Biology subjects

Nguyen, N.

Publications and source records attributed to Nguyen, N..

At least 55 records · Page 3Linked to original sources

bioRxiv2022

α-synuclein over expression, NRF2 suppression, and enhanced ferroptosis creates a vicious cycle of neuronal loss in Parkinson's disease

Parkinsons disease (PD) is the second most common neurodegenerative disorder, affecting millions each year. Most PD cases ([~]90%) are sporadic, resulting from the age-dependent accumulation of pathogenic effects. One key pathological hallmark of PD progression is the accumulation of alpha-synuclein (-syn), which has been shown to negatively affect neuronal function and viability. Here, using 3- and 6-month-old Nrf2+/+ and Nrf2-/- mice overexpressing human -syn (PD model), we show that loss of NRF2 increases markers of ferroptosis across PD-relevant brain regions. Increased ferroptosis was associated with an age- and genotype-dependent increase in -syn pathology and behavioral deficits. Finally, we demonstrate that -syn overexpression sensitizes neuronal cells and ex vivo brain slices to ferroptosis induction, which may be due to -syn suppression of NRF2 at the protein level. Altogether, these results indicate that NRF2 is a critical anti-ferroptotic mediator of neuronal survival, and that the vicious cycle of -syn overexpression and NRF2 suppression, leading to enhanced neuronal ferroptotic cell death, could represent a targetable and currently untapped means of preventing PD onset and progression.

neuroscience↗

bioRxiv2022

SARS-CoV-2 Omicron BA.2.12.1, BA.4, and BA.5 subvariants evolved to extend antibody evasion

SARS-CoV-2 Omicron subvariants BA.2.12.1 and BA.4/5 have surged dramatically to become dominant in the United States and South Africa, respectively1,2. These novel subvariants carrying additional mutations in their spike proteins raise concerns that they may further evade neutralizing antibodies, thereby further compromising the efficacy of COVID-19 vaccines and therapeutic monoclonals. We now report findings from a systematic antigenic analysis of these surging Omicron subvariants. BA.2.12.1 is only modestly (1.8-fold) more resistant to sera from vaccinated and boosted individuals than BA.2. However, BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections. Mutation at spike residue L452 found in both BA.2.12.1 and BA.4/5 facilitates escape from some antibodies directed to the so-called class 2 and 3 regions of the receptor-binding domain3. The F486V mutation found in BA.4/5 facilitates escape from certain class 1 and 2 antibodies but compromises the spike affinity for the viral receptor. The R493Q reversion mutation, however, restores receptor affinity and consequently the fitness of BA.4/5. Among therapeutic antibodies authorized for clinical use, only bebtelovimab retains full potency against both BA.2.12.1 and BA.4/5. The Omicron lineage of SARS-CoV-2 continues to evolve, successively yielding subvariants that are not only more transmissible but also more evasive to antibodies.

microbiology↗

bioRxiv2022

Visual Perception of 3D Space and Shape in Time - Part III: 2D Shape Recognition by Log-Scaling

Human vision has a remarkable ability to recognize complex 3D objects such as faces that appear with any size and 3D orientations at any 3D location. If we initially memorize a face only with a normalized size and viewed from directly head on, the direct comparison between the one-sized memory and a new incoming image would demand tremendous mental frame translations in 7D. How can we perform such a demanding task so promptly and reliably as we experience the objects in the world around us? Intriguingly, our primary visual cortex exhibits a 2D retinotopy with a log-polar coordinate system, where scaling up/down of shape is converted to linear frame translation. As a result, mental scaling can be performed by linearly translating the memory or the perceptual image until they overlap with each other. According to our new model of NHT (Neural Holography Tomography), alpha brainwaves traveling at a constant speed can conduct this linear translation. With this scheme, every scaling up/down by a factor of two should take the same amount of extra mental time to recognize a smaller/larger face. To test this hypothesis, we designed a reaction time (RT) experiment, where participants were first asked to memorize sets of unfamiliar faces with a given specific size (4{degrees} or 8{degrees}). Following the memorization phase, similar stimuli with a wide range of sizes (from 1{degrees} to 32{degrees}) were presented, and RTs were recorded. As predicted, the increase in RT was proportional to the scaling factor in the log scale. Furthermore, we observed that RTs were fastest for 8{degrees} faces even if the memorized face was 4{degrees}. This supports our hypothesis that we always memorize faces at the exact size of ~8 {degrees}. To our surprise, the increases in RT were also consistent with the mentally-estimated depth sensation, which indicates that the apparent size of the recognized face can create a proper depth sensation.

neuroscience↗

bioRxiv2022

A single cell atlas of the cycling murine ovary

The estrous cycle is regulated by rhythmic endocrine interactions of the nervous and reproductive systems, which coordinate the hormonal and ovulatory functions of the ovary. Folliculogenesis and follicle progression require the orchestrated response of a variety of cell types to allow the maturation of the follicle and its sequela, ovulation, corpus luteum (CL) formation, and ovulatory wound repair. Little is known about the cell state dynamics of the ovary during the estrous cycle, and the paracrine factors that help coordinate this process. Herein we used single-cell RNA sequencing to evaluate the transcriptome of > 34,000 cells of the adult mouse ovary and describe the transcriptional changes that occur across the normal estrous cycle and other reproductive states to build a comprehensive dynamic atlas of murine ovarian cell types and states.

developmental biology↗

bioRxiv2021

High-altitude adaptation and incipient speciation in geladas

Survival at high altitude requires adapting to extreme conditions such as environmental hypoxia. To understand high-altitude adaptations in a primate, we assembled the genome of the gelada (Theropithecus gelada), an endemic Ethiopian monkey, and complemented it with population resequencing, hematological, and morphometric data. Unexpectedly, we identified a novel karyotype that may contribute to reproductive isolation between gelada populations. We also identified genomic elements including protein-coding sequences and gene families that exhibit accelerated changes in geladas and may contribute to high-altitude adaptation. Our findings lend insight into mechanisms of speciation and adaptation while providing promising avenues for functional hypoxia research.

genomics↗

bioRxiv2021

Pleiotropy is associated with fitness consequences of new mutations in mutation accumulation lines

Understanding the mechanisms by which mutations affect fitness and the distribution of mutational effects are central goals in evolutionary biology. Mutation accumulation (MA) lines have long been an important tool for understanding the effect of new mutations on fitness, phenotypic variation, and mutational parameters. However, there is a clear gap in predicting the effect of specific new mutations to their effects on fitness. Here, we complete gene ontology analysis and metabolomics experiments on Arabidopsis thaliana MA lines to determine how spontaneous mutations directly affect global metabolic output in lines that have measured fitness consequences. For these analyses, we compared three lines with relative fitness consistently higher than the unmutated progenitor and three lines with lower relative fitness as measured in four different field trials. In a gene ontology analysis, we find that the high fitness lines were significantly enriched in mutations in or near genes with transcription regulator activity. We also find that although they do not have an average difference in the number of mutations, low fitness lines have significantly more metabolic subpathways disrupted than high fitness lines. Taken together, these results suggest that the effect of a new mutation on fitness depends less on the specific metabolic pathways disrupted and more on the pleiotropic effects of those mutations, and that organisms can explore a considerable amount of physiological space with only a few mutations. Significance StatementAs the source of all genetic variation, new mutations are crucial for understanding how organisms adapt to their environment. However, the ways in which new mutations affect the range of metabolic reactions that occur in the cell is unknown. With a combination of gene functional analyses and measurement of the small molecules that drive cellular function and physiology, we find that mutations associated with high fitness are disproportionately found in or near proteins-coding genes that regulate the specific timing and location of gene expression and are less disruptive of cellular physiology.

evolutionary biology↗

bioRxiv2021

Gastrointestinal Helminths Increase Bordetella bronchiseptica Shedding and Host Variation in Supershedding

Multi-species infections have been suggested to facilitate pathogen transmission and the emergence of supershedding events. However, how the interactions between co-infecting pathogens affect their dynamics of shedding, and how this is related to the host immune response, remains largely unclear. We used laboratory experiments and a modeling approach to examine temporal variations in the shedding of the respiratory bacterium Bordetella bronchiseptica in rabbits challenged with one or two gastrointestinal helminth species. Experimental data showed that rabbits co-infected with one or both helminths shed significantly more B. bronchiseptica by direct contact with an agar petri dish than rabbits with bacteria alone. There was also evidence of synergistic effects when both helminth species were present (triple infection). Co-infected hosts generated supershedding events of higher intensity and more frequently than hosts with no helminths. Model simulations revealed that the two helminths affected the relative contribution of neutrophils and specific IgA and IgG to B. bronchiseptica neutralization in the respiratory tract. In turn, these changes led to differences in the magnitude and duration of shedding among the various types of infection. However, the rapid variation in individual shedding, including supershedding, could not be explained by the interactions between infection and immune response at the scale of analysis that we used. We suggest that local rapid changes at the level of respiratory tissue probably played a more important role. This study provides novel insight into the role of helminths to the dynamics of respiratory infections and offers a quantitative explanation for the differences generated by two helminth species. Author summaryThe dynamics of bacterial infections can be facilitated by the presence of gastrointestinal helminths. Understanding the immunological processes that underline the pathogen-parasite interactions, and how they affect the dynamics of shedding, is important particularly for infections where control of the parasite maybe more effective than trying to reduce the bacterial infection. In this study, we examined the role of two gastrointestinal helminth species on the shedding of the respiratory Bordetella bronchiseptica using laboratory experiments of rabbits together with mathematical modeling. Hosts infected with helminths shed significantly more bacteria with evidence of supershedding, than hosts with only B. bronchiseptica. Simulations showed that by altering the relative contribution of neutrophils, specific IgA and IgG, helminths affected the control of bacterial infection in the respiratory tract. These interactions altered the intensity and duration of bacterial shedding, including the frequency and intensity of supershedding events. However, at the host level our model did not explain the rapid variation in shedding observed, suggesting that local processes in the respiratory tissue are critical for the prediction of the daily shed in the environment. This study advances our understanding of the dynamics of shedding in bacteria-helminth co-infections and provides insight that can be used to control disease spread.

ecology↗

bioRxiv2021

DNA METHYLATION PROFILING OF A CNIDARIAN-ALGAL SYMBIOSIS USING NANOPORE SEQUENCING

Symbiosis with protists is common among cnidarians such as corals and sea anemones, and is associated with homeostatic and phenotypic changes in the host that could have epigenetic underpinnings, such as methylation of CpG dinucleotides. We leveraged the sensitivity to base modifications of nanopore sequencing to probe the effect of symbiosis with the chlorophyte Elliptochloris marina on methylation in the sea anemone Anthopleura elegantissima. We first validated the approach by comparison of nanopore-derived methylation levels with CpG depletion analysis of a published transcriptome, finding that high methylation levels are associated with CpG depletion as expected. Next, using reads generated exclusively from aposymbiotic anemones, a largely complete draft genome comprising 243 Mb was assembled. Reads from aposymbiotic and symbiotic sea anemones were then mapped to this genome and assessed for methylation using the program Nanopolish, which detects signal disruptions from base modifications as they pass through the nanopore. Based on assessment of 452,841 CpGs for which there was adequate read coverage (approximately 8% of the CpGs in the genome), symbiosis with E. marina was, surprisingly, associated with only subtle changes in the host methylome. However, we did identify one extended genomic region with consistently higher methylation among symbiotic individuals. The region was associated with a DNA polymerase zeta that is noted for its role in translesion synthesis, which opens interesting questions about the biology of this symbiosis. Our study highlights the power and relative simplicity of nanopore sequencing for studies of nucleic acid base modifications in non-model species.

genomics↗

bioRxiv2020

BBrowser: Making single-cell data easily accessible

BioTurings BBrowser is a software solution that helps scientists effectively analyze single-cell omics data. It combines big data with big computation and modern data visualization to create a unique platform where scientists can interact and obtain important biological insights from the massive amounts of single-cell data. BBrowser has three main components: a curated single-cell database, a big-data analytics layer, and a data visualization module. BBrowser is available for download at: https://bioturing.com/bbrowser/download.

bioinformatics↗

bioRxiv2020

Novel Cluster AZ Arthrobacter phages Powerpuff, Lego, and YesChef exhibit close functional relationships with Microbacterium phages

Bacteriophages exhibit a vast spectrum of relatedness and there is increasing evidence of close genomic relationships independent of host genus. The variability in phage similarity at the nucleotide, amino acid, and gene content levels confounds attempts at quantifying phage relatedness, especially as more novel phages are isolated. This study describes three highly similar novel Arthrobacter globiformis phages-Powerpuff, Lego, and YesChef-which were assigned to Cluster AZ using a nucleotide-based clustering parameter. Phages in Cluster AZ and Microbacterium Cluster EH, as well as the former Microbacterium singleton Zeta1847, exhibited low nucleotide similarity but gene content similarity in excess of the recently adopted Microbacterium clustering parameter, which resulted in the reassignment of Zeta1847 to Cluster EH. Additionally, Clusters AZ and EH phages encode a shared integrase indicative of a lysogenic life cycle; in the first experimental verification of a Cluster AZ phages life cycle, we show that phage Powerpuff is a true temperate phage and forms stable lysogens that exhibit immunity to superinfection by related phages, despite lacking identifiable repressors typically required for lysogenic maintenance and superinfection immunity. The ability of phage Powerpuff to undergo and maintain lysogeny suggests that other closely related phages encoding an integrase but lacking an identified repressor may be temperate as well. Our findings further highlight the importance of using multiple metrics to capture phage relatedness, provide additional evidence of significant shared phage genomic content spanning multiple actinobacterial host genera, and demonstrate the continued need for verification and characterization of life cycles in newly isolated phages.

microbiology↗

bioRxiv2020

Distinct clonal evolution of B-cells in HIV controllers with neutralizing antibody breadth

A minor subset of individuals infected with HIV-1 develop antibody neutralization breadth during the natural course of the infection, often linked to chronic, high level viremia. Despite significant efforts, vaccination strategies have been unable to induce similar neutralization breadth and the mechanisms underlying neutralizing antibody induction remain largely elusive. Broadly neutralizing antibody responses can also be found in individuals who control HIV to low and even undetectable plasma levels in the absence of antiretroviral therapy, suggesting that high antigen exposure is not a strict requirement for neutralization breadth. We therefore performed an analysis of paired heavy and light chain B-cell receptor repertoires in 12,591 HIV-1 Envelope-specific single memory B-cells to determine alterations in the BCR immunoglobulin gene repertoire and B-cell clonal expansions that associate with neutralizing antibody breadth in 22 HIV controllers. We found that the frequency of genomic mutations in IGHV and IGLV was directly correlated with serum neutralization breadth. The repertoire of the most mutated antibodies was dominated by a small number of large clones with evolutionary signatures suggesting that these clones had reached peak affinity maturation. These data demonstrate that even in the setting of low plasma HIV antigenemia, similar to what a vaccine can potentially achieve, BCR selection for extended somatic hypermutation and clonal evolution can occur in some individuals suggesting that host-specific factors might be involved that could be targeted with future vaccine strategies.

immunology↗

bioRxiv2020

The genome of North American beaver provides insights into the mechanisms of its longevity and cancer resistance

The North American beaver (Castor canadensis) is an exceptionally long-lived and cancer-resistant rodent species, and thus an excellent model organism for comparative genomic studies of longevity. Here, we utilize a significantly improved beaver genome assembly to assess evolutionary changes in gene coding sequences, copy number, and expression. We found that the beaver Aldh1a1, a stem cell marker gene encoding an enzyme required for detoxification of ethanol and aldehydes, is expanded (~10 copies vs. two in mouse and one in human). We also show that the beaver cells are more resistant to ethanol, and beaver liver extracts show higher ability to metabolize aldehydes than the mouse samples. Furthermore, Hpgd, a tumor suppressor gene, is uniquely duplicated in the beaver among rodents. Our evolutionary analysis identified beaver genes under positive selection which are associated with tumor suppression and longevity. Genes involved in lipid metabolism show positive selection signals, changes in copy number and altered gene expression in beavers. Several genes involved in DNA repair showed a higher expression in beavers which is consistent with the trend observed in other long-lived mammals. In summary, we identified several genes that likely contribute to beaver longevity and cancer resistance, including increased ability to detoxify aldehydes, enhanced tumor suppression and DNA repair, and altered lipid metabolism.

genomics↗

bioRxiv2020

ISG15 drives immune pathology and respiratory failure during viral infection

Cytokine storm during respiratory viral infection is an indicator of disease severity and poor prognosis. Type 1 interferon (IFN-I) production and signaling has been reported to be causal in cytokine storm-associated pathology in several respiratory viral infections, however, the mechanisms by which IFN-I promotes disease pathogenesis remain poorly understood. Here, using Usp18-deficient, USP18 enzymatic-inactive and Isg15-deficient mouse models, we report that lack of deISGylation during persistent viral infection leads to severe immune pathology characterized by hematological disruptions, cytokine amplification, lung vascular leakage and death. This pathology requires T cells but not T cell-intrinsic deletion of Usp18. However, lack of Usp18 in myeloid cells mimicked the pathological manifestations observed in Usp18-/- or Usp18C61A mice which were dependent on Isg15. We further mechanistically demonstrate that interrupting the ISGylation/deISGylation circuit increases extracellular levels of ISG15 which is accompanied by inflammatory neutrophil accumulation to the lung. Importantly, neutrophil depletion reversed morbidity and mortality in Usp18C61A mice. In summary, we reveal that the enzymatic function of Usp18 is crucial for regulating extracellular release of ISG15. This is accompanied by altered neutrophil differentiation, cytokine amplification and mortality following persistent viral infection. Moreover, our results suggest that extracellular ISG15 may drive the inflammatory pathology observed and could be both a prospective predictor of disease outcome and a therapeutic target during severe respiratory viral infections.

immunology↗

bioRxiv2020

Analysis of biosynthesis and composition of cuticular wax in wild type bilberry (Vaccinium myrtillus L.) and its glossy mutant

Cuticular wax plays an important role in fruits in protection against environmental stresses and desiccation. In this study, biosynthesis and chemical composition of cuticular wax in wild type (WT) bilberry fruit was studied during development and compared with its natural glossy type (GT) mutant. The cuticular wax load in GT fruit was comparable to WT fruit. In both fruits, triterpenoids were the dominant wax compounds with decreasing proportion during the fruit development accompanied with increasing proportion of aliphatic compounds. Gene expression studies supported the pattern of compound accumulation during fruit development. Genes CER26-like, FAR2, CER3-like, LTP, MIXTA, and BAS exhibited prevalent expression in fruit skin indicating role in cuticular wax biosynthesis and secretion. In GT fruit, higher proportion of triterpenoids in cuticular wax was accompanied by lower proportion of fatty acids and ketones compared to WT fruit as well as lower density of crystalloid structures on berry surface. Our results suggest that a marked reduction in ketones in cuticular wax may play a significant role in the formation of glossy phenotype leading to the loss of rod-like structures in epicuticular wax layer of GT fruit. HighlightChemical composition and morphology of cuticular wax along with gene expression for wax biosynthetic genes varied between glossy type mutant (GT) and wild type (WT) fruit.

plant biology↗

bioRxiv2020

Traceback of Core Transcription Factors for Soybean Root Growth Maintenance under Water Deficit

Some crops inhibit shoot growth but maintain root growth under water-deficit conditions. Unraveling the molecular mechanisms of root plasticity under water deficit conditions in plants remains a major challenge. We developed an efficient platform for identifying core transcription factors (TFs) that collectively regulate each other and/or themselves in response to water stress, and exploring their interconnected regulatory circuitry involved in root growth maintenance under water deficit in soybean. We performed multi-species phylogenetic footprinting combined with spatial-temporal transcriptome analysis of soybean (Glycine max) roots under water deficit to identify conserved motifs that function in the water-stress response. Using these functional conserved cis-motifs, we applied a new approach to trace back motifs-associated core TFs ingroup as signal mediators, which mediate signaling between abiotic and endogenous stimuli. We integrated a co-functional TF-TF network and conserved motif-centered TF-DNA networks to construct a core TF network defined by mutual cross-regulation among core TFs. We found that core TF ARG (Abscisic acid response element binding factor-like Root Growth regulator) represses BRG (Brassinosteroid enhanced expression-like Root Growth regulator) expression through binding to its promoter at a conserved binding site. ARG and BRG antagonistically regulate Phytochrome-interacting factor-like Root Growth regulator (PRG) and combinatorially regulate some other core TFs. These core TFs form complex regulatory circuits to integrate light and multiple hormone signaling pathways and maintain root growth in response to varying degrees of water stress. Our study provides valuable information to unravel the complicated mechanisms of molecular networks involved in the regulation of root growth under water deficit.

plant biology↗

bioRxiv2020

D-Retro Inverso (DRI) Amylin and the Stability of Amylin Fibrils

Motivated by the role that amylin aggregates pay in type-II diabetes, we compare the stability of regular amylin fibrils with the stability of fibrils where L-amino acid chains are replaced by D-Retro Inverso (DRI) amylin, i.e., peptides where the sequence of amino acids is reversed, and at the same time the L-amino acids are replaced by their mirror images. Our molecular dynamics simulations show that despite leading to only marginal difference in fibril structure and stability, aggregating DRI-amylin peptides have different pattern of contacts and hydrogen bonding. Because of these differences does DRI-amylin, when interacting with regular (L) amylin, alter the elongation process and lowers the stability of hybrid amylin fibrils. Our results suggest not only a potential use of DRI-amylin as inhibitor of amylin fibril-formation, but points also to the possibility of using insertion of DRI-proteins in L-assemblies as a way to probe the role of certain kinds of hydrogen bonds in supra-molecular assemblies or aggregates.

molecular biology↗

bioRxiv2019

Frequent extrachromosomal oncogene amplification drives aggressive tumors

Extrachromosomal DNA (ecDNA) amplification promotes high oncogene copy number, intratumoral genetic heterogeneity, and accelerated tumor evolution1-3, but its frequency and clinical impact are not well understood. Here we show, using computational analysis of whole-genome sequencing data from 1,979 cancer patients, that ecDNA amplification occurs in at least 26% of human cancers, of a wide variety of histological types, but not in whole blood or normal tissue. We demonstrate a highly significant enrichment for oncogenes on amplified ecDNA and that the most common recurrent oncogene amplifications arise on ecDNA. EcDNA amplifications resulted in higher levels of oncogene transcription compared to copy number matched linear DNA, coupled with enhanced chromatin accessibility. Patients whose tumors have ecDNA-based oncogene amplification showed increase of cell proliferation signature activity, greater likelihood of lymph node spread at initial diagnosis, and significantly shorter survival, even when controlled for tissue type, than do patients whose cancers are not driven by ecDNA-based oncogene amplification. The results presented here demonstrate that ecDNA-based oncogene amplification plays a central role in driving the poor outcome for patients with some of the most aggressive forms of cancers.

cancer biology↗

bioRxiv2019

Incipient local adaptation in a fungus: evolution of heavy metal tolerance through allelic and copy-number variation

Human-altered environments can shape the evolution of organisms. Fungi are no exception, though little is known about how they withstand anthropogenic pollution. Here, we document incipient polygenic local adaptation in the mycorrhizal fungus Suillus luteus driven by recent soil heavy metal contamination. Genome scans across individuals from recently polluted and nearby unpolluted soils in Belgium revealed no evidence of population structure but detected allelic divergence and gene copy number variation in genes involved in metal exclusion, storage, immobilization, and reactive oxygen species detoxification. Standing genetic variation included multiple alleles of small effects contributing to heavy metal tolerance, suggesting the existence of different strategies to withstand contamination. These variants were shared across the whole population but under selection in isolates exposed to pollution. Together, our results point to S. luteus undergoing the initial steps of adaptive divergence and contribute to understanding the processes underlying local adaptation under strong environmental selection.

evolutionary biology↗