we generate mock MICADO images using SimCADO and mock HARMONI integral-field spectroscopic data cubes using hsim. The HARMONI simulations utilize input stellar kinematics derived from Jeans Anisotropic Models (JAM). We then process these mock observations: the simulated MICADO images are fitted with Multi-Gaussian Expansion (MGE) to derive stellar mass models, and stellar kinematics are extracted from mock HARMONI cubes with pPXF. Finally, these derived stellar mass models and kinematics are used to constrain JAM dynamical models within a Bayesian framework. Our analysis demonstrates that SMBH masses can be recovered with an accuracy of 10 per cent. We find that MICADO can provide detailed stellar mass models with 1 hour of on-source exposure. HARMONI requires longer minimum integrations for reliable stellar kinematic measurements of SMBHs. The required on-source time scales with apparent brightness, ranging from 5–7.5 hours for galaxies at (F814W, 20–20.5 mag) to 5 hours for galaxies at (F160W, 20.8 mag). These findings highlight the ELT’s capability to push the frontier of SMBH mass measurements to , enabling crucial tests of SMBH-galaxy co-evolution at the top end of the galaxies mass function
Data set for commercial group III-V metal alkoxide catalysts for selective epoxide and anhydride ring opening copolymerization delivering poly(ester-alt-ethers)
No full textData supporting the experiments described in the above manuscript
Constructing imperial authority: the intersection of British imperial constitutional law and private international law
No full textHistorians and constitutional law scholars are starting to uncover the imperial dimensions of the British constitution. But our accounts of the nature of authority in the British imperial context remain incomplete without an engagement with private international law, which played a significant role in conceptualising imperial authority. This article focuses on the forgotten interplay between imperial constitutional law and private international law. It shows how key doctrinal principles of private international law were referenced either as alternatives to, or counterparts of, key imperial constitutional law principles. Imperial actors would appeal to one or another image of imperial authority constructed by either imperial constitutional law or private international law to gain more autonomy or to tighten control. Far from being a relic of the past, the significance of this history can be traced in contemporary cases and debates about the nature of authority in the UK and its overseas territories