The distribution of ascents of size d or more in compositions

Combinatoric

KA-Search, a method for rapid and exhaustive sequence identity search of known antibodies

Antibodies with similar amino acid sequences, especially across their complementarity-determining regions, often share properties. Finding that an antibody of interest has a similar sequence to naturally expressed antibodies in healthy or diseased repertoires is a powerful approach for the prediction of antibody properties, such as immunogenicity or antigen specificity. However, as the number of available antibody sequences is now in the billions and continuing to grow, repertoire mining for similar sequences has become increasingly computationally expensive. Existing approaches are limited by either being low-throughput, non-exhaustive, not antibody specific, or only searching against entire chain sequences. Therefore, there is a need for a specialized tool, optimized for a rapid and exhaustive search of any antibody region against all known antibodies, to better utilize the full breadth of available repertoire sequences. We introduce Known Antibody Search (KA-Search), a tool that allows for the rapid search of billions of antibody variable domains by amino acid sequence identity across either the variable domain, the complementarity-determining regions, or a user defined antibody region. We show KA-Search in operation on the ∼2.4 billion antibody sequences available in the OAS database. KA-Search can be used to find the most similar sequences from OAS within 30 minutes and a representative subset of 10 million sequences in less than 9 seconds. We give examples of how KA-Search can be used to obtain new insights about an antibody of interest. KA-Search is freely available at https://github.com/oxpig/kasearch

3D genital shape complexity in female marine mammals

Comparisons of 3D shapes have recently been applied to diverse anatomical structures using landmarking techniques. However, discerning evolutionary patterns can be challenging for structures lacking homologous landmarks. We used alpha shape analyses to quantify vaginal shape complexity in 40 marine mammal specimens including cetaceans, pinnipeds, and sirenians. We explored phylogenetic signal and the potential roles of natural and sexual selection on vaginal shape evolution. Complexity scores were consistent with qualitative observations. Cetaceans had a broad range of alpha complexities, while pinnipeds were comparatively simple and sirenians were complex. Intraspecific variation was found. Three‐dimensional surface heat maps revealed that shape complexity was driven by invaginations and protrusions of the vaginal wall. Phylogenetic signal was weak and metrics of natural selection (relative neonate size) and sexual selection (relative testes size, sexual size dimorphism, and penis morphology) did not explain vaginal complexity patterns. Additional metrics, such as penile shape complexity, may yield interesting insights into marine mammal genital coevolution. We advocate for the use of alpha shapes to discern patterns of evolution that would otherwise not be possible in 3D anatomical structures lacking homologous landmarks

“This doesn’t feel like living”: How the COVID-19 Pandemic Affected the Mental Health of Vulnerable University Students in the United Kingdom

Introduction: Concerns about student mental health have been rising globally. The COVID-19 pandemic triggered unprecedented disruption in higher education as universities were forced to close and adapt their education delivery. Understanding the impact of this on vulnerable students can inform higher education’s response to future similar events. Aims: To understand the lived experience of first year university students studying in the United Kingdom, who had a history of poor mental health and lived on a low income, we examined the inter-relatedness between mental health, financial strain, remote learning and engagement, and well-being. Methods: At the start of their first year of study, whilst the UK was in periods of lockdown, we conducted in-depth semi-structured interviews with 20 diverse first-year university students. We analyzed data using interpretative phenomenological analysis. Results: The pandemic’s impact on student mental health, engagement and learning remained pervasive and serious. Key themes conveyed how isolation triggered past mental health difficulties and a perception that the universities – and government – had forgotten about them. Students also experienced greater difficulty in navigating the liminal threshold between being a child and an adult, and having the additional worry of financial instability left students with fewer coping resources. Conclusions: To mitigate the impact of future pandemic responses, constant and effective communication is needed between faculty and students to safeguard against isolation and low motivation. Vulnerable students need guidance in coping skills to manage mental health risks when they are away from family and familiar support network

The patent and literature antibody database (PLAbDab): an evolving reference set of functionally diverse, literature-annotated antibody sequences and structures

Antibodies are key proteins of the adaptive immune system, and there exists a large body of academic literature and patents dedicated to their study and concomitant conversion into therapeutics, diagnostics, or reagents. These documents often contain extensive functional characterisations of the sets of antibodies they describe. However, leveraging these heterogeneous reports, for example to offer insights into the properties of query antibodies of interest, is currently challenging as there is no central repository through which this wide corpus can be mined by sequence or structure. Here, we present PLAbDab (the Patent and Literature Antibody Database), a self-updating repository containing over 150,000 paired antibody sequences and 3D structural models, of which over 65,000 are unique. We describe the methods used to extract, filter, pair, and model the antibodies in PLAbDab, and showcase how PLAbDab can be searched by sequence, structure, or keyword. PLAbDab uses include annotating query antibodies with potential antigen information from similar entries, analysing structural models of existing antibodies to identify modifications that could improve their properties, and facilitating the compilation of bespoke datasets of antibody sequences/structures that bind to a specific antigen. PLAbDab is freely available via Github (https://github.com/oxpig/PLAbDab) and as a searchable webserver (https://opig.stats.ox.ac.uk/webapps/plabdab/)

Molecular determinants and intracellular targets of taurine signalling in pancreatic islet β‐cells

AbstractAimDespite its abundance in pancreatic islets of Langerhans and proven antihyperglycemic effects, the impact of the essential amino acid, taurine, on islet β‐cell biology has not yet received due consideration, which prompted the current studies exploring the molecular selectivity of taurine import into β‐cells and its acute and chronic intracellular interactions.MethodsThe molecular aspects of taurine transport were probed by exposing the clonal pancreatic BRIN BD11 β‐cells and primary mouse and human islets to a range of the homologs of the amino acid (assayed at 2–20 mM), using the hormone release and imaging of intracellular signals as surrogate read‐outs. Known secretagogues were employed to profile the interaction of taurine with acute and chronic intracellular signals.ResultsTaurine transporter TauT was expressed in the islet β‐cells, with the transport of taurine and homologs having a weak sulfonate specificity but significant sensitivity to the molecular weight of the transporter. Taurine, hypotaurine, homotaurine, and β‐alanine enhanced insulin secretion in a glucose‐dependent manner, an action potentiated by cytosolic Ca2+ and cAMP. Acute and chronic β‐cell insulinotropic effects of taurine were highly sensitive to co‐agonism with GLP‐1, forskolin, tolbutamide, and membrane depolarization, with an unanticipated indifference to the activation of PKC and CCK8 receptors. Pre‐culturing with GLP‐1 or KATP channel inhibitors sensitized or, respectively, desensitized β‐cells to the acute taurine stimulus.ConclusionTogether, these data demonstrate the pathways whereby taurine exhibits a range of beneficial effects on insulin secretion and β‐cell function, consistent with the antidiabetic potential of its dietary low‐dose supplementation

The dispersion time of random walks on finite graphs

We study two random processes on an $n$-vertex graph inspired by the internal diffusion limited aggregation (IDLA) model. In both processes $n$ particles start from an arbitrary but fixed origin. Each particle performs a simple random walk until first encountering an unoccupied vertex, and at which point the vertex becomes occupied and the random walk terminates. In one of the processes, called $\textit{Sequential-IDLA}$, only one particle moves until settling and only then does the next particle start whereas in the second process, called $\textit{Parallel-IDLA}$, all unsettled particles move simultaneously. Our main goal is to analyze the so-called dispersion time of these processes, which is the maximum number of steps performed by any of the $n$ particles. In order to compare the two processes, we develop a coupling that shows the dispersion time of the Parallel-IDLA stochastically dominates that of the Sequential-IDLA; however, the total number of steps performed by all particles has the same distribution in both processes. This coupling also gives us that dispersion time of Parallel-IDLA is bounded in expectation by dispersion time of the Sequential-IDLA up to a multiplicative $\log n$ factor. Moreover, we derive asymptotic upper and lower bound on the dispersion time for several graph classes, such as cliques, cycles, binary trees, $d$-dimensional grids, hypercubes and expanders. Most of our bounds are tight up to a multiplicative constant.ERC Grant Dynamic Marc