Biology subjects

Taylor, C.

Publications and source records attributed to Taylor, C..

34 records · Page 2Linked to original sources

bioRxiv2023

Investigating a Gulf Stream Frontal Eddy North of Cape Hatteras: Questioning Overall Impacts on Ecology

Ocean physics and biology can interact in myriad and complex ways. Eddies, features found at many scales in the ocean, can drive substantial changes in physical and biogeochemical fields with major implications for marine ecosystems. Mesoscale eddies are challenging to model and difficult to observe synoptically at sea due to their fine-scale variability yet broad extent. In this work we observed a frontal eddy just north of Cape Hatteras via an intensive hydrographic, biogeochemical, and optical sampling campaign. Frontal eddies occur in western boundary currents around the globe and there are major gaps in our understanding of their ecosystem impacts. In the Gulf Stream, frontal eddies have been studied in the South Atlantic Bight, where they are generally assumed to shear apart passing Cape Hatteras. However, we found that the observed frontal eddy had different physical properties and phytoplankton community composition from adjacent water masses, in addition to continued cyclonic rotation. In this work we first synthesize the overall ecological impacts of frontal eddies in a simple conceptual model. This conceptual model led to the hypothesis that frontal eddies could be well timed to supply zooplankton to secondary consumers off Cape Hatteras where there is a notably high concentration and diversity of top predators. Towards testing this hypothesis and our conceptual model we report on the biogeochemical state of this particular eddy connecting physical and biological dynamics, analyze how it differs from Gulf Stream and shelf waters even in "death", and refine our initial model with this new data. Key PointsO_LIIn-depth investigation of a frontal eddy in the Gulf Stream off Cape Hatteras, North Carolina C_LIO_LIContinued physical and biogeochemical differences are observed between the eddy and adjacent water masses even as it begins to shear apart C_LIO_LIWe share a conceptual model of the ecological impact of frontal eddies with a hypothesis that they supply zooplankton to secondary consumers C_LI Plain Language SummaryFrontal eddies are spinning masses of water (~30km in diameter) that move along western boundary currents like the Gulf Stream. When they form they carry productive coastal water into the Gulf Stream and drive upwelling within their cores. Together this leads to an increase in the amount of phytoplankton within them - much higher compared to surrounding nutrient-limited Gulf Stream water. On the east coast of the United States one common area of frontal eddy formation is just off Charleston, SC. Eddies then travel up the coast and dissipate near Cape Hatteras, NC. In this work we measured a wide range of physical and biological properties of a frontal eddy just north of Cape Hatteras. We compared these properties within the eddy to the coastal water on one side and the Gulf Stream water on the other, finding clear differences in phytoplankton community composition and other physical and chemical properties. Using the results of these observations together with previous studies we share a simple model for how frontal eddies may impact phytoplankton, zooplankton, and fish - hypothesizing that they may contribute to the high diversity and density of top predators off Cape Hatteras.

ecology↗

bioRxiv2023

Deep sequencing of the T cell Receptor reveals common and reproducible CD8+ signatures of response to checkpoint immunotherapy

Immune checkpoint blockade (ICB) has markedly improved outcomes across a range of tumours, including metastatic melanoma (MM). However, peripheral biomarkers of response remain lacking and underlying mechanisms of action incompletely described. A number of studies have demonstrated the value of T cell receptor (TCR) repertoire analysis in determining associations with response, however identifying key groups of T cells based on their TCR usage has remained elusive. Here we performed deep sequencing of the TCR of CD8+ T cells isolated from peripheral blood of patients receiving ICB for MM (n=91) at multiple time points, along with healthy control samples (n=42) and resected tumour specimens (from n=7 patients). Using the GLIPH2 algorithm to cluster TCR based on putative shared antigen specificity, we describe groups of TCR which expand post-ICB in responding patients which we term Emergent Responder (ER) clones. We find that these ER clones are typically large and of a memory phenotype, with increased expression of genes encoding cytotoxic proteins. Analysis of tumours resected in advance of ICB demonstrates ER clones are enriched and expanded within the tumour compared to the periphery at pre-treatment. Significantly, we note the proportion of the peripheral repertoire occupied by ER clones strongly correlates with long-term clinical response. Clinical outcome further associated with HLA type and, crucially, can be validated across replication and independent datasets. This work provides the first-in-kind description of TCR-defined CD8+ T cells that mediate the response to ICB in MM, demonstrating the prognostic utility of the peripheral immune repertoire with potential widespread therapeutic and prognostic applications.

immunology↗

bioRxiv2023

OH 89: A newly described ~1.8-million-year-old hominid clavicle from Olduvai Gorge

ObjectivesHere, we describe the morphology and geologic context of OH 89, a [~]1.8million-year-old partial hominid clavicle from Olduvai (Oldupai) Gorge, Tanzania. We compare the morphology and clavicular curvature of OH 89 to modern humans, extant apes, and a sample of other hominid fossil clavicles. Materials and MethodsComparative samples include 25 modern human clavicles, 30 Gorilla, 31 Pan, 7 Papio, and five hominid clavicles. Length regression on midshaft size using the extant comparative samples is used to estimate the total length of OH 89. A set of 9 linear measurements are taken from each individual. We also describe a new methodology for measuring clavicular curvature using measurements of sternal and acromial curvature, from which an overall curvature measurement is calculated. A principal component analysis (PCA) and a t-distributed stochastic neighbor embedding (tSNE) analysis are used to compare the morphology of OH 89 with the extant and fossil comparative samples. ResultsOur new method of measuring clavicular curvature successfully separates the different genera of the extant clavicles. The length estimate and sternal and acromial curve measurements for OH 89 falls within the larger male humans. The PCA shows OH 89 and most of the fossil hominids falling between the modern human and Pan groups, while the t-SNE suggests that OH 89, KSD-VP-1/1, KNM-ER 1808, and OH 48 are more similar to each other than to any of the other groups. This analysis also plots KNM-WT 15000 with the modern humans and Krapina 158 with the Pan individuals. DiscussionThe OH 89 clavicle derives from an individual of unknown hominid species with a shoulder breadth similar to that of a large human male. The curvature of OH 89 is relatively human-like relative to its length. Our new methodology for measuring clavicular curvature, combined with the utilization of t-SNE analyses and comparison of t-SNE results to PCA results, provides greater separation of genera than previously used methods, and wider use of t-SNE may be useful in paleoanthropological work.

evolutionary biology↗

bioRxiv2023

A new mouse model of ATR-X syndrome carrying a common patient mutation exhibits neurological and morphological defects

ATRX is a chromatin remodelling ATPase that is involved in transcriptional regulation, DNA damage repair and heterochromatin maintenance. It has been widely studied for its role in ALT-positive cancers, but its role in neurological function remains elusive. Hypomorphic mutations in the X-linked ATRX gene cause a rare form of intellectual disability combined with alpha-thalassemia called ATR-X syndrome in hemizygous males. Patients also have facial dysmorphism, microcephaly, musculoskeletal defects and genital abnormalities. Since complete deletion of ATRX in mice results in early embryonic lethality, the field has largely relied on conditional knockout models to assess the role of ATRX in multiple tissues. Given that null alleles are not found in patients, a more patient-relevant model was needed. Here, we have produced and characterised the first patient mutation knock-in model of ATR-X syndrome, carrying the most common patient mutation, R246C. This is one of a cluster of missense mutations located in the chromatin interaction domain that disrupts its function. The knock-in mice recapitulate several aspects of the patient disorder, including craniofacial defects, microcephaly and impaired neurological function. They provide a powerful model for understanding the molecular mechanisms underlying ATR-X syndrome and for testing potential therapeutic strategies.

neuroscience↗

bioRxiv2022

Striatal dopamine synthesis and cognitive flexibility differ between hormonal contraceptive users and non-users

In rodents and nonhuman primates, sex hormones are powerful modulators of dopamine neurotransmission. Yet little is known about hormonal regulation of the dopamine system in the human brain. Using Positron Emission Tomography (PET), we address this gap by comparing hormonal contraceptive users and non-users across multiple aspects of dopamine function: dopamine synthesis capacity via the PET radioligand 6-[18F]fluoro-m-tyrosine ([18F]FMT), baseline D2/3 receptor binding potential using [11C]raclopride, and dopamine release using methylphenidate-paired [11C]raclopride. Participants consisted of 36 healthy women (n=21 naturally cycling; n=15 hormonal contraceptive users), and men (n=20) as a comparison group. A behavioral index of cognitive flexibility was assessed prior to PET imaging. Hormonal contraceptive users exhibited greater dopamine synthesis capacity than naturally cycling participants, particularly in dorsal caudate, and greater cognitive flexibility. Further, across individuals the magnitude of striatal DA synthesis capacity was associated with cognitive flexibility. No group differences were observed in D2/3 receptor binding or dopamine release. Analyses by sex alone may obscure underlying differences in DA synthesis tied to womens hormone status. Hormonal contraception (in the form of pill, shot, implant, ring or IUD) is used by ~400 million women worldwide, yet few studies have examined whether chronic hormonal manipulations impact basic properties of the dopamine system. Findings from this study begin to address this critical gap in womens health.

neuroscience↗

bioRxiv2022

Structural conservation of MALAT1 long non-coding RNA in cells and in evolution

Although not canonically polyadenylated, the long non-coding RNA MALAT1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) is stabilized by a highly conserved 159 nucleotide triple helix structure on its 3 end. The entire MALAT1 transcript is over 8,000 nucleotides long in humans and is considered one of the most conserved lncRNAs, at both the sequence and structure levels. The strongest structural conservation signal (as measured by co-variation of base-pairs) is in the triple helix structure. Primary sequence analysis of co-variation alone cannot confirm the degree of structural conservation of the entire full-length transcript. Furthermore, RNA structure is often context dependent; RNA binding proteins that are differentially expressed in different cell types may alter structure. We investigate here the in cell and cell free structures of the full-length human and green monkey (Chlorocebus sabaeus) MALAT1 transcripts in multiple tissue-derived cell lines using SHAPE chemical probing. Our data reveals surprising levels of uniform structural conservation in different cell lines, in cells and cell free, and even between species, despite significant differences in primary sequence. The uniformity of the structural conservation across the entire transcript suggests that, despite seeing co-variation signals only in the three-helix junction of the lncRNA, the rest of the transcripts structure is remarkably conserved at least in primates and across multiple cell types and conditions.

molecular biology↗

bioRxiv2022

Dopamine Activates Astrocytes in Prefrontal Cortex via α1-Adrenergic Receptors

The prefrontal cortex (PFC) is a hub for cognitive control, and dopamine profoundly influences its functions. In other brain regions, astrocytes sense diverse neurotransmitters and neuromodulators and, in turn, orchestrate regulation of neuroactive substances. However, basic physiology of PFC astrocytes, including which neuromodulatory signals they respond to and how they contribute to PFC function, is lacking. Here, we characterize divergent signaling signatures in astrocytes of PFC and primary sensory cortex in mice, which are linked to differential responsivity to locomotion. We find that PFC astrocytes express receptors for dopamine, but are unresponsive through the Gs/Gi-cAMP pathway. Instead, fast calcium signals in PFC astrocytes are time-locked to dopamine release, and are mediated by 1-adrenergic receptors both ex vivo and in vivo. Further, we describe dopamine-triggered regulation of extracellular ATP at PFC astrocyte territories. Thus, we identify astrocytes as active players in dopaminergic signaling in PFC, contributing to PFC function though neuromodulator receptor crosstalk. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/500710v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@e71858org.highwire.dtl.DTLVardef@1ef506forg.highwire.dtl.DTLVardef@89e4edorg.highwire.dtl.DTLVardef@11483e1_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

High-resolution Spatiotemporal Changes in Dominant Frequency and Structural Organization During Persistent Atrial Fibrillation

ObjectiveAnalyze changes in frequency activity and structural organization that occur over time with persistent atrial fibrillation (AF) BackgroundLittle is known about the frequency characteristics of the epicardium during transition from paroxysmal to persistent AF. Accurate identification of areas of high dominant frequency (DF) is often hampered by limited spatial resolution. Improvements in electrode arrays provide high spatiotemporal resolution, allowing for characterization of the changes that occur during this transition. MethodsAF was induced in adult Yorkshire swine by atrial tachypacing. DF mapping was performed using personalized mapping arrays. Histological analysis and late gadolinium enhanced magnetic resonance imaging were performed to determine structural differences in fibrosis. ResultsThe left atrial epicardium was associated with a significant increase in DF in persistent AF (6.5 {+/-} 0.2 vs. 7.4 {+/-} 0.5 Hz, P = 0.03). The organization index (OI) significantly decreased during persistent AF in both the left atria (0.3 {+/-} 0.03 vs. 0.2 {+/-} 0.03, P = 0.01) and right atria (0.33 {+/-} 0.04 vs. 0.23 {+/-} 0.02, P = 0.02). MRI analysis demonstrated increased ECV values in persistent AF (0.19 vs 0.34, paroxysmal vs persistent, P = 0.05). Tissue sections from the atria showed increase in fibrosis in pigs with persistent AF compared to paroxysmal AF. Staining demonstrated decreased myocardial fiber alignment and loss of anisotropy in persistent AF tissue. ConclusionsChanges in tissue organization and fibrosis are observed in the porcine model of persistent AF. Alterations in frequency activity and organization index can be captured with high resolution using flexible electrode arrays.

physiology↗

bioRxiv2022

Unique features of the gut microbiome characterized in animal models of Angelman Syndrome

A large subset of patients with Angelman syndrome (AS) suffer from concurrent gastrointestinal (GI) issues, including constipation, poor feeding, and reflux. AS is caused by the loss of ubiquitin ligase E3A (UBE3A) gene expression in the brain. Clinical features of AS, which include developmental delays, intellectual disability, microcephaly, and seizures, are primarily due to the deficient expression or function of the maternally inherited UBE3A allele. The association between neurodevelopmental delay and GI disorders is part of the increasing evidence suggesting a link between the brain and the gut microbiome via the microbiota-gut-brain (MGB) axis. To investigate the associations between colonization of the gut microbiota in AS, we characterized the fecal microbiome in three animal models of AS containing maternal deletions of Ube3A, including mouse, rat, and pig, using 16S ribosomal RNA amplicon sequencing. Overall changes in the microbial composition of all three animal models of AS in both the phylum and genus levels of bacterial abundance were identified. Specific bacterial groups were significantly increased across all animal models, including: Lachnospiraceae Incertae sedis, Desulfovibrios sp., and Odoribacter, which have been correlated with neuropsychiatric disorders. Taken together, these findings suggest that specific changes to the local environment in the gut are driven by a Ube3a maternal deletion, unaffected by varying housing conditions and are prominent and detectable across multiple small and large model species. These findings may begin to uncover the underlying mechanistic causes of GI disorders in AS patients and provide future therapeutic options for AS patients. IMPORTANCEAngelman syndrome (AS) associated gastrointestinal (GI) symptoms significantly impact quality of life in patients. Using AS models in mouse, rat, and pig, AS animals showed impaired colonization of the gut microbiota compared to wild type (healthy) control animals. Unique changes in AS microbiomes across all three animal models may be important in causing GI symptoms and may help to identify ways to treat these comorbidities in patients in the future.

microbiology↗

bioRxiv2021

Hippocampal disinhibition reduces contextual and elemental fear conditioning while sparing the acquisition of latent inhibition

Hippocampal neural disinhibition, i.e. reduced GABAergic inhibition, is a key feature of schizophrenia pathophysiology. The hippocampus is an important part of the neural circuitry that controls fear conditioning and can also modulate prefrontal and striatal mechanisms, including dopamine signalling, which play a role in salience modulation. Therefore, hippocampal neural disinhibition may contribute to impairments in fear conditioning and salience modulation reported in schizophrenia. To test this hypothesis, we examined the effect of ventral hippocampus (VH) disinhibition in male rats on fear conditioning and salience modulation, as reflected by latent inhibition (LI), in a conditioned emotional response procedure (CER). A flashing light was used as the conditioned stimulus (CS) and conditioned suppression was used to index conditioned fear. In Experiment 1, VH disinhibition via infusion of the GABA-A receptor antagonist picrotoxin prior to CS pre-exposure and conditioning markedly reduced fear conditioning to both the CS and context; LI was evident in saline-infused controls, but could not be detected in picrotoxin-infused rats due to the low level of fear conditioning to the CS. In Experiment 2, VH picrotoxin infusions prior to CS pre-exposure only did not affect the acquisition of fear conditioning or LI. Together, these findings indicate that VH neural disinhibition disrupts contextual and elemental fear conditioning, without affecting the acquisition of LI. The disruption of fear conditioning resembles aversive conditioning deficits reported in schizophrenia and may reflect disruption of neural processing within the hippocampus and its projection sites. Significance StatementHippocampal disinhibition, reduced GABAergic inhibition, is a feature of schizophrenia, but how this contributes to psychological deficits remains to be clarified. Here, we focused on impairments patients show on classical-conditioning assays: aberrant salience allocation to stimuli that healthy participants have learnt to ignore and reduced fear conditioning, which have been linked to psychosis and negative symptoms, respectively. These impairments may be related to hippocampal disinhibition because the hippocampus modulates neural substrates of salience allocation and is part of the fear-conditioning neural circuit. Combining selective pharmacological manipulation of the hippocampus with a conditioning assay in rats, we found hippocampal disinhibition disrupted fear conditioning, without evidence for aberrant salience allocation. This suggests hippocampal disinhibition contributes to fear conditioning deficits in schizophrenia.

neuroscience↗

bioRxiv2021

Birdsong Phrase Verification and Classification Using Siamese Neural Networks

The process of learning good features to discriminate among numerous and different bird phrases is computationally expensive. Moreover, it might be impossible to achieve acceptable performance in cases where training data is scarce and classes are unbalanced. To address this issue, we propose a few-shot learning task in which an algorithm must make predictions given only a few instances of each class. We compared the performance of different Siamese Neural Networks at metric learning over the set of Cassinis Vireo syllables. Then, the network features were reused for the few-shot classification task. With this approach we overcame the limitations of data scarcity and class imbalance while achieving state-of-the-art performance.

bioinformatics↗

bioRxiv2020

Enhancing c-MYC degradation via 20S proteasome activation induces in vivo anti-tumor efficacy

Enhancing proteasome activity is a potential new therapeutic strategy to prevent the accumulation of aberrant high levels of protein that drive the pathogenesis of many diseases. Herein, we examine the use of small molecules to activate the 20S proteasome to reduce aberrant signaling by the undruggable oncoprotein c-MYC, to treat c-MYC driven oncogenesis. Overexpression of c-MYC is found in more than 50% of all human cancer but remains undruggable because of its highly dynamic intrinsically disordered 3-D conformation, which renders traditional therapeutic strategies largely ineffective. We demonstrate herein that small molecule activation of the 20S proteasome targets dysregulated intrinsically disordered proteins (IDPs), including c-MYC, and reduces cancer growth in vitro and in vivo models of multiple myeloma, and is even effective in bortezomib resistant cells and unresponsive patient samples. Genomic analysis of various cancer pathways showed that proteasome activation results in downregulation of many c-MYC target genes. Moreover, proteasome enhancement was well tolerated in mice and dogs. These data support the therapeutic potential of 20S proteasome activation in targeting IDP-driven proteotoxic disorders, including cancer, and demonstrate that this new therapeutic strategy is well tolerated in vivo.

pharmacology and toxicology↗

bioRxiv2019

Chromatin-based techniques map DNA interaction landscapes in psoriasis susceptibility loci and highlight KLF4 as a target gene in 9q31

Genome-wide association studies (GWAS) have uncovered many genetic risk loci for psoriasis, yet many remain uncharacterised in terms of the causal gene and their biological mechanism in disease. Here, we use a disease-focused Capture Hi-C experiment to link psoriasis-associated variants with their target genes in psoriasis-relevant cell lines (HaCaT keratinocytes and My-La CD8+ T cells). We confirm previously assigned genes, suggest novel candidates and provide evidence for complexity at psoriasis GWAS loci. In the 9q31 risk locus we combine further epigenomic evidence to demonstrate how the psoriasis association forms a functional interaction with the distant (>500 kb) KLF4 gene. We use CRISPR activation coupled with RNA-seq to demonstrate how activation of psoriasis-associated enhancers upregulates KLF4 in HaCaT cells. Our study design provides a robust pipeline for following up on GWAS disease-associated variants, paving the way for functional translation of genetic findings into clinical benefit.

genomics↗

bioRxiv2019

Suppressor mutations in Mecp2-null mice reveal that the DNA damage response is key to Rett syndrome pathology

Mutations in X-linked methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome (RTT). We carried out a genetic screen for secondary mutations that improved phenotypes in Mecp2/Y mice after mutagenesis with N-ethyl-N-nitrosourea (ENU), aiming to identify potential therapeutic entry points. Here we report the isolation of 106 founder animals that show suppression of Mecp2-null traits from screening 3,177 Mecp2/Y genomes. Using exome sequencing, genetic crosses and association analysis, we identify 33 candidate genes in 30 of the suppressor lines. A network analysis shows that 61% of the candidate genes cluster into the functional categories of transcriptional repression, chromatin modification or DNA repair, delineating a pathway relationship with MECP2. Many mutations lie in genes that are predicted to modulate synaptic signaling or lipid homeostasis. Surprisingly, mutations in genes that function in the DNA damage response (DDR) also improve symptoms in Mecp2/Y mice. The combinatorial effects of multiple loci can be resolved by employing association analysis. One line, which was previously reported to carry a suppressor mutation in a gene required for cholesterol synthesis, Sqle, carries a second mutation in retinoblastoma binding protein 8 (Rbbp8 or CtIP), which regulates a DDR choice in double stranded break (DSB) repair. Cells from Mecp2/Y mice have increased DSBs, so this finding suggests that the balance between homology directed repair and non-homologous end joining is important for neuronal cells. In this and other lines, the presence of two suppressor mutations confers better symptom improvement than one locus alone, suggesting that combination therapies could be effective in RTT.

genetics↗

bioRxiv2019

JARID2 facilitates transcriptional reprogramming in glioblastoma in response to standard treatment

BackgroundGlioblastoma (GBM) is a fatal and incurable brain cancer with a dismal prognosis. In order to impact on this disease, we need to understand how infiltrating, non resectable tumour cells resist chemoradiation and facilitate disease recurrence. To this end, we generated or acquired bulk tumour RNA sequencing data from 45 paired primary and locally recurrent GBM tumours (split into original and validation cohorts) from patients that received standard treatment. We also generated DNA methylation profiles for 9 pairs and sequenced RNA from single cells isolated from a patient derived GBM spheroid model at different timepoints following in vitro chemoradiation.\n\nResultsWe have identified a set of genes with Jumonji and AT-Rich Interacting Domain 2 (JARID2) binding sites in their promoters that are universally dysregulated in post-standard treatment recurrent GBMs compared to the primary tumour. The direction of dysregulation is patient-dependent and not associated with differential promoter DNA methylation. Our in vitro experiments suggest that this dysregulation occurs dynamically following treatment as opposed to resulting from selection of cells with specific expression profiles.\n\nConclusionJARID2 is an accessory protein to a chromatin remodeling complex, responsible for histone modifications observed during cell state transitions in both normal brain and GBM. We propose that JARID2 facilitates GBM recurrence following treatment by indirect transcriptional reprogramming of surviving cells in whichever manner is needed to reproduce the phenotypic heterogeneity required for tumour regrowth in vivo. The mechanism of this reprogramming may present a therapeutic vulnerability for more effective treatment of GBM.

cancer biology↗

bioRxiv2017

Individual differences in responsivity to social rewards: Insights from two eye-tracking tasks

Humans generally prefer social over nonsocial stimuli from an early age. Reduced preference for social rewards has been observed in individuals with autism spectrum conditions (ASC). This preference has typically been noted in separate tasks that measure orienting toward and engaging with social stimuli. In this experiment, we used two eye-tracking tasks to index both of these aspects of social preference in in 77 typical adults. We used two measures, global effect and preferential looking time. The global effect task measures saccadic deviation toward a social stimulus (related to orienting), while the preferential looking task records gaze duration bias toward social stimuli (relating to engaging). Social rewards were found to elicit greater saccadic deviation and greater gaze duration bias, suggesting that they have both greater salience and higher value compared to nonsocial rewards. Trait empathy was positively correlated with the measure of relative value of social rewards, but not with their salience. This study thus elucidates the relationship of empathy with social reward processing.

animal behavior and cognition↗