Biology subjects

Taylor, L.

Publications and source records attributed to Taylor, L..

44 records · Page 3Linked to original sources

bioRxiv2021

Regulation of CHK1 inhibitor resistance by a c-Rel and USP1 dependent pathway

We previously discovered that deletion of c-Rel in the E-Myc mouse model of lymphoma results in earlier onset of disease, a finding that contrasted with the expected function of this NF-{kappa}B subunit in B-cell malignancies. Here we report that c-rel -/- E{micro}-Myc cells have an unexpected and major defect in the CHK1 pathway, with almost undetectable levels of CHK1 and CLSPN protein leading to therapeutic resistance to the highly specific CHK1 inhibitor (CHK1i) CCT244747. Similar downregulation of CHK1 levels was also seen in CCT244747 resistant U20S osteosarcoma cells. Further investigation revealed that downregulation of the deubiquitinase USP1 is responsible, at least in part, for these effects. Importantly, we demonstrate that c-rel -/- E{micro}-Myc lymphoma cells survive though upregulation of compensatory PI3K/AKT pathway activity. Moreover, targeting this pathway with Pictilisib (GDC-0941) effectively killed c-rel -/- E{micro}-Myc in vivo, while having no effect on wild type E-Myc cells. This data reveals an NF-{kappa}B regulated pathway controlling CHK1 activity in cancer cells and identifies a potential mechanism for both acquiring and overcoming CHK1i resistance in cancer patients.

cancer biology↗

bioRxiv2021

A rapid and reliable multiplexed LC-MS/MS method for simultaneous analysis of six monoamines from brain tissues

Monoamines are a class of neuromodulators that are crucial for a variety of brain functions, including control of mood, movement, sleep and cognition. From mammals to insects, the nervous system is enriched in monoamines such as dopamine, serotonin and melatonin, analytes which range from being highly polar to non-polar. Here we developed a method using liquid chromatography coupled with mass spectrometry (LC-MS) to quantify in a single run the amounts of six distinct monoamines in extracts from dissected Drosophila and mouse brain tissues. The measured monoamines were dopamine (DA), serotonin (also known as 5-hydroxytryptamine (5-HT)), octopamine (OA, an insect equivalent of norepinephrine), tyramine (TA), melatonin (MT) and N-acetyl-hydroxy-serotonin (NAS). The analytical range of these monoamines was between 0.25 to 5.0 ng/mL.

neuroscience↗

bioRxiv2020

Single generation allele introgression into pure chicken breeds using Sire Dam Surrogate (SDS) mating

Poultry is the most abundant livestock species with over 60 billion chickens raised globally per year. While most chicken are produced from highly selected commercial flocks the many indigenous chicken breeds, which have low productivity and have not been highly selected, play an important role in rural economies across the world as they are well adapted to local environmental and scavenging conditions. The ability to rapidly transfer genetic changes between breeds of chicken will permit the transfer of beneficial alleles between poultry breeds as well as allow validation of genetic variants responsible for different phenotypic traits. Here, we generate a novel inducibly sterile surrogate host chicken. Introducing donor genome edited primordial cells into the sterile male and female host embryos produces chicken carrying only exogenous germ cells. Subsequent direct mating of the surrogate hosts, Sire Dam Surrogate (SDS) mating, recreates pure chicken breeds carrying the edited allele in heterozygous or homozygous states. We demonstrate the transfer and validation of two feather trait alleles, Dominant white and Frizzle traits into two pure chicken breeds using the SDS surrogate hosts. This technology will allow the rapid reconstitution of chicken breeds carrying desired genetic changes to investigate climate adaptation and disease resilience traits.

genetics↗

bioRxiv2020

Lineage Functional Types (LFTs): Characterizing functional diversity to enhance the representation of ecological behavior in Earth System Models

Process-based vegetation models attempt to represent the wide range of trait variation in biomes by grouping ecologically similar species into plant functional types (PFTs). This approach has been successful in representing many aspects of plant physiology and biophysics, but struggles to capture biogeographic history and ecological dynamics that determine biome boundaries and plant distributions. Grass dominated ecosystems are broadly distributed across all vegetated continents and harbor large functional diversity, yet most Earth System Models (ESMs) summarize grasses into two generic PFTs based primarily on differences between temperate C3 grasses and (sub)tropical C4 grasses. Incorporation of species-level trait variation is an active area of research to enhance the ecological realism of PFTs, which form the basis for vegetation processes and dynamics in ESMs. Using reported measurements, we developed grass functional trait values (physiological, structural, biochemical, anatomical, phenological, and disturbance-related) of dominant lineages to improve ESM representations. Our method is fundamentally different from previous efforts, as it uses phylogenetic relatedness to create lineage-based functional types (LFTs), situated between species-level trait data and PFT-level abstractions, thus providing a realistic representation of functional diversity and opening the door to the development of new vegetation models.

ecology↗

bioRxiv2019

North American Birds Require Mitigation and Adaptation to Reduce Vulnerability to Climate Change

Biodiversity is being lost at an alarming rate across the globe, with extinction rates up to a hundred times greater than historical norms. Climate change will only exacerbate this crisis. The rapid pace of projected climate change is set to push birds to seek new locations, drastically reshuffling the avian communities of North America. In an emerging climate crisis, effective conservation requires both adaptation and mitigation to improve the resilience of species. However, the pledged reductions in greenhouse gas emissions outlined in the Paris Agreement framework would still lead to a 3.2{degrees}C or greater increase in global mean temperature by the end of this century. In this study, we use big data analytics to develop species distribution models and assess the vulnerability of 604 North American birds to multiple climate change scenarios. We assess how climate change mitigation can affect the number of species vulnerable to climate change, as well as the species and locations at risk if emissions continue unchecked. Our results indicate that over two-thirds of North American birds are moderately or highly vulnerable to climate change under a 3.0{degrees}C global warming scenario. Of these climate-vulnerable species, 76% would have reduced vulnerability and 38% of those would be considered non-vulnerable if warming were stabilized at 1.5{degrees}C. Thus, the current pledge in greenhouse gas reductions set by the Paris Agreement is inadequate to reduce vulnerability to birds. Additionally, if climate change proceeds on its current trajectory, arctic birds, waterbirds and boreal and western forest birds will be highly vulnerable to climate change; groups that are currently not considered of high conservation concern. Thus, there is an urgent need for both aggressive policies to mitigate emissions and focused conservation adaptation actions to protect birds and the places they need in a changing climate.

ecology↗

bioRxiv2019

Risk to North American Birds from Climate Change-Related Threats

Climate change is a significant threat to biodiversity globally, compounded by threats that could hinder species ability to respond through range shifts. However, little research has examined how future bird ranges may coincide with multiple stressors at a broad scale. Here, we assess the risk to 544 birds in the United States from future climate change threats under a mitigation-dependent global warming scenario of 1.5{degrees}C and an unmitigated scenario of 3.0{degrees}C. Threats considered included sea level rise, lake level change, human land cover conversion, and extreme weather events. We developed a gridded index of risk based on coincident threats, species richness, and richness of vulnerable species. To assign risk to individual species and habitat groups, we overlaid future bird ranges with threats to calculate the proportion of species ranges affected in both the breeding and non-breeding seasons. Nearly all species will face at least one new climate-related threat in each season and scenario analyzed. Even with lower species richness, the 3.0{degrees}C scenario had higher risk for species and groups in both seasons. With unmitigated climate change, multiple coincident threats will affect over 88% of the conterminous United States, and 97% of species could be affected by two or more climate-related threats. Some habitat groups will see up to 96% species facing three or more threats. However, climate change mitigation would reduce risk to birds from climate change-related threats across over 90% of the US. Across the threats included here, extreme weather events have the most significant influence on risk and the most extensive spatial coverage. Urbanization and sea level rise will also have disproportionate impacts on species relative to the area they cover. By incorporating threats into predictions of climate change impacts, this assessment provides a comprehensive picture of how climate change will affect birds and the places they need.

ecology↗

bioRxiv2019

Telomeric Double Strand Breaks Facilitate Formation of 5’ C-Rich Overhangs in G1 Human Cells

Telomeres are repetitive nucleoprotein complexes that protect chromosomal termini and prevent them from activating an inappropriate DNA damage response (DDR). Here, we characterized the human cellular response to targeted telomeric DSBs in telomerase positive and telomerase-independent alternative lengthening of telomeres (ALT) cells, specifically in G1. Telomeric DSBs in G1 human cells elicited early signatures of a DDR, however, localization of 53BP1, an important regulator of resection at broken ends, was not observed at telomeric break sites. Consistent with this finding and previously reported repression of classical nonhomologous end-joining (c-NHEJ) at telomeres, evidence for c-NHEJ was also lacking. Likewise, no evidence of homologous recombination (HR)-dependent repair of telomeric DSBs in G1 was observed. Rather, and supportive of rapid truncation events, telomeric DSBs in G1 human cells facilitated formation of extensively resected tracks of 5 C-rich telomeric single-stranded (ss)DNA, a previously proposed marker of the recombination dependent ALT pathway. Indeed, induction of telomeric DSBs in human ALT cells also resulted in significant increases in 5 C-rich (ss)telomeric DNA in G1, which rather than RPA, were bound by the complementary telomeric RNA, TERRA. These results suggest that targeting TERRA-mediated protection at damaged telomeres may represent a promising therapeutic strategy, particularly against ALT-positive cancers.

molecular biology↗

bioRxiv2018

Signal sequences in the genome of Mononegavirales regulate the generation of copy-back defective viral genomes

Defective viral genomes of the copy-back type (cbDVGs) are the primary initiators of the antiviral immune response during infection with respiratory syncytial virus (RSV) both in vitro and in vivo. However, the mechanism governing cbDVG generation remains unknown, thereby limiting our ability to manipulate cbDVG content in order to modulate the host response to infection. Here we report a specific genomic signal that mediates the generation of RSV cbDVGs. Using a customized bioinformatics tool, we identified regions in the RSV genome frequently used to generate cbDVGs during infection. We then created a minigenome system to validate the function of one of these sequences and to determine if specific nucleotides were essential for cbDVG generation at that position. Further, we created a recombinant virus that selectively produced a specific cbDVG based on variations introduced in this sequence. The identified sequence was also found as a common site for cbDVG generation during natural RSV infections, and common cbDVGs generated at this sequence were found among samples from various infected patients. These data demonstrate that sequences encoded in the viral genome are critical determinants of the location of cbDVG generation and, therefore, this is not a stochastic process. Most importantly, these findings open the possibility of genetically manipulating cbDVG formation to modulate infection outcome. Author summaryCopy-back defective viral genomes (cbDVGs) regulate infection and pathogenesis of Mononegavirales. cbDVG are believed to arise from random errors that occur during virus replication and the predominant hypothesis is that the viral polymerase is the main driver of cbDVG generation. Here we describe a specific genomic sequence in the RSV genome that is necessary for the generation of a large proportion of the cbDVG population present during infection. We identified specific nucleotides that when modified altered cbDVG generation at this position, and we created a recombinant virus that selectively produced cbDVGs based on mutations in this sequence. These data demonstrate that the generation of RSV cbDVGs is regulated by specific viral sequences and that these sequences can be manipulated to alter the content and quality of cbDVG generated during infection.

microbiology↗