Biology subjects

Williams, M.

Publications and source records attributed to Williams, M..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

The effects of genome size on cell size and the functional composition and morphology of leaves: a case study in Rhododendron (Ericaceae)

Background and AimsDespite the predominance of scaling photosynthetic metabolism by two-dimensional leaf surface area, leaves are three-dimensional structures composed of multiple tissues that directly and indirectly influence photosynthetic metabolism. The structure of leaf surfaces for CO2 diffusion and light transmission and the internal volume of tissues that process energy and matter work together to control rates of resource acquisition and turnover. Here we investigate the influence of cell size and packing density on resource acquisition as measured by surface conductance to CO2 and water vapor and on resource turnover as measured by leaf water turnover time. MethodsWe sampled wild and cultivated congeneric species in the genus Rhododendron (Ericaceae) and measured genome size, anatomical traits related to cell sizes and packing densities, and morphological traits related to water content and dry mass allocation. ResultsAmong Rhododendron, anatomical traits related to cell size and morphological traits related to water content and dry mass investment varied largely orthogonally to each other, allowing for many combinations of leaf traits to exist. However, there was a strong, negative relationship between the leaf water residence time ({tau}) and the maximum leaf surface conductance per leaf volume (gmax,vol), both of which are influenced by cell size and cell packing densities. ConclusionsDespite leaf function being controlled by many potential combinations of leaf cell- and tissue-level traits, cell size has a pervasive effect on leaf function. Small cells allow for higher diffusion of CO2 and water vapor per unit leaf volume (gmax,vol) even at constant leaf thickness, but small cells also result in shorter leaf water residence times ({tau}). The strong tradeoff between gmax,vol and ({tau}) illuminates how genome size-cell size allometry influences the fast-slow continuum of plant carbon and water economy.

plant biology↗

bioRxiv2023

Single cell decoding of drug induced transcriptomic reprogramming in triple negative breast cancers

BackgroundThe encoding of cell intrinsic resistance states in breast cancer reflects the contributions of genomic and non-genomic variation. However, identifying the potential contributions of each requires accurate measurement and subtraction of the contribution of clonal fitness from co-measurement of transcriptional states. Somatic genomic variation in gene dosage, copy number variation, is the dominant mutational mechanism in breast cancer contributing to transcriptional variation and has recently been shown to contribute to platinum chemotherapy resistance states. Here we deploy time series measurements of triple negative breast cancer single cell transcriptomes in conjunction with co-measured single cell copy number associated clonal fitness to identify the contributions of genomic and non-genomic mechanisms to drug associated transcription states. ResultsWe generated serial scRNA-seq data (126,556 cells) from triple negative breast cancer (TNBC) patient-derived xenograft (PDX) experiments over 2.5 years in duration, and matched it against genomic copy number single cell data from the same biological samples. We show that the cell memory of transcriptional states of TNBC tumors serially exposed to platinum identifies distinct clonal responses within individual tumours. Copy-number clones with high drug fitness leading to clonal sweeps exhibit less transcriptional reversion, whereas clones with weak drug fitness exhibit highly dynamic transcription on drug withdrawal. Pathway analysis shows that copy number associated and copy number independent transcripts converge on epithelial-mesenchymal transition (EMT) and cytokine signaling states associated with resistance. We show from trajectory analysis that transcriptional reversion exhibits hysteresis, indicating that new intermediate transcriptional states are generated by platinum exposure. ConclusionsWe discovered that copy number clones with strong genotype associated fitness under platinum became fixed in their states, resulting in minimal transcriptional reversion on drug withdrawal. In contrast clones with weaker fitness undergo non-genomic transcriptional plasticity and these distinct responses co-exist within single tumours. Together the data suggest that copy number associated and copy number independent transcriptional states may contribute to platinum drug resistance within individual tumours. The dominance of genomic or non-genomic mechanisms within individual polyclonal tumours has implications for approaches to restoration of drug sensitivity and re-treatment strategies. Data availabilityUploaded Data URL: https://ega-archive.org/studies/EGAS00001007242 Github manuscript: https://github.com/molonc/drug_resistant_material/

genomics↗

bioRxiv2023

Ancient mitogenomes reveal evidence for the late Miocene dispersal of mergansers to the Southern Hemisphere

Mergansers are riverine and coastal piscivorous ducks that are widespread throughout North America and Eurasia but uncommon in the Southern Hemisphere. One species occurs in South America and at least two extinct species from New Zealand. It has been proposed that Southern Hemisphere mergansers were founded by independent dispersal events from the Northern Hemisphere. However, some morphological and behavioural evidence suggests that Southern Hemisphere mergansers may be closely related to one another. They share several characteristics that differ from Northern Hemisphere mergansers (e.g., non-migratory vs. migratory, sexual monochromatism vs. sexual dichromatism, long vs. short pair bonds). We sequenced complete mitogenomes from the Brazilian merganser and an extinct merganser from New Zealand--the Auckland Island merganser. Our results show the Brazilian and Auckland Island mergansers form a monophyletic clade with the common merganser, and that a sister relationship between Southern Hemisphere mergansers cannot be rejected. We cannot exclude the possibility that the Brazilian and Auckland Island mergansers descend from a single dispersal event from the Northern Hemisphere at least seven million years ago. Nuclear (palaeo)genomic data may help to resolve the relationship between living and extinct mergansers, including merganser fossils from New Zealand that have not been subjected to palaeogenetic analysis.

genetics↗

bioRxiv2023

Trithorax regulates long-term memory in Drosophila through epigenetic maintenance of mushroom body metabolic identity and translation capacity.

The role of epigenetics and chromatin in the maintenance of postmitotic neuronal cell identities is not well understood. Here, we show that the histone methyltransferase trithorax (trx) is required in postmitotic memory neurons of the Drosophila mushroom body (MB) to enable their capacity for long-term memory (LTM), but not short-term memory (STM). Using MB-specific RNA-, ChIP-, and ATAC-sequencing, we find that trx maintains expression of several non-canonical MB-enriched transcripts, including the orphan nuclear receptor Hr51, and the metabolic enzyme lactate dehydrogenase. Through these key targets, trx establishes a metabolic state characterized by high lactate levels in MB{gamma} neurons. This metabolic identity supports a high capacity for protein translation, a process that is essential for LTM, but not STM. These data suggest that trx, a classic regulator of cell type specification during development, has an alternative function in maintaining underappreciated aspects of postmitotic neuron identity, such as metabolic state. Our work supports a body of evidence suggesting that a high capacity for energy metabolism is an essential cell identity characteristic for neurons that mediate LTM.

molecular biology↗

bioRxiv2023

Extraordinary preservation of gene collinearity over three hundred million years revealed in homosporous lycophytes

Homosporous lycophytes (Lycopodiaceae) are a deeply diverged lineage in the plant tree of life, having split from heterosporous lycophytes (Selaginella and Isoetes) [~]400 million years ago (MYA). Compared to the heterosporous lineage, Lycopodiaceae has markedly larger genome sizes and remains the last major plant clade for which no genomic data has been available. Here, we present chromosomal genome assemblies for two homosporous lycophyte species, the allotetraploid Huperzia asiatica and the diploid Diphasiastrum complanatum. Remarkably, despite that the two species diverged [~]350 MYA, around 30% of the genes are still in syntenic blocks. Furthermore, both genomes had undergone independent whole genome duplications and the resulting intra-genomic syntenies have likewise been preserved relatively well. Such slow genome evolution over deep time is in stark contrast to heterosporous lycophytes and is correlated with a decelerated rate of nucleotide substitution. Together, the genomes of H. asiatica and D. complanatum not only fill a crucial gap in the plant genomic landscape, but also uncover a possibly unique genomic contrast between homosporous and heterosporous species.

genomics↗

bioRxiv2023

Conserving a threatened North American walnut: a chromosome-scale reference genome for butternut (Juglans cinerea)

With the advent of affordable and more accurate third generation sequencing technologies and the associated bioinformatic tools, it is now possible to sequence, assemble, and annotate more species of conservation concern than ever before. Juglans cinerea, commonly known as butternut or white walnut, is a member of the walnut family, native to the Eastern United States and Southeastern Canada. The species is currently listed as Endangered on the IUCN Red List due to decline from an invasive fungus known as Ophiognomonia clavigignenti-juglandacearum (Oc-j) that causes butternut canker. Oc-j creates visible sores on the trunks of the tree which essentially starves and slowly kills the tree. Natural resistance to this pathogen is rare. Conserving butternut is of utmost priority due to its critical ecosystem role and cultural significance. As part of an integrated undergraduate and graduate student training program in biodiversity and conservation genomics, the first reference genome for Juglans cinerea is described here. This chromosome-scale 539 Mb assembly was generated from over 100X coverage of Oxford Nanopore long reads and scaffolded with the Juglans mandshurica genome. Scaffolding with a closely related species oriented and ordered the sequences in a manner more representative of the structure of the genome without altering the sequence. Comparisons with sequenced Juglandaceae revealed high levels of synteny and further supported J. cinereas recent phylogenetic placement. Comparative assessment of gene family evolution revealed a significant number of contracting families, including several associated with biotic stress response.

genomics↗

bioRxiv2023

Myomatrix arrays for high-definition muscle recording

Neurons coordinate their activity to produce an astonishing variety of motor behaviors. Our present understanding of motor control has grown rapidly thanks to new methods for recording and analyzing populations of many individual neurons over time. In contrast, current methods for recording the nervous systems actual motor output - the activation of muscle fibers by motor neurons - typically cannot detect the individual electrical events produced by muscle fibers during natural behaviors and scale poorly across species and muscle groups. Here we present a novel class of electrode devices ("Myomatrix arrays") that record muscle activity at unprecedented resolution across muscles and behaviors. High-density, flexible electrode arrays allow for stable recordings from the muscle fibers activated by a single motor neuron, called a "motor unit", during natural behaviors in many species, including mice, rats, primates, songbirds, frogs, and insects. This technology therefore allows the nervous systems motor output to be monitored in unprecedented detail during complex behaviors across species and muscle morphologies. We anticipate that this technology will allow rapid advances in understanding the neural control of behavior and in identifying pathologies of the motor system.

neuroscience↗

bioRxiv2022

Logging alters tropical forest structure, while conversion reduces biodiversity and functioning

The impacts of degradation and deforestation on tropical forests are poorly understood, particularly at landscape scales. We present an extensive ecosystem analysis of the impacts of logging and conversion of tropical forest to oil palm from a large-scale study in Borneo, synthesizing responses from 82 variables categorized into four ecological levels spanning a broad suite of ecosystem properties: 1) structure and environment, 2) species traits, 3) biodiversity, and 4) ecosystem functions. Responses were highly heterogeneous and often complex and non-linear. Variables that were directly impacted by the physical process of timber extraction, such as soil structure, were sensitive to even moderate amounts of logging, whereas measures of biodiversity and ecosystem functioning were generally resilient to logging but more affected by conversion to oil palm plantation. One-Sentence SummaryLogging tropical forest mostly impacts structure while biodiversity and functions are more vulnerable to habitat conversion.

ecology↗

bioRxiv2022

Ultra-long-acting refillable nanofluidic implant confers full protection against SHIV infection in non-human primates

The impact of pre-exposure prophylaxis (PrEP) on slowing the global human immunodeficiency virus (HIV) epidemic hinges on effective drugs and delivery platforms. Oral regimens have represented the pillar of HIV PrEP for years. However, variable adherence has spurred development of long-acting delivery systems, which also aim at increasing PrEP access, uptake and persistence. Here we present an ultra-long-acting and transcutaneously refillable subcutaneous nanofluidic implant for constant and sustained release of islatravir (ISL), a nucleoside reverse transcriptase translocation inhibitor, for HIV PrEP. In rhesus macaques, the ISL-eluting implants (nISL) achieved constant plasma ISL levels (median 3.14 nM) and peripheral blood mononuclear cells (PBMCs) ISL-triphosphate levels (ISL-TP) (median 0.16 pmol/106 cells) for over 20 months uninterrupted. These drug concentrations are above the established PrEP protection threshold. In two non-blinded, placebo-controlled studies with repeated low-dose rectal and vaginal SHIVSF162P3 challenges in male and female rhesus macaques, respectively, nISL implants conferred 100% protection against infection (p=0.0005 and 0.0009, respectively between nISL and placebo control groups). The nISL implants were well tolerated with mild local tissue inflammation and no signs of systemic toxicity over the 20-month period. Overall, our refillable nISL implant is a promising ultra-long-acting delivery technology for HIV PrEP. One Sentence SummaryAn ultra-long-acting and subcutaneous refillable nanofluidic implant achieved preventive levels of islatravir in non-human primates for 20 months without refilling and conferred 100% protection against rectal and vaginal SHIV transmission.

bioengineering↗

bioRxiv2022

The Children's Brain Tumor Network (CBTN) - Accelerating Research in Pediatric Central Nervous System Tumors through Collaboration and Open Science

Pediatric brain tumors are the leading cause of cancer-related death in children in the United States and contribute a disproportionate number of potential years of life lost compared to adult cancers. Moreover, survivors frequently suffer long-term side effects, including secondary cancers. The Childrens Brain Tumor Network (CBTN) is a multi-institutional international clinical research consortium created to advance therapeutic development through the collection and rapid distribution of biospecimens and data via open-science research platforms for real-time access and use by the global research community. The CBTNs 32 member institutions utilize a shared regulatory governance architecture at the Childrens Hospital of Philadelphia to accelerate and maximize the use of biospecimens and data. As of August 2022, CBTN has enrolled over 4,700 subjects, over 1,500 parents, and collected over 65,000 biospecimen aliquots for research. Additionally, over 80 preclinical models have been developed from collected tumors. Multi-omic data for over 1,000 tumors and germline material is currently available with data generation for > 5,000 samples underway. To our knowledge, CBTN provides the largest open-access pediatric brain tumor multi-omic dataset annotated with longitudinal clinical and outcome data, imaging, associated biospecimens, child-parent genomic pedigrees, and in vivo and in vitro preclinical models. Empowered by NIH-supported platforms such as the Kids First Data Resource and the Childhood Cancer Data Initiative, the CBTN continues to expand the resources needed for scientists to accelerate translational impact for improved outcomes and quality of life for children with brain and spinal cord tumors.

cancer biology↗

bioRxiv2022

Evaluating user experience with immersive technology in simulation-based education: a modified Delphi study with qualitative analysis

BackgroundImmersive technology is becoming more widespread in simulation-based medical education with applications that both supplement and replace traditional teaching methods. There is a lack of validated measures that capture user experience to inform of the technology utility. We aimed to establish a consensus of items and domains that different simulation experts would include in a measure for immersive technology use. MethodsA 3-stage modified Delphi using online software was conducted to support the conceptual framework for the proposed measure. The first round was informed by prior work on immersive technology in simulation. In the first round, participants were asked to describe what we could measure in simulation-based education and technology. Thematic analysis generated key themes that were presented to the participants in the second round. Ranking of importance in round 2 was determined by mean rank scores. The final round was an online meeting for final consensus discussion and most important domains by experts were considered. ResultsA total of 16 simulation experts participated in the study. A consensus was reached on the ideal measure in immersive technology simulation that would be a user questionnaire and domains of interest would be: what was learnt, the degree of immersion experienced, fidelity provided, debrief, psychological safety and patient safety. No consensus was reached with the barriers that this technology introduces in education. ConclusionsThere is varied opinion on what we should prioritise in measuring the experience in simulation practice. Importantly, this study identified key areas that aids our understanding on how we can measure new technology in educational settings. Synthesising these results in to a multidomain instrument requires a systematic approach to testing in future research

scientific communication and education↗

bioRxiv2022

Inactivated SARS-CoV-2 Reprograms the Tumor Immune Microenvironment and Improves Murine Cancer Outcomes

Following the breakthrough of immune check point inhibitors (ICIs), a new era of immuno-oncology agents has emerged and established immunotherapy as a part of cancer treatment. Despite the improving outcomes of ICIs, many patients with initial response are known to develop acquired resistance later. There is increasing interest in utilizing other stimulatory means, such as anti-pathogen immune responses to induce anti-tumor immune responses. The immunostimulatory effects of anti-pathogen-treated tumors in combinations with ICI are known to potentially amplify anti-tumor immunity resulting in increased tumor responses and improved outcomes. Anti-pathogen-treated tumors can become immune-infiltrated "hot" tumors and demonstrate higher treatment response rates and improved survival. Our research group has previously demonstrated that tumors can be converted from "cold" to "hot" by intratumoral injection of a commercially available seasonal influenza vaccine. In continuation with our work, in deciphering the role of anti-viral immunity in the context of tumor immunology, we studied the role of inactivated SARS-CoV-2 virus as anti-tumor agent. Here we report that intratumoral injections of inactivated SARS-CoV-2 convert the immunologically cold tumors to hot by generating anti-tumor-mediated CD8+ T cells. Our findings suggest that inactivated SARS-CoV-2 can be used as an immune modulator in immunotherapy for melanoma and triple-negative breast cancer.

cancer biology↗

bioRxiv2022

Activation of ChvG-ChvI regulon by cell wall stress confers resistance to β-lactam antibiotics and initiates surface spreading in Agrobacterium tumefaciens

A core component of nearly all bacteria, the cell wall is an ideal target for broad spectrum antibiotics. Many bacteria have evolved strategies to sense and respond to antibiotics targeting cell wall synthesis, especially in the soil where antibiotic-producing bacteria compete with one another. Here we show that cell wall stress caused by both chemical and genetic inhibition of the essential, bifunctional penicillin-binding protein PBP1a prevents microcolony formation and activates the canonical host-invasion two-component system ChvG-ChvI in Agrobacterium tumefaciens. Using RNA-seq, we show that depletion of PBP1a for 6 hours results in a downregulation in transcription of flagellum-dependent motility genes and an upregulation in transcription of type VI secretion and succinoglycan biosynthesis genes, a hallmark of the ChvG-ChvI regulon. Depletion of PBP1a for 16 hours, results in differential expression of many additional genes and may promote a general stress response. Remarkably, the overproduction of succinoglycan causes cell spreading and deletion of the succinoglycan biosynthesis gene exoA restores microcolony formation. Treatment with cefsulodin phenocopies depletion of PBP1a and we correspondingly find that chvG and chvI mutants are hypersensitive to cefsulodin. This hypersensitivity only occurs in response to treatment with {beta}-lactam antibiotics and moenomycin, suggesting that the ChvG-ChvI pathway may play a key role in resistance to antibiotics targeting cell wall synthesis. Finally, we provide evidence that ChvG-ChvI likely has a conserved role in conferring resistance to cell wall stress within the Alphaproteobacteria. AUTHOR SUMMARYSoil dwelling bacteria reside in changing environments requiring them to frequently adapt to stressful conditions to ensure survival. The bacterial envelope provides structural integrity and protection against osmotic stress and turgor pressure imposed by the environment. While the mechanisms of cell membrane and cell wall biogenesis have been extensively studied, our understanding of how diverse microbes respond to cell envelope and cell wall stress to increase their fitness remains limited. In this work, we identify ChvG-ChvI regulon as an envelope stress response system that confers protection under cell wall stress conditions in the bacterial plant pathogen Agrobacterium tumefaciens. This is a new function for the well-characterized ChvG-ChvI pathway which is also acid induced and promotes plant host invasion. Our results suggest that the ChvG-ChvI pathway has a broadly conserved role in protecting Alphaproteobacterial cells from extracellular stress and a more specific role in response to acid stress and promoting plant-microbe interactions.

microbiology↗

bioRxiv2022

Transcriptome and DNA methylome dynamics reveal differential characteristics of inflorescence development between two ecotypes in Panicum hallii

The morphological diversity of the inflorescence determines flower and seed production, which is critical for plant adaptation and fitness. Cytosine methylation is an epigenetic mark that contributes to gene expression regulation during inflorescence development. Panicum hallii is a wild perennial grass in the subfamily Panicoideae that has been developed as a model to study perennial grass biology and adaptive evolution. Highly divergent inflorescences have evolved between the two major ecotypes in P. hallii, the upland ecotype with compact inflorescence and large seed and the lowland ecotype with an open inflorescence and small seed. Here we performed a comparative transcriptome and DNA methylome analysis across different stages of inflorescence between these two divergent ecotypes of P. hallii. Global transcriptome analysis identified differentially expressed genes (DEGs) involved in panicle divergence, stage-specific expression, and co-expression modules underlying inflorescence development. Comparing DNA methylome profiles revealed a remarkable level of differential DNA methylation associated with the evolution of the P. hallii inflorescence. We found that most differentially methylated regions (DMRs) occurred within the flanking regulatory regions of genes, especially the promoter. Integrative analysis of DEGs and DMRs characterized the global features of DMR-associated DEGs in the divergence of P. hallii inflorescence, which includes homologs of important inflorescence and seed developmental genes that have been previously identified in domesticated crops. Evolutionary analysis measured by Ka/Ks ratio suggested that most DMR-associated DEGs are under relatively strong purifying selection. This study provides insights into the transcriptome and epigenetic landscape of inflorescence divergence in P. hallii and a novel genomic resource for perennial grass biology. One sentence summaryA comparative transcriptome and DNA methylome analysis of inflorescence between upland and lowland ecotypes reveal gene expression and DNA methylation variation underlying inflorescence divergence in Panicum hallii.

evolutionary biology↗

bioRxiv2021

#COVIDisAirborne: AI-Enabled Multiscale Computational Microscopy of Delta SARS-CoV-2 in a Respiratory Aerosol

We seek to completely revise current models of airborne transmission of respiratory viruses by providing never-before-seen atomic-level views of the SARS-CoV-2 virus within a respiratory aerosol. Our work dramatically extends the capabilities of multiscale computational microscopy to address the significant gaps that exist in current experimental methods, which are limited in their ability to interrogate aerosols at the atomic/molecular level and thus ob-scure our understanding of airborne transmission. We demonstrate how our integrated data-driven platform provides a new way of exploring the composition, structure, and dynamics of aerosols and aerosolized viruses, while driving simulation method development along several important axes. We present a series of initial scientific discoveries for the SARS-CoV-2 Delta variant, noting that the full scientific impact of this work has yet to be realized. ACM Reference FormatAbigail Dommer1{dagger}, Lorenzo Casalino1{dagger}, Fiona Kearns1{dagger}, Mia Rosenfeld1, Nicholas Wauer1, Surl-Hee Ahn1, John Russo,2 Sofia Oliveira3, Clare Morris1, AnthonyBogetti4, AndaTrifan5,6, Alexander Brace5,7, TerraSztain1,8, Austin Clyde5,7, Heng Ma5, Chakra Chennubhotla4, Hyungro Lee9, Matteo Turilli9, Syma Khalid10, Teresa Tamayo-Mendoza11, Matthew Welborn11, Anders Christensen11, Daniel G. A. Smith11, Zhuoran Qiao12, Sai Krishna Sirumalla11, Michael OConnor11, Frederick Manby11, Anima Anandkumar12,13, David Hardy6, James Phillips6, Abraham Stern13, Josh Romero13, David Clark13, Mitchell Dorrell14, Tom Maiden14, Lei Huang15, John McCalpin15, Christo- pherWoods3, Alan Gray13, MattWilliams3, Bryan Barker16, HarindaRajapaksha16, Richard Pitts16, Tom Gibbs13, John Stone6, Daniel Zuckerman2*, Adrian Mulholland3*, Thomas MillerIII11,12*, ShantenuJha9*, Arvind Ramanathan5*, Lillian Chong4*, Rommie Amaro1*. 2021. #COVIDisAirborne: AI-Enabled Multiscale Computational Microscopy ofDeltaSARS-CoV-2 in a Respiratory Aerosol. In Supercomputing 21: International Conference for High Perfor-mance Computing, Networking, Storage, and Analysis. ACM, New York, NY, USA, 14 pages. https://doi.org/finalDOI

biophysics↗

bioRxiv2021

Fluoroquinolone-Resistant Escherichia coli Originating on Dairy Farms are an Infrequent Cause of Bacteriuria in Humans Living in the Same Geographical Region

SynopsisO_ST_ABSBackgroundC_ST_ABSOur primary aim was to test whether cattle-associated fluoroquinolone-resistant (FQ-R) Escherichia coli found on dairy farms were a significant cause of bacteriuria in humans living in the same 50 x 50 km geographical region located in South West England. Another aim was to identify risk factors for the presence of FQ-R E. coli on dairy farms. MethodsFQ-R E. coli were isolated during 2017-18 from 42 dairy farms and from community urine samples. Forty-two cattle and 489 human urinary isolates were subjected to WGS, allowing phylogenetic comparisons. Risk factors were identified using a Bayesian regularisation approach. ResultsOf 489 FQ-R human isolates, 255 were also 3rd generation cephalosporin-resistant (3GC-R), with strong genetic linkage between aac(6)Ib-cr and blaCTX-M-15. We identified possible farm-to-human sharing for pairs of ST744 and ST162 isolates, but core genome SNP distances (71 and 63, respectively) were smaller in pairs of ST744 and ST162 isolates from different farms (7 and 3 SNPs, respectively). Total farm fluoroquinolone use showed a positive association with the odds of isolating FQ-R E. coli while total dry cow therapy use showed a negative association. ConclusionsThis work suggests that FQ-R E. coli found on dairy farms have a limited impact on community bacteriuria within the local human population, however, this appears greater than observed for 3GC-R E. coli when studied in parallel. Reducing fluoroquinolone use may reduce the on-farm prevalence of FQ-R E. coli, and this reduction may be greater when dry cow therapy is targeted to the ecology of resistant E. coli on the farm.

microbiology↗

bioRxiv2021

Antidepressants are complex regulators of lipoprotein(a) macropinocytosis

We recently found that plasminogen receptors regulate the plasma membrane binding and uptake of Lp(a) via macropinocytosis. In this study, we sought to further define lipoprotein(a) [Lp(a)] macropinocytosis, discovering an unexpected role for antidepressants and serotonin in the regulation of this process. We found that the tricyclic antidepressant imipramine enhanced Lp(a) uptake, in contradiction of its published role as a macropinocytosis inhibitor. Extending these experiments to the commonly used serotonin uptake inhibitors (SSRIs) citalopram and sertraline, we found that citalopram stimulated, while sertraline inhibited, Lp(a) uptake. Imipramine and citalopram enhanced cell surface binding of Lp(a) rather than upregulating macropinocytosis. Consistent with imipramine and citalopram boosting extracellular serotonin levels, serotonin itself also enhanced Lp(a) surface binding and uptake. Imipramine and serotonin increased expression of the plasminogen receptor with a C-terminal lysine (PlgRKT), a receptor known to enhance cell surface binding of Lp(a), likely accounting for their effects on Lp(a) uptake. Finally, imipramine and citalopram increased Lp(a) delivery into Rab11 recycling endosomes, but not degradative pathways in the cell. These findings indicate citalopram and imipramine may have utility as a potential Lp(a)-lowering therapeutic in people suffering from depression who often have elevated Lp(a) levels and an increased risk of cardiovascular disease.

cell biology↗

bioRxiv2021

An exceptionally preserved euarthropod with unique feather-like appendages from the Chengjiang biota

Micro-CT scanning of the Cambrian euarthropod Chuandianella ovata reveals unprecedented three-dimensional soft-part details. It has an elongate uniramous antennule and a short uniramous second appendage, followed by ten homonomous biramous appendages, each comprising a short paddle-shaped exopod and a unique feather-like endopod with at least 27 podomeres each of which bears a long blade-like endite with a short terminal seta. Based on its carapace and previously known soft-part anatomy C. ovata was compared with the Burgess Shale mandibulate euarthropod Waptia. However, Waptia has recently been shown to bear specialized head appendages that are interpreted as a mandible and maxillula, posterior to which are four appendages each with five-segmented endopods. In contrast, we interpret Chuandianella as an upper stem-group euarthropod that possessed neither a differentiated mandible nor a maxillula. Chuandianella further demonstrates that early Cambrian upper stem-group euarthropods were experimenting with a range of different limb arrangements and morphologies.

evolutionary biology↗