MLCut : exploring Multi-Level Cuts in dendrograms for biological data

Choosing a single similarity threshold for cutting dendrograms is not sufficient for performing hierarchical clustering analysis of heterogeneous data sets. In addition, alternative automated or semi-automated methods that cut dendrograms in multiple levels make assumptions about the data in hand. In an attempt to help the user to find patterns in the data and resolve ambiguities in cluster assignments, we developed MLCut: a tool that provides visual support for exploring dendrograms of heterogeneous data sets in different levels of detail. The interactive exploration of the dendrogram is coordinated with a representation of the original data, shown as parallel coordinates. The tool supports three analysis steps. Firstly, a single-height similarity threshold can be applied using a dynamic slider to identify the main clusters. Secondly, a distinctiveness threshold can be applied using a second dynamic slider to identify “weak-edges” that indicate heterogeneity within clusters. Thirdly, the user can drill-down to further explore the dendrogram structure - always in relation to the original data - and cut the branches of the tree at multiple levels. Interactive drill-down is supported using mouse events such as hovering, pointing and clicking on elements of the dendrogram. Two prototypes of this tool have been developed in collaboration with a group of biologists for analysing their own data sets. We found that enabling the users to cut the tree at multiple levels, while viewing the effect in the original data, isa promising method for clustering which could lead to scientific discoveries.Postprin

FFPred 3: feature-based function prediction for all Gene Ontology domains

Predicting protein function has been a major goal of bioinformatics for several decades, and it has gained fresh momentum thanks to recent community-wide blind tests aimed at benchmarking available tools on a genomic scale. Sequence-based predictors, especially those performing homology-based transfers, remain the most popular but increasing understanding of their limitations has stimulated the development of complementary approaches, which mostly exploit machine learning. Here we present FFPred 3, which is intended for assigning Gene Ontology terms to human protein chains, when homology with characterized proteins can provide little aid. Predictions are made by scanning the input sequences against an array of Support Vector Machines (SVMs), each examining the relationship between protein function and biophysical attributes describing secondary structure, transmembrane helices, intrinsically disordered regions, signal peptides and other motifs. This update features a larger SVM library that extends its coverage to the cellular component sub-ontology for the first time, prompted by the establishment of a dedicated evaluation category within the Critical Assessment of Functional Annotation. The effectiveness of this approach is demonstrated through benchmarking experiments, and its usefulness is illustrated by analysing the potential functional consequences of alternative splicing in human and their relationship to patterns of biological features

Understanding the genetics and function of complex human retinal phenotypes

The human retina is the tissue at the back of the eye responsible for converting light stimulus into neuronal signal that can be interpreted by the brain. To perform this integral role within the central nervous system, the retina has a complex and layered structure, with each layer performing a vital step in the signal transformation process. Changes in the morphology of this structure are often a consequence of disease, which can affect the function of the eye. Better understanding of the genetics influencing this structure may teach us about the biological processes underlying these diseases as well as general eye development. The retina is imaged routinely in the clinic using optical coherence tomography (OCT), providing a non-invasive imaging technique that produces high-resolution, three-dimensional representations of the retina from which measures describing retinal morphology can be extracted. This thesis summarises my research into the genetic variation underlying retinal morphology. Firstly, I explored the morphology of the inner retina, whose thickness is used as a biomarker of glaucoma, using quantitative phenotypes extracted from OCT. I conducted genome-wide association studies (GWAS) of the thickness of the retinal nerve fibre layer and the ganglion cell inner plexiform layer to understand the genetic variation driving inner retinal morphology. I further explored the causal relationship between the inner retina and glaucoma using Mendelian randomisation analysis. I next performed GWAS of the thickness of the outer retinal layers, including both the component photoreceptor cell layers (the outer nuclear layer, inner segment, and outer segment), and the retinal pigment epithelium layer. I explored how genetic variation was affecting the outer retinal morphology at a higher dimension by looking for genetic variants that were differentially affecting the outer retinal thickness at the central macula compared to the peripheral macula. To further explore the rich dimensionality of OCT data, I developed several image analysis techniques to gain more granular information about the morphological variation being affected by the discovered genetic variants. In doing so I established a novel population level trait and examined its effect on visual acuity. In summary, this thesis provides a well-rounded and detailed look into the genetic variation underlying morphological variation of the retinal layers. As the largest study of retinal layer genetics of its kind, it offers insight into clinical ophthalmology and retinal development, and furthermore opens new avenues for clinical research.Funding was provided via the EMBL international PhD programme

Middle and Late Pleistocene environmental history of the Marsworth area, south-central England

To elucidate the Middle and Late Pleistocene environmental history of south-central England, we report the stratigraphy, sedimentology, palaeoecology and geochronology of some deposits near the foot of the Chiltern Hills scarp at Marsworth, Buckinghamshire. The Marsworth site is important because its sedimentary sequences contain a rich record of warm stages and cold stages, and it lies close to the Anglian glacial limit. Critical to its history are the origin and age of a brown pebbly silty clay (diamicton) previously interpreted as weathered till. The deposits described infill a river channel incised into chalk bedrock. They comprise clayey, silty and gravelly sediments, many containing locally derived chalk and some with molluscan, ostracod and vertebrate remains. Most of the deposits are readily attributed to periglacial and fluvial processes, and some are dated by optically stimulated luminescence to Marine Isotope Stage (MIS) 6. Although our sedimentological data do not discriminate between a glacial or periglacial interpretation of the diamicton, amino-acid dating of three molluscan taxa from beneath it indicates that it is younger than MIS 9 and older than MIS 5e. This makes a glacial interpretation unlikely, and we interpret the diamicton as a periglacial slope deposit. The Pleistocene history reconstructed for Marsworth identifies four key elements: (1) Anglian glaciation during MIS 12 closely approached Marsworth, introducing far-travelled pebbles such as Rhaxella chert and possibly some fine sand minerals into the area. (2) Interglacial environments inferred from fluvial sediments during MIS 7 varied from fully interglacial conditions during sub-stages 7e and 7c, cool temperate conditions during sub-stage 7b or 7a, temperate conditions similar to those today in central England towards the end of the interglacial, and cool temperate conditions during sub-stage 7a. (3) Periglacial activity during MIS 6 involved thermal contraction cracking, permafrost development, fracturing of chalk bedrock, fluvial activity, slopewash, mass movement and deposition of loess and coversand. (4) Fully interglacial conditions during sub-stage 5e led to renewed fluvial activity, soil formation and acidic weathering

A consensus of playwriting theory

Call number: LD2668 .T4 1985 C87Master of Art

Imagining Compassionate Assessment

Compassionate pedagogy has grown in interest following the pandemic, which highlighted the urgency of responding to student wellbeing. However, compassionate pedagogy and particularly compassionate assessment are challenging concepts, both conceptually and practically. In this workshop we address the question of how to implement compassionate assessment by co-creating solutions and guidance together

Once upon a time: Designing a narrative-inspired curriculum for a Postgraduate Certificate in Teaching in Higher Education

Once upon a time, there was a group of old teachers (well, maybe not so old, thanks very much) whose job it was to help other people learn to teach. They had high satisfaction with their jobs (as everyone in HE seems to have nowadays) and they liked the new teachers they worked with. Most of the new teachers seemed to find the old teachers useful, and they went out into the world with good ideas about how to teach. But something was troubling the old teachers. Some of the new teachers were finding it difficult to use the reflecting pool to think about their teaching. Some of them were scared to look into the pool afraid of what they might see, while others preferred to copy how teaching was done around them and did not want to use the pool at all. The old teachers scratched their heads, and had meetings where they argued about different ideas, and eventually they had a solution: they would tell the new teachers lots of stories, about themselves and about teaching, and encourage the new teachers in turn to tell stories. They wrote a big book (well a modest Moodle book called the ‘Module Anthology’) about teaching, with a chapter devoted to each of the main aspects of teaching, and in each chapter they encouraged the new teachers to use the reflecting pool and to tell their own stories. Did they live happily ever after? We don’t know yet, but we’re starting to think that maybe they did..

How warm was Britain during the Last Interglacial? A critical review of Ipswichian (MIS 5e) palaeotemperature reconstructions

The Last Interglacial (LIG, equivalent to marine isotope stage (MIS) 5e) was a period of enhanced global warmth, with potential significance for understanding future climate warming. It has long been proposed that the LIG in Britain (the Ipswichian Interglacial) was significantly warmer than present, based on the occurrence of fossils of extant thermophilous plant and animal species intolerant of the current climate. Here, we review the evidence for palaeotemperatures that can be derived from such fossil taxa (beetles, ostracods, plant macrofossils and herpetiles) in order to assess the level of warmth that Britain experienced during the LIG. Quantified palaeotemperature reconstructions generated for eight British sequences indicate that the LIG was likely to have been warmer than the present but at only one site (Trafalgar Square) is there strong evidence for climates that were significantly warmer than those experienced curing the Holocene. Consequently, whilst there is evidence to support the idea that the thermal regime of the LIG in Britain was different from that of the Holocene this evidence is restricted to a single site. The paper concludes by discussing the thermal regime of the LIG in Britain in the context of its role as an analogue for future warming in the 21st century and beyond