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Sources of error in uncovering of the low level mitochondrial heteroplasmy landscape
No full textAs organelles descendant from an ancient endosymbiont, mitochondria retain their own short circular genomes, with multiple copies of the mitochondrial DNA (mtDNA) distributed through the mitochondrial network within a cell. The multi-copy nature of the mitochondrial genome enables variant mtDNA copies to coexist within the same cell or organism. This well documented phenomenon, known as heteroplasmy, is a key feature of mitochondrial genetics that distinguishes mtDNA from its nuclear counterpart, and requires careful application of population genetics principles to the study of mitochondrial genetics.Presence of multiple mitochondrial genome copies in a cell may allow deleterious variants to emerge at sub-phenotypic frequencies, with their dynamics governed by the principles of by mutation, selection and genetic drift. Unlike the nuclear genome, mitochondrial DNA is also subject to bottlenecks during cell division capable of altering heteroplasmic allele balance in the descendant cell populations.A sub-threshold heteroplasmy landscape could exist within an organism, reflecting the balance between the opposing forces of new variant introduction via DNA damage or replication errors on one side, and the maintenance of the genome integrity through repair and quality control mechanics on the other side, with the patterns of such a landscape being be a direct reflection of the equilibrium dynamics. This thesis aims to assess whether such a low level mitochondrial heteroplasmy landscape can be observed and described in the human population using large scale, publicly available whole genome sequence datasets.Sequencing errors present a challenge for studying very low frequency heteroplasmic variants, with false positives resulting from systematic context-dependent sequencing errors (CSEs) being especially problematic for any investigation into heteroplasmy dependence on sequence context. We address this by systematically measuring CSE levels in our dataset, reporting CSE rates associated with up to 8bp long sequence motifs. The patterns of sequencing error rate variability between samples and between motifs are assessed in a first-of-its-kind systematic analysis of population-level CSE dynamics. Applying our insights in CSEs to mitochondrial heteroplasmy analyses, we propose an additional sequence data clean-up step intended to exclude sequence reads most likely to result from CSEs. Application of the additional data clean-up step results in a demonstrable decrease in the measured minor allele frequency estimates of the detected heteroplasmies. This suggests a possible benefit for applications such as low-level heteroplasmy quantification.This thesis aims to provides a framework for systematic CSE variability analysis on a population scale and describes a possible strategy for mitigation of CSE-induced false positive risks in low frequency variant discovery, that can be applicable in mitochondrial or other genetic system. The proposed strategy in itself does not however mitigate against other artefacts besides CSEs, and is intended to supplement other data quality control steps
Emigration, democratic norms, and the political economy of democracies in Central and Eastern Europe
Full text linkStarting in 2004, the accession of eleven Central and Eastern European countries to the European Union led to a new major wave of emigration on the continent. This thesis examines the impact of this wave of emigration on politics in countries of origin. It focuses on the effects of emigration on attitudes and behaviour in countries of origin – primarily support for democracy, political participation, and preferences for redistribution – and investigates the ultimate impact of these effects on political dynamics in the region. Previous evidence from other regions of the world suggested that emigration may have led to a process of democratic diffusion through political remittances by increasing support for democratic principles and participation, and may have led to a decline in demand for redistribution and constrained the development of welfare states through the impact of financial remittances. However, I show that these mechanisms do not adequately describe the political impact of emigration in Central and Eastern Europe. Through the constituent papers of this thesis, I ask three main questions: (1) What is the extent of democratic diffusion through political remittances in the region? (2) How has emigration affected support for redistribution among people living in origin countries? and (3) Do left-wing governments increase public spending in the region relative to other cabinets? – with the third question aimed at establishing the mechanisms that may connect changes in preferences driven by emigration to policy changes at an aggregate level. I find that emigration has only led to a very limited degree of democratic diffusion through political remittances in the region, driving an increase in non-electoral participation but also a decrease in electoral turnout among returnees, while leaving support for democracy and political interest largely unchanged. I show that emigration has led to higher demand for redistribution among people living in areas that experienced significant outflows, an effect concentrated among high earners and explained as the result of local consequences of emigration increasing expected returns from redistribution. Finally, I provide evidence that partisan spending effects persist in the region, with left-wing governments increasing public spending conditional on high levels of economic growth. On the whole, emigration has exacerbated existing vulnerabilities in the region’s democracies, which may have fuelled anti-establishment sentiment and the rise of the populist radical right. However, my findings also highlight that origin countries in the region have the potential to adapt to some of the challenges posed by emigration
Additive Structure in Convex Sets
Full text linkThis paper considers some different measures for how additively structured a convex set can be. The main result gives a construction of a convex set A containing Ω(|A|3/2) three-term arithmetic progressions
NanoBondy Reaction through NeissLock Anhydride Allows Covalent Immune Cell Decoration
Full text linkCell-surface conjugation has enormous therapeutic and research potential. Existing technologies for cell-surface modification are usually reversible, nonspecific, or rely on genetic editing of target cells. Here, we present the NanoBondy, a nanobody modified for covalent ligation to an unmodified protein target at the cell surface. The NanoBondy utilizes the 20 naturally occurring amino acids, harnessing NeissLock chemistry engineered from Neisseria meningitidis. We evaluated the binding and specificity of a panel of nanobodies to CD45, a long-lived surface marker of nucleated hematopoietic cells. We demonstrated the conversion of existing nanobodies to covalently reacting NanoBondies using a disulfide clamp to position the self-processing module of FrpA close to the nanobody antigen-binding site. The addition of calcium induces anhydride formation at the NanoBondy C-terminus, enabling proximity-directed ligation to surface amines on CD45. We optimized the NanoBondy reaction by fine-tuning linkers and disulfide clamp sites to modulate anhydride positioning. Tandem mass spectrometry mapped reaction sites between NanoBondy and CD45. NanoBondy ligation was robust to buffer, pH, and temperature and was detected within 2 minutes. We established the reaction specificity of NanoBondies to endogenous CD45 at the surface of NK cells and T cells. NanoBondy technology provides a modular approach for targeted, inducible, and covalent cell-surface modification of immune cells without their genetic modification
First-in-human phase 1 dose-escalation study of W0180, an anti-VISTA monoclonal antibody, with and without pembrolizumab in patients with locally advanced or metastatic solid tumours
Full text linkObjective: W0180 is a humanised IgG1κ antagonistic monoclonal antibody against the V domain-containing immunoglobulin suppressor of T-cell activation (VISTA) designed to enhance antitumour activities by inhibiting the immunosuppressive role of VISTA in myeloid cells and T cells in solid tumours. Methods and analysis: Preclinical experiments evaluated the pharmacodynamics and antitumour activity of W0180. A first-in-human phase 1 dose-escalation study investigated the maximum tolerated dose (MTD), safety/tolerability, preliminary efficacy, pharmacokinetics and pharmacodynamics of W0180, both as monotherapy and in combination with pembrolizumab (an anti-programmed cell death protein-1 (PD-1) therapy), with the aim of establishing a recommended dose for expansion (RDE). In the monotherapy arm, cohorts of patients with locally advanced/metastatic solid tumours received once-weekly W0180 at increasing doses (from 3.5 to 600 mg). In the combination therapy arm, patients with relapsed/refractory, advanced/metastatic solid tumours and ≥1 prior anti-PD (ligand)-1 therapy line received W0180 (60 or 300 mg)+pembrolizumab. Results: W0180 exhibited pH-independent blockade of the VISTA-ligand interaction in vitro and showed antitumour activity in a syngeneic preclinical murine model expressing human VISTA. In the phase 1 study, of the 33 patients in the monotherapy (n=24) or combination therapy (n=9) arms, 28 contributed to dose determination. Dose-limiting toxicities were Grade 2 cerebral infarction and Grade 3 infusion-related reaction (IRR; n=1 each). The study was terminated prematurely in the dose-escalation phase (due to a business decision by the sponsor) before the MTD/RDE was reached. Common related treatment-emergent adverse events were IRR and fatigue; most were of mild severity. No patients achieved Response Evaluation Criteria in Solid Tumours objective response; two had prolonged stable disease (SD; one from each arm). Biomarker analysis suggested a dose-dependent pharmacodynamic effect of W0180. Conclusion: W0180 demonstrated manageable safety, preliminary signs of clinical activity with prolonged SD and dose-dependent pharmacodynamics consistent with preclinical data (even though MTD was not reached) in patients with locally advanced/metastatic tumours, both as monotherapy and in combination with anti-programmed cell death protein-1 therapy. Trial registration number: NCT04564417
Temperature and sex ratios at birth
Full text linkHuman sex ratios at birth (SRBs) shape population composition and are closely linked to maternal health and gender discrimination. In the context of environmental change, SRBs may theoretically be skewed by physiological or behavioral responses to exposure to extreme heat. However, evidence for this is limited. In this study, we estimate the effect of prenatal exposure to temperature on birth sex by linking survey data on 5 million live births in 33 sub-Saharan African countries and India with high-resolution temperature data. To distinguish between spontaneous and induced abortions, we exploit sociodemographic differentials, exposure timing, and regional differences in son preference. We find that days with a maximum temperature above 20 °C are negatively associated with male births in both regions. In sub-Saharan Africa, we observe fewer male births after high first-trimester temperature exposure, consistent with increased spontaneous abortions from maternal heat stress. This is particularly true for births by mothers in rural areas, with little formal education, and for higher birth orders. By contrast, in India, we find that second-trimester temperature exposure is associated with fewer male births, consistent with reductions in induced sex-selective abortions. As expected, these reductions are concentrated in high birth orders and older mothers. We also find large reductions in male births by sonless mothers in northern Indian states, where son preference is greater. These findings demonstrate that heat exposure harms maternal health, increases prenatal mortality, and influences family planning behavior, leading to a complex effect on SRBs
Evaluation of evolocumab on saphenous vein graft patency following coronary artery bypass graft surgery in people living with and without diabetes in the NEWTON ‐ CABG CardioLink ‐5 trial
Full text linkAIM review tool: artificial intelligence for smarter systematic review screening
Full text linkIn this study, we present the AIM Review Tool, a modern web-based application that integrates active and supervised machine learning to accelerate the screening of publications for systematic reviews. AIM Review combines advanced text vectorization methods with machine learning models executed directly in the web browser, enabling rapid and privacy-preserving analysis. Unlike existing tools, AIM Review uniquely incorporates nested cross-validation and semi-automated screening strategies, enhancing both efficiency and precision in evidence synthesis. Using six real-world case studies across various topics, we demonstrate substantial workload reductions through active learning, with the percentage of publications not requiring screening while achieving ≥95% recall (WSS95%) ranging from 20% to 95%. Supervised learning pipelines trained on a subset of screened records predicted the relevance of unscreened publications with balanced accuracies between 75% and 87%. AIM Review provides a flexible, scalable, and accessible solution for large-scale literature screening and can be readily integrated into existing manual workflows
Effects of print exposure on formulaic language and predictive processing of English
Full text linkCompared to speech, writing offers more complex vocabulary and grammar. Consequently, reading provides essential exposure to "book language" which influences language processing. An Author Recognition Test (ART) is often used to measure first language (L1) print exposure, but may not be as reliable or valid in second language (L2) populations. This thesis explores an alternative method, the Author Fluency Task (AFT), where respondents name as many authors as possible in three minutes. Initial results from a pilot study comparing the two print exposure measures in a sample of L1 speakers showed AFT correlated best with reading habits surveys. Participants were also tested using a novel lexical decision task which used low-prevalence keywords of literary fiction from a large corpus of books. Here, a combined measure of ART and AFT improved models of accuracy scores compared to either measure alone, suggesting the two measures assess print exposure through different facets of memory. Subsequent chapters investigated the use of AFT for measuring L2 English print exposure, focusing on formulaic language. AFT outperformed ART in L1 French / L2 English speakers in models predicting accuracy scores for both discourse connectives and collocations. In comparison, ART was a better predictor for L1 English speakers. An attempted replication in an L1 Korean / L2 English sample showed AFT and ART were virtually identically correlated with both vocabulary scores. In a final study using a novel visual world paradigm, eye-tracking data revealed that print exposure correlated with predictive processing of L2 idioms during speech comprehension. Overall, AFT is a more effective measure of print exposure in certain L2 populations and is equivalent to ART in others. This research emphasises the importance of reading for pleasure for second language acquisition, and provides support for usage-based frameworks