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Authority and methodology: can theories 'come out negative'?: Autoridad y metodología: ¿pueden las teorías “dar resultados negativos”?
Get PDFThis article considers which methodological factors might be relevant in developing and defending accounts of law’s authority. It examines whether it should ‘count against’ theories of authority that they ‘come out negative’ in various senses – for example, that they contend that law has little, or none, of the authority that it claims to have. In its opening sections, the article considers whether there is an uphill explanatory task for theories which reach conclusions about the character and extensiveness of law’s authority that are significantly at odds with beliefs held about law’s authority by those living under and subject to law. As the discussion proceeds, it then explores whether theories of law’s authority that hold that there are gaps between: (i) the authority law claims, and the legitimate authority that it actually possesses, and (ii) law’s ideals, and its ability successfully to live up to those ideals, are problematic, and whether such accounts should consider ways in which the apparent gap(s) can be closed. The discussion concludes that while it should not, as a general methodological precept, count against theories of law’s authority that they reach negative conclusions in certain respects, that nonetheless such conclusions have relevance for evaluating the success of such theories, and may impose on them explanatory burdens of a certain kind. Este artículo analiza qué factores metodológicos podrían ser relevantes a la hora de desarrollar y defender explicaciones sobre la autoridad del derecho. Examina si debería “contraponerse” a las teorías de la autoridad que “resultan negativas” en varios sentidos, por ejemplo, que sostienen que el derecho tiene poca o ninguna autoridad de la que dice tener. En sus primeras secciones, el artículo analiza si existe una difícil tarea explicativa para las teorías que llegan a conclusiones sobre el carácter y el alcance de la autoridad del derecho que están en contradicción significativa con las creencias que tienen sobre la autoridad del derecho quienes viven bajo él y están sujetos a él. A medida que avanza el debate, se explora si las teorías de la autoridad del derecho que sostienen que existen diferencias entre: (1) la autoridad que el derecho reclama y la autoridad legítima que realmente posee, y (2) los ideales del derecho y su capacidad para estar a la altura de esos ideales son problemáticas, y si tales explicaciones deberían considerar formas de cerrar las diferencias aparentes. El debate concluye que, si bien no debe considerarse, como precepto metodológico general, en contra de las teorías sobre la autoridad de la ley el hecho de que lleguen a conclusiones negativas en ciertos aspectos, dichas conclusiones son relevantes para evaluar el éxito de tales teorías y pueden imponerles cargas explicativas de cierto tipo
Assessment of the immunological modulation following high intensity focused ultrasound treatment of soft tissue sarcoma and renal cell carcinoma
Get PDFHigh intensity focused ultrasound (HIFU) is a treatment modality using ultrasound waves to thermally ablate tissues, including tumours. The coagulative necrosis caused has been hypothesised to increase anti-tumour immune response. This thesis investigated ‘immunecold’ sarcoma tumours and ‘immune-hot’ renal cell carcinoma tumours to explore this effect.Within this thesis an in vivo murine fibrosarcoma model was established to investigate local and systemic immune modulation with associated HIFU treatment(Chapter 3). The immune profile of untreated tumour highlighted a high proportion of CD4 T cells to be Tregs compared to the other tissues. In the first HIFU study a significant increase in the CD8 Tcm T cell memory population was seen in the dLN 24-hours after treatment. In subsequent studies, the treatment area was reduced due to welfare concerns. This showed that in the dLN there was a significantly increase in neutrophils 24-hours after HIFU therapy. When the treatment included aPD-L1 antibody therapy, there was an aPD-L1 associated significant reduction in the tumour growth 5-days post-treatment.Clinical sarcomas have been reported to have varying immune infiltration based on subtype, which may be of interest in HIFU treatment of these tumours. Transcriptomic profiling of the immune populations within different sarcoma subtypes were assessed in Chapter 4. The transcriptomic profile of undifferentiated pleomorphic sarcoma (UPS) and leiomyosarcoma (LMS) showed that tumours that have been historically reported with ‘high’ immune infiltration (UPS) were characterised by increased antigen presentation and macrophages signature, whereas ‘low’ immune infiltration subtype (LMS), was shown to have high expression of structural genes.Finally, the investigation of the immunological changes associated with HIFU treatment in subtypes of ‘immune hot’renal cell carcinoma was conducted using spatial transcriptomics (Chapter 5). Interestingly, HIFU treatment increased interferon pathway (I and II) expression regardless of subtype and treatment specific macrophage and antigen presentation signatures in clear cell RCC (ccRCC), which in untreated patients, showed lower abundance of these signatures compared to the papillary RCC (pRCC) tumours
Measuring exceptional growth? A reappraisal of the Athenian economy in the 4th century BC
Get PDFThis thesis interrogates two interlocked approaches that lie at the forefront of our current understanding of the Classical Athenian economy. The qualitative insights of New Institutional Economics, a paradigm that evaluates economies’ development transhistorically through market formation, transaction costs, and institutional safeguards, are joined by quantitative measurements of performance. Together, they dovetail to present an influential picture of 4th century Athens as a vibrant economy, resembling modern frameworks in its organization and undergoing an efflorescence rarely achieved by pre-industrial societies. The thesis probes both the conclusions and premises of this portrait, claiming that its explanatory power is low. On the quantitative side, the use of statistical models to discern Athenian inequality, wages, and other indicators of living standards is beset by manifold problems regarding the data’s construction. The thesis maintains that numbers are less open to scrutiny by fellow ancient historians, yet they frequently suffer from cognitive fallacies, misleading conclusions, and poor proxy data without requisite uncertainties. It is then demonstrated that even when accepting the premises of a modernist, institutionally-driven Athenian economy, the data purporting to measure its unusually-high performance is itself driven by the hypothesis it is supposed to verify. A revised consumption basket—the first metric of its kind to be constructed specifically for the Athenian household—illustrates that both Athenian consumption needs and incomes were low, and provides more robust figures for subsistence household production. The Athenians subsisted within their means without being destitute; there is little support for economic growth or unusual development. On the qualitative side, much progress has been made by scholars who deployed New Institutional Economics to reveal complex market participation and a dynamic economy. The thesis acknowledges the advances made by the ‘formalist’ side of a longstanding debate about the nature of ancient economies, but offers the argument that a neo-substantivist viewpoint has superior explanatory power in ascertaining the nature of Athenian economic activity. Rather than a formal structure that behaved in rational, modern-equivalent ways, the Athenian economy was frequently subject to exogenous shocks and subordinate to non-economic concerns about political stability, individual social relations, and even ethical considerations. The thesis does not backpedal to previous stances in the formalist-substantivist debate, but considers new nuances of co-existence—including the very real role of divinities as economic agents. Neither growth nor measurement has much of a place in the Athenian economy of the 4th century, which exhibited features recognizable to modern economists yet more often remained alien and characterized by unquantifiable actors and intents
Targeting surface cell antigen 2 increases sensitivity of Rickettsia typhi detection
Get PDFBackground: Murine typhus is a flea-borne disease caused by Rickettsia typhi that typically presents as an acute febrile illness. The diagnosis is often missed, leading to delays in appropriate treatment. A qPCR targeting a single gene (ompB) for R. typhi is widely used for diagnosis; however, it has low sensitivity for detecting bacterial DNA in patients’ blood. We aimed to increase sensitivity of detection of R. typhi using qPCR by targeting a gene containing repetitive sequences, sca2 (surface cell antigen 2). Methodology: We compared diagnostic accuracy with the standard assay targeting single sequence ompB (outer membrane protein B). Specificity, sensitivity, and bacterial load measurement of both assays were compared using stored EDTA-anticoagulated buffy coat samples from 88 patients with febrile illness at Mahosot Hospital or provincial hospitals in Laos. Among these, 55 cases were confirmed as positive or negative by first culturing Rickettsia spp. from patients’ EDTA blood, followed by assessment with IFA and ompB PCR, and buffy coat from 6 additional cases was confirmed by ompB PCR. Ten further positive cases were confirmed by IFA using paired sera, and 17 cases classified as negative for scrub typhus and murine typhus based on Rapid Diagnostic Test (RDT) results were included in the evaluation. Results: The sca2 qPCR assay showed 59.09% sensitivity (95% CI, 38.73-76.74%) and 100% specificity (93.98-100%) for detection of R. typhi. In comparison, ompB assay demonstrated 36.36% sensitivity (95% CI, 19.73-57.05%) and 100% specificity (95% CI 93.98-100%). DNA copy number determined using the sca2 gene was approximately 2.933 log unit higher than that determined using ompB gene (median, 16,500 copies/μL; IQR, 13,045–40,000 versus median, 19.25 copies/μL; IQR, 11.11-56.62, P < 0.0001). Conclusion: This study suggests qPCR targeting sca2 increases frequency of detection of R. typhi in patients with low bacterial DNA concentrations
Synapse types are spatially associated with regional hemodynamics in the mouse brain
Get PDFSynapses are the connections that transform neurons from simple electrically charged cells into complex circuits that support perception, cognition and action. Recent advances in single-punctum synapse mapping in mice make studying synapse diversity and differential expression possible. How do diverse synapses relate to the spatial patterning of whole-brain dynamics? Here we map the spatial distribution of multiple synapse types to >6 000 time-series features from fMRI recordings in awake mice to understand the comprehensive dynamical phenotype of multiple synapse types. We find that specific synapse types are associated with specific features of haemodynamics, including high-amplitude events and signal stationarity. These variations in synapse types and dynamics are associated with the structural and functional network embedding of brain regions. Finally, using two additional fMRI datasets in anaesthetized mice, we show that synaptic protein lifetime reflects differential synaptic engagement across behavioural states. Collectively, this work suggests that the spatial organization of microscale synapse types may shape whole-brain dynamics
Dataset for “Single-molecule quantification of RNA modifications using a probabilistic framework”
No full textThis dataset supports the study “Path Signatures Enable Model‑Free Mapping of RNA Modifications” (arXiv:2511.08855v1), authored by Maud Lemercier, Paola Arrubarrena, Salvatore Di Giorgio, Julia Brettschneider, Thomas Cass, Isabel S. Naarmann‑de Vries, Anastasia Papavasiliou, Alessia Ruggieri, Irem Tellioglu, Chia Ching Wu, F. Nina Papavasiliou, and Terry Lyons. The dataset contains raw and processed single‑molecule measurements used to develop and validate a model‑free, signature‑based approach for detecting RNA modifications. It is provided as a compressed archive () together with a checksum file (). The archive includes molecule‑level data from mouse, dengue virus, and E. coli, as well as IVT controls and native RNA measurements. The file hierarchy is as follows: BM_mouse-chr10_mettl3koP2E224hLPS-g_M-sup-I-m6A-I-m6A.sorted_chr10.bam.txt BM_mouse-chr10_ctr2-24hLPS-g_M-sup-I-m6A.sorted_chr10.bam.txt Bm_mouse-chr10-IVT_ctr1-24hLPS-g_IVT-sup-I-m6A.sorted_chr10.bam.txt Dengue_Data/ 20241002_DENV_IVT_gRNA.txt.gz 20241029_DENV_gRNA-pA_oligo.txt.gz IVT.txt.gz Native_sfRNA.txt.gz Ecoli_Data/ Native_rRNa_1623.txt.gz IVT_rRNa_1623.txt.g
An empirical potential to simulate helium and hydrogen in irradiated tungsten, applied to a mechanistic model for the energetics of gas-filled voids
Get PDFMaterials used in commercial D–T fusion reactors will be exposed to irradiation and a mixture of helium and hydrogen plasma. Modeling the microstructural evolution of such materials requires the use of large-scale molecular dynamics simulations. The focus of this study is to develop a fast embedded atom method potential for the interactions among the three elements (W, H, and He), fitted to accurately reproduce both the ab initio formation energies and relaxation volumes of small defect clusters containing light gases within tungsten. The potential enables the study of tungsten under irradiation and in the presence of light gases. To demonstrate the utility of the potential, we construct a thermodynamically motivated model for predicting the energetics of light-gas-filled voids. The W–He–H system energy is represented by analytical expressions that describe the energetics of hydrogen occupying distinct configurations. The model is validated using molecular dynamics simulations with the new interatomic potential and results in a simple expression that quantifies the difference in hydrogen trapping between a mono-vacancy and a large void
Transcatheter Aortic Valve Implantation: British Cardiovascular Intervention Society Position Statement
Get PDFReproducibility and associated regression dilution bias of accelerometer-derived physical activity and sleep in UK Biobank
Get PDFBackground: Previous studies on the reproducibility of 7-day accelerometer measurements have been limited by small sample sizes and short follow-up periods. We aimed to assess the long-term reproducibility of accelerometer-derived physical activity and sleep, and to illustrate the impact of regression dilution bias on the association between daily step count and coronary heart disease (CHD) in UK Biobank. Methods: We analysed data from 3138 UK Biobank participants in the main accelerometry sub-study with up to four repeat accelerometer measurements after 3–4 years. Nine physical activity and sleep phenotypes were extracted to capture different movement behaviours. Reproducibility was assessed by using intraclass correlation coefficients (ICCs). The impact on disease associations was illustrated by considering daily step count and incident CHD using Cox regression (87 038 participants; 3879 CHD events), before and after correction for regression dilution. Results: Among the 3138 participants, 51% were women and the mean (SD) age was 63.1 (9.4) years. Reproducibility was good for overall activity, with an ICC (95% confidence interval) of 0.75 (0.74–0.76), and moderate for other phenotypes, with ICCs ranging from 0.58 (0.56–0.59) for sleep efficiency to 0.69 (0.68–0.70) for sedentary behaviour. In our example, the inverse association between daily step count and CHD showed a 20% lower risk of CHD per usual 4000 steps after correcting for regression dilution compared with 13% before correction. Conclusion: Accelerometer measurements are moderately reproducible and comparable to measures such as blood pressure. Correction for regression dilution bias is crucial to quantify associations of usual physical activity and sleep with disease risk
Financial burden of severe childhood illness on households in Lao People’s Democratic Republic: A prospective cohort study
Get PDFLao People’s Democratic Republic (PDR) introduced a National Health Insurance (NHI) scheme in 2016 to all provinces except Vientiane Capital City. We describe the financial impact on households related to treatment of severe childhood illness at a hospital covered by NHI, and one without NHI. We conducted a prospective cohort study (2022–2024) in Lao PDR of children aged one month to 10% annual household expenditure) rates and analysed relative risk (RR) of CHE by socioeconomic status. 200 participants were recruited from each hospital with demographic differences observed between hospitals in urban residence (NCH 87.0%, SPH 14.5%), maternal education (primary level: NCH 95.9%, SPH 76.3%) and wealth status (wealthiest quintile: NCH 79.0%, SPH 20.5%). Median household OOP costs were higher at NCH (USD290.6 [IQR 206.9–422.9]) compared to SPH (USD92.4 [IQR 56.3–52.9]). Impoverishment at two months post-discharge was 0.5% (95%CI 0.0-3.0) at NCH and 10.2% (95%CI 6.2-15.4) at SPH. CHE rates were 34.5% (95%CI 27.9-41.1) at NCH and 26.0% (95%CI 19.9-32.1) at SPH, with higher RR in the poorest versus wealthiest households (NCH: RR 6.6, 95%CI 4.5-9.5; SPH: RR 4.9, 95%CI 1.7-13.7) and households with no formal maternal education versus secondary education (NCH: RR 2.6, 95%CI 1.2-5.5; SPH: RR 4.6, 95%CI 1.92-11.1). Direct medical costs were lower at the provincial hospital where NHI is available, but total OOP costs and CHE rates were high at both hospitals, particularly among disadvantaged households. Additional interventions are required to prevent severe illness and provide financial protection for socioeconomically disadvantaged groups to reduce health-related economic burden on households in Lao PDR