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Composite grey matter fingerprints for genetic frontotemporal dementia
Get PDFBackground: Brain structural changes in frontotemporal dementia (FTD) can occur decades before symptom onset. Precise characterisation of grey matter changes is necessary for developing models of biomarker progression, while better understanding the trajectory of the pathology is invaluable for prognosis and detecting treatment effects as we enter the era of clinical trials. Methods: Cortical and subcortical grey matter volume and thickness from structural MRI were assessed in a large cohort of 892 participants including presymptomatic and symptomatic carriers of mutations within the three main genetic causes of FTD (C9 open reading-frame 72 (C9orf72), progranulin (GRN) and microtubule-associated protein tau (MAPT)) compared with mutation-negative relatives (controls). We compared the distribution of grey matter changes of each metric at different stages of the disease cross sectionally. We aimed to identify grey matter composites for each genetic group which would show the earliest changes and which separated presymptomatic carriers from controls. Results: While C9orf72 mutation carriers showed widespread presymptomatic grey matter changes, MAPT and particularly GRN mutation carriers showed changes more proximally to symptom onset. Our composite grey matter signatures, which discriminate asymptomatic/prodromal carriers from controls with high to very high areas under the curve, involved bilateral thalami volumes, precuneus and postcentral thickness in C9orf72; left caudal middle frontal thickness, frontal pole and pars orbitalis volumes in GRN; right temporal pole volume and left insula thickness in MAPT mutation carriers. Conclusion: We propose the use of cortical thickness and volume measurements combined from multiple regions into a composite region of interest for each FTD genetic group to identify the earliest changes and track disease progression. Our quasi-longitudinal design illustrates that these regions continue to evolve throughout the symptomatic stages. Investigating how our selected composites progress and validating these in longitudinal samples will be invaluable for future clinical trials
China looks at Africa: modernity, morality and hierarchy in 21st century Chinese worldviews: China Looks at Africa
No full textThis monograph offers a sustained study and theoretical analysis of how Chinese actors in the 21st century imagine Africa and their relations with it. Granted, there is a significant corpus of existing research that examines the actual conduct of China in its relations with Africa. But less has been done to explore how varied actors within China understand Africa, Chinese relations with Africa, and their respective and relative positionalities within the global landscape. Answering these questions not only helps to understand the ideational foundations of China’s relations with Africa, but also offers a window into Chinese actors’ conceptual frameworks on the structure and the constitution of the world. Using qualitative, interpretivist methods, this thesis draws upon more than forty published memoirs and non-fiction works by one-hundred-twenty diplomats and quasi-official practitioners, around one hundred academic articles by Chinese scholars on China-Africa relations, as well as hundreds of social media posts on Weibo by Chinese netizens. This monograph makes the central argument that modernity is a crucial lens through which varied Chinese actors commonly make sense of international hierarchy, and their understandings are further complicated by notions of postcolonial moral ideals. Modernity informs the way in which these actors discursively assign relative positions to China, Africa, and the West (the latter two often understood in homogenous terms). Against this background, China is increasingly imagined as superior and modernized as compared to Africa. On the other hand, postcolonial moral ideals create expectations of natural solidarity between China and Africa, which justify perceptions of the West as morally inferior. This thesis outlines how conceptions of modernity and postcolonial morality shape Chinese views, the ways in which these intersect with racial, gendered and civilisational understandings, and the frictions this also generates
Learning the Manchu writing system: the role of intra-symbol processing in orthography acquisition
No full textCharacteristics of the Manchu writing system provide an excellent testing ground for current theorizing about orthography acquisition. Using traditionally demarcated orthographic units called uju hergen—symbol blocks representing phonological syllables—we investigated the role of visual features and phonological representations in learning the Manchu symbol set. Novice Manchu learners (n = 196; 89.8% female; Mage = 18.79) participated in two experiments. Experiment 1 focused on visual complexity effects and Experiment 2 on mapping complexity effects and switching costs. Among visual characteristics, the number of connected points was found to make a unique contribution to uju hergen recognition. Naming error rate was lower for a list of uju hergen with single (one-toone) mapping between a phoneme marker and sound compared to a matched list but with multiple (one-to-many) mapping. No switching cost was observed between lists with low- and high-switching-demand. Established explanatory constructs of grain size, orthographic depth and orthographic breadth, referenced together as the construct of orthographic scale, explain the results. But reading uju symbol blocks also requires processing within symbol blocks: at the visual level, connected points provide the sub-symbol cues to decompose discrete simple features and recompose them into phoneme markers; and at the level of phonological representation, the resultant markers must be read by appropriate symbolto-sound mapping. Together, our study expands theorising on orthography acquisition by bringing focus on the under-studied construct of intrasymbol processing
Measuring Advanced Practice in Health Visiting: Development and Psychometric Testing of the Health Visiting Advanced Practice Scale in Public Health Nursing
Get PDFBackground: The debate about whether health visiting, a specialist community public health nursing role, is at the level of advanced practice nurse has gone on for more than a decade. There is little empirical evidence that the role matches the traditional role of an advanced practice nurse, although many of the attributes of advanced practice nursing such as prescribing rights, managing complex cases, caseloads with undifferentiated need and advanced assessment and decision‐making are certainly present. Aim: The current study aimed to develop, refine and test the Health Visiting Advanced Practice Scale to assess the scope of advanced practice of UK health visitors. Design: A cross‐sectional and methodological scale validation design, following classical test theory. Methods: The design consisted of three phases; the first involved scale development including item generation, phase two assessed the content validity index, and the third phase involved a cross‐sectional survey to establish construct validity, content validity, and internal consistency reliability, and conduct exploratory and confirmatory factor analysis. Results: The initial 44‐item scale underwent iterative exploratory and confirmatory factor analyses, leading to a refined 5‐factor structure with 29 items covering domains such as family‐centred care, leadership, prescribing, diagnostic reasoning, and professional practice. This final version demonstrated strong reliability and construct validity in the EFA but mixed fit indices in the CFA, supporting both internal consistency and validity of the scale. Conclusion: The final scale offers a rigorously validated tool for assessing advanced practice among UK health visitors, capturing core domains such as family‐centred care, leadership, prescribing, and diagnostic reasoning. By bridging theoretical frameworks with real‐world practice, it fills a critical gap in evaluating and supporting the professional scope of this public health nursing specialty. Impact: These findings provide valid and reliable insights for measuring and improving health visitors' advanced practice and developing future professional policies. Patient or Public Contribution: No patient or public contribution. Reporting Method: STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for cross‐sectional studies
Glutathione responsive iNOS inhibiting polymeric prodrug for targeted Inhibition of angiogenesis
Get PDFBackground: Inducible nitric oxide synthase (iNOS) is a key driver of aberrant angiogenesis in inflammatory conditions and cancer, making it an attractive therapeutic target. Nevertheless, its function can be affected by the complex immune responses and tumor microenvironment (TME). Hence, combinatorial treatment approaches that simultaneously target iNOS and immune-modulatory signaling are strongly recommended for cancer therapy. Moreover, the current iNOS inhibitors are limited by poor pharmacokinetics and a lack of selectivity. Results: To address these challenges, we developed a glutathione (GSH)-responsive iNOS-inhibiting polymeric prodrug (GRIP) decorated with betamethasone succinate (NPBeS). These dual-function nanoparticles (NPBeS) remain stable under physiological conditions but selectively release their payload in response to elevated GSH levels, a hallmark of the TME. Only upon activation by GSH, NPBeS inhibits iNOS, as evidenced by suppressed lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages. NPBeS also normalized vascular endothelial growth factor (VEGF)-mediated tube formation in HUVECs and 3T3-L1 fibroblast cell migration, and angiogenesis in the CAM assay, demonstrating its anti-angiogenic activity. Importantly, GRIP did not impair acetylcholine (ACh)-induced vasodilation in rat aorta, even at elevated concentrations, indicating preservation of eNOS function. Conclusions: This is the first report of a GSH-responsive polymeric prodrug system that leverages intracellular GSH for both controlled release of anionic therapeutic agents and in situ synthesis of an iNOS antagonist. Through these two complementary pathways, the system enables targeted, sustained anti-angiogenic effects and promotes vascular normalization. This dual-function platform holds strong potential for the treatment of cancer-associated angiogenesis. Graphical Abstract
hoppet v2 release note
Get PDFWe document the three main new features in the v2 release series of the hoppet parton distribution function evolution code, specifically support for N 3 LO QCD evolution in the variable flavour number scheme, for the determination of hadronic structure functions for massless quarks up to N 3 LO, and for QED evolution to an accuracy phenomenologically equivalent to NNLO QCD. Additionally we describe a new Python interface, CMake build option, functionality to save a hoppet table as an LHAPDF grid and update our performance benchmarks, including optimisations in interpolating PDF tables
Cognitive function is associated with the progression of non-tremor motor symptoms in Parkinson’s disease
Get PDFBackground: Parkinson’s disease (PD) is characterized by motor impairment which consists of tremor and non-tremor symptoms. Cognitive function may overlap with specific aspects of voluntary movement and action initiation. This study aims to investigate associations between global cognition and the severity and longitudinal progression of tremor and non-tremor motor symptoms in PD. Methods: As part of the Oxford Quantification in Parkinsonism (OxQUIP) study, 84 participants with PD were tested over seven visits at three-month intervals. At each visit, participants completed standardized global cognitive (MoCA) and motor (MDS-UPDRS-III) assessments. Tremor and non-tremor motor subscores were derived from corresponding MDS-UPDRS-III items. Linear mixed-effects models were calculated to analyze the effect of global cognition at baseline on the progression of (i) overall motor impairment, (ii) non-tremor motor symptoms, and (iii) tremor symptoms. Results: We did not find an association between MoCA scores and MDS-UPDRS-III severity, but there was a significant interaction between global cognition and the progression of motor impairment (p = 0.005). Lower MoCA scores were linked with steeper progression of non-tremor motor symptoms (p < 0.001), but not tremor symptoms (p = 0.380). Conclusion: Global cognition at baseline is associated with the progression, but not severity, of motor impairment in PD; this finding is specific to non-tremor and not tremor motor symptoms. While both motor subdomains are known to be linked with dysfunction of sub-cortical circuits, non-tremor symptoms may also be influenced by disrupted cognitive inputs. Our results highlight the potential value of incorporating cognitive tools to complement motor examination in PD assessment
On (1)−2-invariant special lagrangian -folds
Get PDFThis paper develops a construction of families of -invariant special Lagrangian -folds in , extending the analytic framework introduced by Joyce () to arbitrary dimension. By reducing the special Lagrangian condition to a quasilinear elliptic system of two-dimensional non-linear Cauchy--Riemann equations, we analyse both the resulting geometry and its degenerations at singular points. We show that the structure and multiplicity of singularities are governed by an associated polynomial arising from the symmetry reduction. Explicit examples are constructed, including affine and perturbative solutions, and are compared with the classical Harvey--Lawson -invariant submanifolds. We further show that the key elements of Joyce’s analysis in the non-singular case, in particular the potential formulation and Dirichlet problem, extend to this higher-dimensional setting, with the proofs unchanged
Consequences of the Black Sea Slave Trade: Long-Run Development in Eastern Europe
Get PDFWe investigate the developmental consequences of slave-raiding in Eastern Europe, the largest source of slaves in the early modern world after West Africa. Drawing on a wide-ranging new dataset, we estimate that at least five million people were captured from hundreds of locations across Eastern Europe between the fifteenth and eighteenth centuries. We hypothesize that, over time, raids encouraged an economically advantageous process of defensive state-building linked to raided societies’ resistance to and lack of integration into the slave trade. Using difference-in-differences and instrumental variables strategies, we find that exposure to raids is positively associated with long-run urban growth and related indicators of demographic and commercial development. Consistent with our posited mechanism, raided areas constructed more robust defensive infrastructures and attained higher levels of military, administrative, and fiscal capacity. Our findings suggest that the structure of slave production conditions its developmental legacies, cautioning against drawing generalizations from the African context
