Biology subjects

Miller, T.

Publications and source records attributed to Miller, T..

24 records · Page 2Linked to original sources

bioRxiv2021

Predicting TCR-epitope Binding Specificity Using Deep Metric Learning and Multimodal Learning

Understanding the recognition of specific epitopes by cytotoxic T cells is a central problem in immunology. Although predicting binding between peptides and the class I Major Histocompatibility Complex (MHC) has had success, predicting interactions between T cell receptors (TCRs) and MHC class I-peptide complexes (pMHC) remains elusive. This paper utilizes a convolutional neural network model employing deep metric learning and multimodal learning to perform two critical tasks in TCR-epitope binding prediction: identifying the TCRs that bind a given epitope from a TCR repertoire, and identifying the binding epitope of a given TCR from a list of candidate epitopes. Our model can perform both tasks simultaneously and reveals that inconsistent preprocessing of CDR3B sequences can confound binding prediction. Applying a neural network interpretation method identifies key amino acid sequence patterns and positions within the TCR important for binding specificity. Contrary to the common assumption, known crystal structures of TCR-pMHC complexes show that the predicted salient amino acid positions are not necessarily the closest to the epitopes, implying that physical proximity may not be a good proxy for importance in determining TCR-epitope specificity. Our work thus provides insight into the learned predictive features of TCR-epitope binding specificity and advances associated classification tasks.

bioinformatics↗

bioRxiv2019

A tree-planting decision support tool for urban heat island mitigation

Heat poses an urgent threat to public health in cities, as the urban heat island (UHI) effect can amplify exposures, contributing to high heat-related mortality and morbidity. Urban trees have the potential to mitigate by providing substantial cooling, as well as co-benefits such as reductions in energy consumption. The City of Boston has attempted to expand its urban canopy, yet maintenance costs and high tree mortality have hindered successful canopy expansion. Here, we present an interactive web application called "Right Place, Right Tree - Boston" that aims to support informed decision-making for planting new trees. To highlight priority regions for canopy expansion, we developed a Boston-specific Heat Vulnerability Index (HVI) and present this alongside maps of summer temperatures. We also provide information about tree pests and diseases, suitability of species for various conditions, land ownership, maintenance tips, and alternatives to tree planting.

scientific communication and education↗

bioRxiv2019

The ALBA RNA-binding proteins function redundantly to promote growth and flowering in Arabidopsis.

RNA-binding proteins (RBPs) are critical regulators of gene expression, but have been poorly studied relative to other classes of gene regulators. Recently, mRNA-interactome capture identified many Arabidopsis RBPs of unknown function, including a family of ALBA domain containing proteins. Arabidopsis has three short-form ALBA homologues (ALBA1-3) and three long-form ALBA homologues (ALBA4-6), both of which are conserved throughout the plant kingdom. Despite this ancient origin, ALBA-GUS translational fusions of ALBA1, ALBA2, ALBA4, and ALBA5 had indistinguishable expression patterns, all being preferentially expressed in young, rapidly dividing tissues. Likewise, all four ALBA proteins had indistinguishable ALBA-GFP subcellular localizations in roots, all being preferentially located to the cytoplasm, consistent with being mRNA-binding. Genetic analysis demonstrated redundancy within the long-form ALBA family members; in contrast to single alba mutants that all appeared wild-type, a triple alba456 mutant had slower rosette growth and a strong delay in flowering-time. RNA-sequencing found most differentially expressed genes in alba456 were related to metabolism, not development. Additionally, changes to the alba456 transcriptome were subtle, suggesting ALBA4-6 participates in a process that does not strongly affect transcriptome composition. Together, our findings demonstrate that ALBA protein function is highly redundant, and is essential for proper growth and flowering in Arabidopsis.\n\nHighlightThe RNA-binding ALBA proteins have indistinguishable expression patterns and subcellular localizations in Arabidopsis, acting redundantly to promote growth and flowering via a mechanism that does not strongly affect transcriptome composition.

plant biology↗

bioRxiv2019

BMP-signalling inhibition in Drosophila secondary cells remodels the seminal proteome, and self and rival ejaculate functions

Seminal fluid proteins (SFPs) exert potent effects on male and female fitness. Rapidly evolving and molecularly diverse, they derive from multiple male secretory cells and tissues. In Drosophila melanogaster, most SFPs are produced in the accessory glands, which are composed of [~]1000 fertility-enhancing main cells and [~]40, more functionally cryptic, secondary cells. Inhibition of BMP-signalling in secondary cells suppresses secretion, leading to a unique uncoupling of normal female post-mating responses to the ejaculate: refractoriness stimulation is impaired, but offspring production is not. Secondary cell secretions might therefore make a highly specific contribution to the seminal proteome and ejaculate function; alternatively, they might regulate more global - but hitherto-undiscovered - SFP functions and proteome composition. Here, we present data that supports the latter model. We show that in addition to previously reported phenotypes, secondary cell-specific BMP-signalling inhibition compromises sperm storage and increases female sperm use efficiency. It also impacts second male sperm, tending to slow entry into storage and delay ejection. First male paternity is enhanced, which suggests a novel constraint on ejaculate evolution whereby high female refractoriness and sperm competitiveness are mutually exclusive. Using quantitative proteomics, we reveal a mix of specific and widespread changes to the seminal proteome that surprisingly encompass alterations to main cell-derived proteins, indicating important cross-talk between classes of SFP-secreting cells. Our results demonstrate that ejaculate composition and function emerge from the integrated action of multiple secretory cell-types suggesting that modification to the cellular make-up of seminal fluid-producing tissues is an important factor in ejaculate evolution.

evolutionary biology↗

bioRxiv2019

Advection and habitat loss interactively reduce persistence: maintaining threatened riverine populations while restoring natural flow regimes

Modification of flow regimes and habitat degradation are the strongest, most common, and often co-occurring human activities affecting riverine populations. Ongoing efforts to restore peak flow events found under pristine flow regimes could increase advection-driven dispersal for many species. In rivers with extensive habitat loss, increased advection could transport individuals from remnant populations into degraded downstream areas, causing restored flow regimes to decrease persistence of threatened species. To resolve the capacity for such washout effects across imperiled taxa, we evaluate population growth in spatial matrix models of insect, fish, and mollusc taxa experiencing advective dispersal and either long-term habitat loss or temporary disturbances. As a case study to quantify advective dispersal in threatened species, we use intensive mark-recapture methods in a Rio Grande population of the federally endangered unionid mussel Texas horhshell (Popenaias popeii). Among unionids, the most threatened freshwater taxa of North America, we find high levels of annual downstream emigration (16-51%) of adult P. popeii, concomitant with strong immigration from upstream habitats. For different taxa experiencing such advective dispersal during specific life stages, our population model shows that washout effects strongly reduce population recovery under high levels of habitat loss. Averting this negative consequence of restoring hydrology requires simultaneously restoring or protecting long, contiguous stretches of suitable habitats. Across taxa in heavily impacted systems, we suggest integrating hydrodynamic studies and field surveys to detect the presence of advective dispersal and prioritize areas for habitat restoration to enhance population persistence.

ecology↗

bioRxiv2017

Positively Selected Enhancer Elements Endow Tumor Cells with MetastaticCompetence

Metastasis results from a complex set of traits acquired by tumor cells, distinct from those necessary for tumorigenesis. Here, we investigate the contribution of enhancer elements to the metastatic phenotype of osteosarcoma. Through epigenomic profiling, we identify substantial differences in enhancer activity between primary and metastatic tumors in human patients as well as nearisogenic pairs of high and low lung-metastatic osteosarcoma cells. We term these regions Metastatic Variant Enhancer Loci (Met-VELs). We demonstrate that these Met-VELs drive coordinated waves of gene expression during metastatic colonization of the lung. Met-VELs cluster non-randomly, indicating that activity of these enhancers and their associated gene targets are positively selected. As evidence of this causal association, osteosarcoma lung metastasis is inhibited by global interruptions of Met-VEL-associated gene expression via pharmacologic BET inhibition, by knockdown of AP-1 transcription factors that occupy Met-VELs, and by knockdown or functional inhibition of individual genes activated by Met-VELs, such as F3. We further show that genetic deletion of a single Met-VEL at the F3 locus blocks metastatic cell outgrowth in the lung. These findings indicate that Met-VELs and the genes they regulate play a functional role in metastasis and may be suitable targets for anti-metastatic therapies.

cancer biology↗