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Bayesian chronological modelling for early pottery in the far western Pacific: evidence from the Raja Ampat Islands of West New Guinea
Get PDFThe initial dispersal routes and subsequent exchange networks of Austronesian speaking populations in Island Southeast Asia (ISEA) and Near Oceania continue to be debated. Accurate and precise chronologies on pottery assemblages are key in clarifying these population movements and dynamics. Previous scholars have suggested red-slipped pottery may be a proxy for Malayo-Polynesian speakers’ presence, and Lapita pottery may be a proxy for Proto-Oceanic speakers. Under this premise, pottery assemblages found between eastern Indonesia and the Bismarck Archipelago have the potential to inform us about the arrivals and movements of new Austronesian languages to the region and their possible connections with Lapita peoples that voyaged into the Pacific. The generally poor resolution of the archaeological and radiocarbon record from this part of the Pacific calls for more research to settle the debate. Mololo Cave is a site in the Raja Ampat Islands off the western coast of New Guinea, containing the earliest reported pottery assemblages in the area, including red-slipped and plainware Lapitoid pottery. This paper presents 11 new radiocarbon dates and Mololo’s first two Bayesian age models to increase the robusticity of the date estimates at the site and enable chronological comparisons with similar pottery assemblages from the region. Most of the pottery sherds, including both red-slipped and Lapitoid pottery, emerge after 3090 – 2258 cal BP, potentially being as early as 3903–3420 cal BP. This chronological model provides critical information about the dispersal of pottery-making groups around the far western Pacific during the initial expansion of Austronesian languages into the region
Developing Concepts for Neuroscience: A Philosophical Toolkit
Get PDFAlongside models and methods, concepts are crucial tools to study and understand the brain. They help us pursue various goals, such as describing phenomena based on patterns in the data or explaining why these phenomena occur. Yet while terms such as “action potential” or “network” guide our efforts to reach these goals, other concepts have failed to advance our understanding of the brain. In this paper, we draw on recent work from philosophy of science to show that the success or failure of concepts in neuroscience depends on the epistemic goals the field aims to achieve. Looking at cases such as “default mode network,” “cortical column,” and “hierarchy,” we formulate conditions under which introducing, refining, or replacing a concept succeeds or fails. These cases suggest that to better evaluate our concepts, we should make explicit which goals we aim to achieve when using them
Biomarkers of activity from a phase I study of cergutuzumab amunaleukin in patients with advanced solid tumors
Get PDFBackground: Cergutuzumab amunaleukin (CA) is an immunocytokine comprising an anticarcinoembryonic antigen (CEA) linked to an interleukin-2 (IL-2) variant. CA does not bind to CD25 (IL-2 receptor α) and was designed to maintain the T and natural killer (NK) cell stimulatory effect, while avoiding stimulating effects on regulatory T cells (Tregs). In mouse models, CA previously demonstrated superior tumor targeting to CEA surface expression-positive (CEA+) tumors and increased CD8+ T cells and NK cell numbers in peripheral blood and tumor tissue when compared with wild-type IL-2. We present biomarker data from the first-in-human, open-label, multicenter, phase I, dose-escalation study investigating CA in patients with metastatic/unresectable CEA+ solid tumors (NCT02004106). Methods: Patients received ascending doses of CA intravenously weekly (qw: 6/10/20 mg) or every 2 weeks (q2w: 10/20/30/40 mg). Flow cytometry determined absolute numbers/mL of CD4+ and CD8+ T cells, NK cells, macrophages/monocytes, Tregs, and B cells and their expression of activation and proliferation markers in circulation. Sequential pretreatment and on-treatment paired tumor biopsies were studied by flow cytometry, multicolor immunohistochemistry, and bulk RNA sequencing. Antitumor activity was used for correlative studies. Results: Biomarker data were collected from 55 patients. After treatment, peripheral blood samples showed increased proliferating NK cells, CD8+ T cells, and CD4+ T cells, without an apparent dose effect. Levels of circulating soluble CD25 increased in patients with intermediate/high CA doses on-treatment; levels of cytokines, such as tumor necrosis factor, also increased with high CA dose levels. On-treatment tumor samples showed increases in total and proliferating CD8+ T cells as well as CD3+ perforin+ T cells but, importantly, not in Tregs. Notably, increases in the ratio of CD8+/CD4+ T cells were more pronounced for qw than for q2w dosing, while programmed death ligand-1-positive CD14+ cells increased, particularly for the q2w schedule. Higher on-treatment circulating levels of cytokines correlated with longer progression-free survival (PFS). Apart from the positive correlation with NK cell density, no other correlations between PFS and infiltrating immune cell populations in the tumor were observed. Conclusions: CA-induced immune pharmacodynamic effects in peripheral blood and in the tumor microenvironment without preferential Treg cell activation in patients with metastatic/unresectable CEA+ solid tumors. Trial registration number: NCT02004106; BP2892
The impact of rare variation on extreme and unexpected phenotypes in the UK Biobank
Get PDFHuman disease can be characterised by deviation from a ``normal'' or healthy state. Using exome sequencing data from the UK Biobank (UKB), I examined the effect of rare coding variants on deviations from normality to better understand disease. Biomarker deviations from reference ranges are commonly used to indicate disease. For the first time, I quantified the proportion of individuals in UKB with abnormal biomarker values across 32 blood and urine biomarkers. Disease risk increased with the number of abnormal biomarkers, highlighting their clinical relevance. By contrasting traditional linear association between continuous biomarker level with dichotomised (extreme vs. non-extreme value) biomarkers, I identified associations which would not otherwise have been found, including a PNPLA3 missense variant associated with extreme serum triglyceride levels. Polygenic scores (PGS) predict complex traits and stratify disease risk but fail to fully capture individual-level variation. Misaligned individuals, whose phenotypes deviate from expectation based on PGS, allow us to identify risk factors beyond common-variant effects. I tested whether rare damaging variation in rare disorder genes can explain this deviation for ten traits: type 2 diabetes (T2D) cases carrying pathogenic variants have significantly lower PGS than non-carriers, and both coronary artery disease and T2D controls carrying protective variants have significantly higher PGS than non-carriers. Using this framework, I searched for novel protective or pathogenic genes, identifying KANK1 as a therapeutic target for primary ovarian insufficiency. Finally, I led the largest-ever systematic functional characterisation of genes associated with fat accumulation, a disease mechanism in which abnormal deviations cause obesity and lipodystrophy. I identified SLTM as a novel therapeutic target for obesity, due to its effect on earlier onset of obesity, its replication in an independent dataset (All of Us), and the significant effect of SLTM knockdown on lipid accumulation in human fat cells. Taken together, this thesis advances understanding of the impact of rare variants on extreme and unexpected phenotypic deviations, and contributes meaningful insights into the genetic aetiology of human disease
Kantian-Republicanism: toward a new theory of political authority
Get PDFStates claim to have normative powers that ordinary people, like you and me, do not. These include the powers to give others binding moral obligations and enforce those obligations with violence. Since ordinary moral agents lack these abilities, states are claiming to be exceptional. Obviously, claims to be exceptional require justification. If none can be found, then we ought to conclude that these claims are mistaken — we should all become anarchists. This would require a seismic shift in the way we see the world. Most people on earth are governed by states that claim to have these powers, and much of day-to-day life is built around institutions that take these powers for granted. Moreover, many see the obligations purportedly created by their states as partly constitutive of their national identity and sense of self. Therefore, agreeing with the anarchist is not something we should do lightly. This is the problem of political authority. In this thesis, I examine the political philosophy of Immanuel Kant in search of ideas that might help us make progress on this problem. The result of this investigation is the sketching of a new(ish) theory of authority: Kantian-Republicanism. This combines the structure of Kant’s theory with the republican apparatus of popular control. I argue that this theory is worthy of further consideration and development because it helps move the debate forward on the problem of political authority
‘I’d been Chaucer for a week!’: Forging the Medieval in Kipling’s ‘Dayspring Mishandled’
Get PDFRudyard Kipling’s ‘Dayspring Mishandled’ describes the creation of a Chaucerian forgery in immense detail. The short story, first published in 1928, revolves around two men: one, in an act of revenge, uses the other’s expertise as a Chaucerian scholar to forge a ‘new’ fragment of The Canterbury Tales with the intention of planting the fragment and ruining the scholar’s career. Much of the narrative is given over to the details of the fake, from the minutiae of a medieval ink recipe to the text’s fraudulent transmission history and ‘discovery’. In this essay I propose that Kipling’s medieval details are not authentic, but rather authenticating: they approximate the medieval rather than representing the ‘real’ medieval world as we or Kipling knew it. The essay first introduces ‘Dayspring’ and Kipling’s particular method of authenticating, while the second section investigates several aspects of the central Chaucerian forgery, including features of materiality, transmission, book history, and Middle English language as they are presented in the text. This ‘fact-checking’ approach is reassessed in the third section, which explores Kipling’s idea of ‘verified references’, as well as the relationship between ‘Dayspring’, forgery theory, and medievalism. While ‘Dayspring’ might not represent a ‘true’ Middle Ages, then, it is highly revealing of Kipling’s attitudes to the medieval period, ideas of authenticity, and his conception of himself as a writer
LiteBIRD science goals and forecasts. E -mode anomalies
Get PDFVarious so-called anomalies have been found in both the WMAP and Planck cosmic microwave background (CMB) temperature data that exert a mild tension against the highly successful best-fit 6 parameter cosmological model, potentially providing hints of new physics to be explored. That these are real features on the sky is uncontested. However, given their modest significance, whether they are indicative of true departures from the standard cosmology or simply statistical excursions due to a mildly unusual configuration of temperature anisotropies on the sky which we refer to as the “fluke hypothesis” cannot be addressed further without new information. No theoretical model of primordial perturbations has to date been constructed that can explain all of the temperature anomalies. Therefore, we focus in this paper on testing the fluke hypothesis, based on the partial correlation between the temperature and E-mode CMB polarisation signal. In particular, we compare the properties of specific statistics in polarisation, built from unconstrained realisations of the ΛCDM cosmological model as might be observed by the LiteBIRD satellite, with those determined from constrained simulations, where the part of the E-mode anisotropy correlated with temperature is constrained by observations of the latter. Specifically, we use inpainted Planck 2018 SMICA temperature data to constrain the E-mode realisations. Subsequent analysis makes use of masks defined to minimise the impact of the inpainting procedure on the E-mode map statistics. We find that statistical assessments of the E-mode data alone do not provide any evidence for or against the fluke hypothesis. However, tests based on cross-statistical measures determined from temperature and E modes can allow this hypothesis to be rejected with a moderate level of probability
Impact of leadership styles on healthcare workers in the Gulf Cooperation Council (GCC) - Scoping Review
Get PDFObjective: This dissertation presents a scoping review on the impact of leadership styles on healthcare workers within healthcare organizations across the six Gulf Cooperation Council (GCC) countries. Background: Healthcare systems in the GCC are undergoing ambitious reforms, characterized by rapid expansion, centralised governance, and a heavy reliance on expatriate healthcare workers. These dynamics create challenges of high turnover, pay inequities, and complex nationalisation policies. In this environment, leadership plays a critical role in shaping morale, resilience, and performance, yet little is known about how different leadership styles are enacted or experienced by healthcare workers in the region. Methods: Guided by the JBI methodology and PRISMA-ScR checklist, the review applied the Population–Concept–Context framework. A systematic search of four databases, including Arabic and English papers with no date restrictions, identified 51 eligible studies. Data were charted to map leadership styles, their impacts on healthcare workers, and contextual influences. Results: Transformational leadership was most frequently studied and linked mainly to positive outcomes such as job satisfaction, organisational commitment, and work engagement, though some studies showed mixed effects. Authentic, democratic, empowering, and servant leadership also demonstrated favourable impacts, often mediated by trust and empowerment. Transactional and autocratic styles had mixed effects, providing clarity and stability in high-pressure contexts but undermining morale when dominant. Laissez-faire, toxic, and dysfunctional leadership were consistently associated with dissatisfaction, burnout, and reduced loyalty. Impacts were shaped by contextual factors, including rigid hierarchies, expatriate–national dynamics, and inequities in pay and progression. Most studies came from Saudi Arabia, with a concentration on public-sector nurses, leaving physicians, other clinical and non-clinical healthcare workers, and private-sector settings underrepresented. Conclusions: The review highlights the need for context-sensitive leadership frameworks tailored to the structural and cultural realities of GCC healthcare organizations, while also identifying gaps in methodology and population diversity. It provides a foundation for future leadership development and workforce policy in the region
SANOS: smooth strictly arbitrage-free non-parametric option surfaces
Get PDFWe present a simple, numerically efficient but highly flexible non-parametric method to construct representations of option price surfaces which are both smooth and strictly arbitrage-free across time and strike. The method can be viewed as a smooth generalization of the widely-known linear interpolation scheme, and retains the simplicity and transparency of that baseline. Calibration of the model to observed market quotes is formulated as a linear program, allowing bid-ask spreads to be incorporated directly via linear penalties or inequalities, and delivering materially lower computational cost than most of the currently available implied-volatility surface fitting routines. As a further contribution, we derive an equivalent parameterization of the proposed surface in terms of strictly positive "discrete local volatility" variables. This yields, to our knowledge, the first construction of smooth, strictly arbitrage-free option price surfaces while requiring only trivial parameter constraints (positivity). We illustrate the approach using S&P 500 index options