Biology subjects

Nguyen, C.

Publications and source records attributed to Nguyen, C..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

Embracing firefly flash pattern variability with data-driven species classification

Many nocturnally active fireflies use precisely timed bioluminescent patterns to identify mates, making them especially vulnerable to light pollution. As urbanization continues to brighten the night sky, firefly populations are under constant stress, and close to half of the species are now threatened. Ensuring the survival of firefly biodiversity depends on a large-scale conservation effort to monitor and protect thousands of populations. While species can be identified by their flash patterns, current methods require expert measurement and manual classification and are infeasible given the number and geographic distribution of fireflies. Here we present the application of a recurrent neural network (RNN) for accurate automated firefly flash pattern classification. Using recordings from commodity cameras, we can extract flash trajectories of individuals within a swarm and classify their species with a precision and recall of approximately seventy percent. In addition to scaling population monitoring, automated classification provides the means to study firefly behavior at the population level. We employ the classifier to measure and characterize the variability within and between swarms, unlocking a new dimension of their behavior. Our method is open source, and deployment in community science applications could revolutionize our ability to monitor and understand firefly populations.

ecology↗

bioRxiv2023

Multivariate adaptive shrinkage improves cross-population transcriptome prediction for transcriptome-wide association studies in underrepresented populations

Transcriptome prediction models built with data from European-descent individuals are less accurate when applied to different populations because of differences in linkage disequilibrium patterns and allele frequencies. We hypothesized methods that leverage shared regulatory effects across different conditions, in this case, across different populations may improve cross-population transcriptome prediction. To test this hypothesis, we made transcriptome prediction models for use in transcriptome-wide association studies (TWAS) using different methods (Elastic Net, Joint-Tissue Imputation (JTI), Matrix eQTL, Multivariate Adaptive Shrinkage in R (MASHR), and Transcriptome-Integrated Genetic Association Resource (TIGAR)) and tested their out-of-sample transcriptome prediction accuracy in population-matched and cross-population scenarios. Additionally, to evaluate model applicability in TWAS, we integrated publicly available multi-ethnic genome-wide association study (GWAS) summary statistics from the Population Architecture using Genomics and Epidemiology Study (PAGE) and Pan-UK Biobank with our developed transcriptome prediction models. In regard to transcriptome prediction accuracy, MASHR models performed better or the same as other methods in both population-matched and cross-population transcriptome predictions. Furthermore, in multi-ethnic TWAS, MASHR models yielded more discoveries that replicate in both PAGE and PanUKBB across all methods analyzed, including loci previously mapped in GWAS and new loci previously not found in GWAS. Overall, our study demonstrates the importance of using methods that benefit from different populations effect size estimates in order to improve TWAS for multi-ethnic or underrepresented populations.

genomics↗

bioRxiv2023

Epigenetic signature of human immune aging: the GESTALT study.

Age-associated DNA methylation in blood cells convey information on health status. However, the mechanisms that drive these changes in circulating cells and their relationships to gene regulation are unknown. We identified age-associated DNA methylation sites in six purified blood borne immune cell types (naive B, naive CD4+and CD8+ T cells, granulocytes, monocytes and NK cells) collected from healthy individuals interspersed over a wide age range. Of the thousand of age-associated sites, only 350 sites were differentially methylated in the same direction in all cell types and validated in an independent longitudinal cohort. Genes close to age-associated hypomethylated sites were enriched for collagen biosynthesis and complement cascade pathways, while genes close to hypermethylated sites mapped to neuronal pathways. In-silico analyses showed that in most cell types, the age-associated hypo- and hypermethylated sites were enriched for ARNT (HIF1{beta}) and REST transcription factor motifs respectively, which are both master regulators of hypoxia response. To conclude, despite spatial heterogeneity, there is a commonality in the putative regulatory role with respect to transcription factor motifs and histone modifications at and around these sites. These features suggest that DNA methylation changes in healthy aging may be adaptive responses to fluctuations of oxygen availability.

molecular biology↗

bioRxiv2022

ApoE isoforms differentially regulate neuronal membrane proteasomes to shift the threshold for pathological aggregation of endogenous Tau

Neuroproteasomes are a subset of 20S proteasomes that are localized to the neuronal plasma membrane and degrade newly synthesized proteins. To date, the molecular composition of neuroproteasomes is undefined, and moreover, whether neuroproteasomes can influence protein aggregation with relevance to neurodegenerative disorders remains unexplored. Using a Cre-dependent conditional knock-in mouse line to endogenously tag the proteasome, we find that neuroproteasomes co-purify with ApoE, the most significant risk factor for late-onset Alzheimers Disease (AD). We discover that neuroproteasome membrane localization is differentially modulated by ApoE isoforms (E4<E3<E2) in vitro, in vivo, and in human postmortem samples. We synthesized selective, neuroproteasome-specific inhibitors and discovered that neuroproteasome inhibition induces aggregation of endogenous mouse and human Tau, without the need for seeding or pathogenic mutations. Using hApoE-KI/hTau-KI crosses, we find that ApoE isoforms differentially shift the aggregation threshold for Tau. Neuroproteasome inhibition in vivo is sufficient to induce sarkosyl-insoluble and Thioflavin-S positive endogenous Tau aggregates in only three days, which are completely abrogated by co-application of cycloheximide. Newly synthesized Tau levels increase threefold after neuroproteasome inhibition, leading us to posit that newly synthesized Tau is uniquely susceptible to aggregation due to neuroproteasome dysfunction. Overall, our data define neuroproteasomes as a pivotal proteostasis mechanism underlying the formation of endogenous Tau aggregates, which is directly regulated by the largest genetic risk factor for late-onset Alzheimers Disease.

neuroscience↗

bioRxiv2022

DNA-PAINT single-particle tracking (DNA-PAINT-SPT) enables extended single-molecule studies of membrane protein interactions

DNA-PAINT based single-particle tracking (DNA-PAINT-SPT) has recently significantly enhanced observation times in in vitro SPT experiments by overcoming the constraints of fluorophore photobleaching. However, with the reported implementation, only a single target can be imaged and the technique cannot be applied straight to live cell imaging. Here we report on leveraging this technique from a proof-of-principle implementation to a useful tool for the SPT community by introducing simultaneous live cell dual-colour DNA-PAINT-SPT for quantifying protein dimerisation and tracking proteins in living cell membranes, demonstrating its improved performance over single-dye SPT.

biophysics↗

bioRxiv2022

Brainstem modulation of nociception by periaqueductal gray neurons expressing the mu-opioid receptor

Pharmacological manipulations directed at the periaqueductal gray (PAG) have revealed the importance of the mu-opioid receptor in the endogenous pain-modulatory system. Despite the clear role for opioidergic signaling within the PAG for the descending modulation of pain, the molecular and anatomical characterizations of neurons containing the mu-opioid receptor remain elusive. Using combinatorial anatomical, optogenetic, and chemogenetic approaches, we delineate a supraspinal pathway centered on PAGMOR neurons in the modulation of pain and itch behaviors. We found that chemogenetic manipulations of PAGMOR neurons in assays of nociception unveiled complex results; whereas activation of these neurons generally facilitated responses to noxious stimuli and jumping behaviors on the hotplate assay, opposing patterns were observed with reflexive responses to sensory testing. Activation of PAGMOR neurons also robustly inhibited itch. These dichotomous findings across distinct types of sensory testing emphasize the contextual behavioral expression of nociception using reflexive and noxious paradigms. Lastly, we uncovered the role for PBN projections in the PAG that modulate pain in an uninjured, post-surgical state of latent sensitization.

neuroscience↗

bioRxiv2022

Noise-mediated self-organization in mutually shading sunflowers

Circumnutations are widespread in plants and typically associated with exploratory movements, however a quantitative understanding of their role remains elusive. In this study we report, for the first time, the role of noisy circumnutations in facilitating an optimal growth pattern within a crowded group of mutually shading plants. We revisit the problem of self-organization observed for sunflowers, mediated by shade response interactions. Our analysis reveals that circumnutation movements conform to a bounded random walk characterized by a remarkably broad distribution of velocities, covering three orders of magnitude. In motile animal systems such wide distributions of movement velocities are frequently identified with enhancement of behavioral processes, suggesting that circumnutations may serve as a source of functional noise. To test our hypothesis, we developed a Langevin-type parsimonious model of interacting growing disks, informed by experiments, successfully capturing the characteristic dynamics of individual and multiple interacting plants. Employing our simulation framework we examine the role of circumnutations in the system, and find that the observed breadth of the velocity distribution represents a sharp transition in the force-noise ratio, conferring advantageous effects by facilitating exploration of potential configurations, leading to an optimized arrangement with minimal shading. These findings represent the first report of functional noise in plant movements, and establishes a theoretical foundation for investigating how plants navigate their environment by employing computational processes such as task-oriented processes, optimization, and active sensing. Since plants move by growing, space and time are coupled, and dynamics of self-organization lead to emergent 3D patterns. As such this system provides conceptual insight for other interacting growth-driven systems such fungal hyphae, neurons and self-growing robots, as well as active matter systems where agents interact with past trajectories of their counterparts, such as stigmergy in social insects. This foundational insight has implications in statistical physics, ecological dynamics, agriculture, and even swarm robotics. One sentence summary of paperThe study highlights noisy circumnutations as a strategy plants use for optimizing growth in crowded conditions.

plant biology↗

bioRxiv2022

Lipid flipping in the omega-3 fatty-acid transporter

Mfsd2a is the primary transporter for the docosahexaenoic acid (DHA), an omega-3 fatty acid, across the blood brain barrier (BBB). Defects in Mfsd2a are linked to ailments from behavioral, learning, and motor dysfunctions to severe microcephaly. Mfsd2a typically transports long-chain unsaturated fatty-acids, including DHA and -Linolenic acid (ALA), that are attached to the zwitterionic lysophosphatidylcholine (LPC) headgroup. Even with two recently determined structures of Mfsd2a the molecular details of how this transporter performs the energetically unfavorable task of translocating and flipping lysolipids across the lipid bilayer remained unclear. Here, we report five single-particle cryo-EM structures of the Danio rerio Mfsd2a (drMfsd2a): in the inward-open conformation in the ligand-free state and bound to ALA-LPC at four unique positions along the substrate translocation pathway. These Mfsd2a snapshots detail the Na+-dependent flipping mechanism of the lipid-LPC from outer to inner membrane leaflet during ligand translocation through the Mfsd2a substrate tunnel and release for membrane integration on the cytoplasmic side. These results also map Mfsd2a mutants that disrupt lipid-LPC transport and are associated with known disease. Together these results provide a model for omega-3 fatty-acid transport and has the potential for the design of the delivery strategies for amphipathic drugs across the BBB.

biophysics↗

bioRxiv2022

Firefly-inspired vocabulary generator for communication in multi-agent systems

Fireflies dazzling light displays are courtship rituals: flying males announce their presence as suitable mates to the females on the ground. Their light signal is composed of a species-specific on/off light sequence repeated periodically. However, thousands of fireflies flashing in a swarm can create immense visual clutter that hinders the detection of potential mates. A partial solution to this visual clutter problem is to flash according to sequences that are more distinct and detectable than those of other individuals. Here, we investigate how distinguishable flash sequences can co-evolve by developing a method for simulating sequences that minimize their mutual similarity with each other while minimizing their energetic cost and predation risk. This simple set of rules produces flash sequences that are remarkably similar to those of real fireflies. In particular, we observe an emergent periodicity in the resulting sequences, despite the lack of any periodicity requirements on the sequences. In addition, we demonstrate a method of reconstructing the evolutionary pressures acting on sets of firefly species. We do so by carrying out simulations that follow known phylogenetic relationships of extant species alongside their characteristic flash patterns.

animal behavior and cognition↗

bioRxiv2022

Osteoclast-mediated resorption primes the skeleton for successful integration during axolotl limb regeneration

Early events during axolotl limb regeneration include an immune response and the formation of a wound epithelium. These events are linked to a clearance of damaged tissue prior to blastema formation and regeneration of the missing structures. Here, we report the resorption of calcified skeletal tissue as an active, cell-driven and highly regulated event. This process, carried out by osteoclasts, is essential for a successful integration of the newly formed skeleton. Indeed, the extent of resorption is directly correlated with the integration efficiency. Moreover, we identified the wound epithelium as a major regulator of skeletal resorption, likely creating a zone of influence in which signals involved in recruitment/differentiation of osteoclasts are released. Finally, we reported a correlation between resorption and blastema formation, particularly, a coordination of resorption with cartilage condensation. In sum, our results identify resorption as a major event upon amputation, playing a critical role in the overall process of skeletal regeneration.

developmental biology↗

bioRxiv2022

Ancestral origins are associated with SARS-CoV-2 susceptibility and protection in a Florida patient population

COVID-19 is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The severity of COVID-19 is highly variable and related to known (e.g., age, obesity, immune deficiency) and unknown risk factors. The widespread clinical symptoms encompass a large group of asymptomatic COVID-19 patients, raising a crucial question regarding genetic susceptibility, e.g., whether individual differences in immunity play a role in patient symptomatology and how much human leukocyte antigen (HLA) contributes to this. To reveal genetic determinants of susceptibility to COVID-19 severity in the population and further explore potential immune-related factors, we performed a genome-wide association study on 284 confirmed COVID-19 patients (cases) and 95 healthy individuals (controls). We compared cases and controls of European (EUR) ancestry and African American (AFR) ancestry separately. We identified two loci on chromosomes 5q32 and 11p12, which reach the significance threshold of suggestive association (p<1x10-5 threshold adjusted for multiple trait testing) and are associated with the COVID-19 susceptibility in the European ancestry (index rs17448496: odds ratio [OR] = 0.173; 95% confidence interval [CI], 0.08-0.36 for G allele; p=5.15x 10-5 and index rs768632395: OR = 0.166; 95% CI, 0.07-0.35 for A allele; p= 4.25x10-6, respectively), which were associated with two genes, PPP2R2B at 5q32, and LRRC4C at 11p12, respectively. To explore the linkage between HLA and COVID-19 severity, we applied fine-mapping analysis to dissect the HLA association with mild and severe cases. Using In-silico binding predictions to map the binding of risk/protective HLA to the viral structural proteins, we found the differential presentation of viral peptides in both ancestries. Lastly, extrapolation of the identified HLA from the cohort to the worldwide population revealed notable correlations. The study uncovers possible differences in susceptibility to COVID-19 in different ancestral origins in the genetic background, which may provide new insights into the pathogenesis and clinical treatment of the disease.

genetics↗

bioRxiv2022

Inflammaging in human photoexposed skin: Early onset of senescence and imbalanced epidermal homeostasis across the decades.

Inflammaging is a theory of aging which purports that low-level chronic inflammation leads to cellular dysfunction and premature aging of surrounding tissue. Skin is susceptible to inflammaging because it is the first line of defense from the environment, particularly solar radiation. To better understand the impact of aging and photoexposure on epidermal biology we performed a systems biology-based analysis of photoexposed face and arm and photoprotected buttock sites from women between the ages of 20s to 70s. Biopsies were analyzed by histology, transcriptomics, and proteomics and skin surface biomarkers collected from tape strips. We identified morphological changes with age of epidermal thinning, rete ridge pathlength loss, and stratum corneum thickening. The SASP biomarkers IL-8 and IL-1RA/IL1- were consistently elevated in face across age and cis/trans-urocanic acid were elevated in arms and face with age. In older arms, the DNA damage response biomarker 53BP1 showed higher puncti numbers in basal layers and epigenetic aging was accelerated. Genes associated with differentiation and senescence show increasing expression in the 30s whereas genes associated with hypoxia and glycolysis increase in the 50s. Proteomics comparing 60s vs 20s confirmed elevated levels of differentiation and glycolytic related proteins. Representative immunostaining for proteins of differentiation, senescence, and oxygen sensing/hypoxia shows similar relationships. This systems biology-based analysis provides a body of evidence that young photoexposed skin is undergoing inflammaging. We propose the presence of chronic inflammation in young skin contributes to an imbalance of epidermal homeostasis that leads to a prematurely aged appearance during later life.

systems biology↗

bioRxiv2022

Single-cell analysis of skeletal muscle macrophages reveals age- associated functional subpopulations

Tissue-resident macrophages represent a group of highly responsive innate immune cells that acquire diverse functions by polarizing towards distinct subgroups. The subgroups of macrophages that reside in skeletal muscle (SKM) and their changes during aging are poorly characterized. By single-cell transcriptomic analysis, we found that mouse SKM macrophages primarily comprise two large populations, "healing" LYVE1+ and "proinflammatory" LYVE1-macrophages. SKM macrophages were further classified into four functional subgroups based on the expression levels of another cell-surface marker, MHCII: LYVE1+/MHCII-lo (similar to alternatively activated M2), LYVE1-/MHCII-hi (similar to classically activated M1), and two new subgroups, LYVE1+/MHCII-hi and LYVE1-/MHCII-lo. Notably, the new subgroup LYVE1+/MHCII-hi had traits of both M2 and M1 macrophages, while the other new subgroup, LYVE1-/MHCII-lo, expressed high levels of mRNAs encoding cytotoxicity proteins. Flow cytometric analysis validated the presence of the four macrophage subgroups in SKM. In old SKM, LYVE1-macrophages were more abundant than LYVE1+ macrophages. Furthermore, complementary unsupervised classification revealed the emergence of specific macrophage subclusters expressing abundant proinflammatory markers, including S100a8 and S100a9 in aged SKM. In sum, our study has identified dynamically polarized mouse SKM macrophages and further uncovered the contribution of specific macrophage subpopulations to the proinflammatory status in old SKM.

cell biology↗

bioRxiv2021

Prolonged nicotine exposure reduces aversion to the drug in mice by altering nicotinic transmission in the interpeduncular nucleus.

Nicotine intake is likely to result from a balance between the rewarding and aversive properties of the drug, yet the individual differences in neural activity that control aversion to nicotine and their adaptation during the addiction process remain largely unknown. Using a two-bottle choice experiment, we observed a high heterogeneity in nicotine-drinking profiles in isogenic adult male mice, with about half of the mice persisting in consuming nicotine even at high concentrations, whereas the other half stopped consuming. We found that nicotine intake was negatively correlated with nicotine-evoked currents in the interpeduncular nucleus (IPN), and that prolonged exposure to nicotine, by weakening this response, decreased aversion to the drug, and hence boosted consumption. Lastly, using knock-out mice and local gene re-expression, we identified {beta}4-containing nicotinic acetylcholine receptors of IPN neurons as the molecular and cellular correlates of nicotine aversion. Collectively, our results identify the IPN as a substrate of individual variabilities and adaptations in nicotine consumption.

neuroscience↗

bioRxiv2021

Improving Lab Culture Through Self-Assessment: A Case Study

PurposeMotivated by perceived dissatisfaction within our labs changed working environment brought about by the COVID-19 pandemic, we performed a self-assessment of our lab culture through anonymous surveys and live sessions. MethodsIn Survey 1, we asked each lab member to identify and rank up to 10 values that are important for a healthy lab environment. They were then asked to rate how well the lab embodied those values at two time points: before the COVID-19 pandemic while working onsite, and at the time of the survey while working remotely (10 months into the pandemic). In a series of live group sessions, we reviewed relevant literature and the survey results to finalize ten themes. We then reflected on each theme and proposed action items to address any deficiencies. Finally, we conducted Survey 2 after the self-assessment to judge the groups finalized themes, implemented changes, and overall satisfaction with the assessment process. ResultsThemes identified were attitude, accountability, teamwork/collaboration, communication, diversity/inclusion, emotional intelligence, integrity, training, well-being, and adaptability in crisis-management. All lab members liked the self-assessment process and felt their voices were heard. On average, there was a 12% increase in satisfaction across all themes from the start to end of the lab assessment. ConclusionWe successfully assessed the culture of our lab and subsequently improved lab member satisfaction. The success of this team project suggests that other scientific labs could benefit from similar interactive self-assessments.

scientific communication and education↗

bioRxiv2021

Opposing roles of Granzymes A and B in the immune response to intestinal infection

Intestinal intraepithelial T lymphocytes (IEL) constitutively express high amounts of the cytotoxic proteases Granzymes (Gzm) A and B and are therefore thought to protect the intestinal epithelium against infection by killing infected epithelial cells. However, the role of IEL granzymes in a protective immune response has yet to be demonstrated. We show that GzmA and GzmB are required to protect mice against oral, but not intravenous, infection with Salmonella enterica serovar Typhimurium, consistent with an intestine-specific role. IEL-intrinsic granzymes mediate the protective effects by controlling intracellular bacterial growth and aiding in cell-intrinsic pyroptotic cell death of epithelial cells. Surprisingly, we found that both granzymes play non- redundant roles. GzmB-/- mice carried significantly lower burdens of Salmonella, as predominant GzmA-mediated cell death effectively reduced bacterial translocation across the intestinal barrier. Conversely, in GzmA-/-mice, GzmB-driven apoptosis favored luminal Salmonella growth by providing nutrients, while still reducing translocation across the epithelial barrier. Together, the concerted actions of both GzmA and GzmB balance cell death mechanisms at the intestinal epithelium to provide optimal control that Salmonella cannot subvert. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/467595v3_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@2b2c9corg.highwire.dtl.DTLVardef@7de81eorg.highwire.dtl.DTLVardef@1209d2org.highwire.dtl.DTLVardef@42dffb_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

Gut microbiota analyses of Saudi populations for type 2 diabetes-related phenotypes reveals significant association

Large-scale gut microbiome sequencing has revealed key links between microbiome dysfunction and metabolic diseases such as T2D. To date, these efforts have largely focused on Western populations, with few studies assessing T2D microbiota associations in Middle Eastern communities where T2D prevalence is now over 20%. We analyzed the composition of stool 16S rRNA from 461 T2D and 119 non-T2Dparticipants from the Eastern Province of Saudi Arabia. We quantified the abundance of microbial communities to examine any significant differences between subpopulations of samples based on diabetes status and glucose level. We observed overall positive enrichment within diabetics compared to healthy individuals and amongst diabetic participants; those with high glucose levels exhibited slightly more positive enrichment compared to those at lower risk of fasting hyperglycemia. In particular, the genus Firmicutes was upregulated in diabetic participants compared to non-diabetic participants, and T2D was associated with an elevated Firmicutes/Bacteroidetes ratio, consistent with previous findings. Based on diabetes status and glucose levels of Saudi participants, relatively stable differences in stool composition were perceived by differential abundance and alpha diversity measures. Author summaryThe rates of Type 2 diabetes (T2D) in Saudi Arabia have risen dramatically in the last several decades due to socio-economic changes resulting in changes in dietary and sedentary lifestyles. This emergence has grown more rapidly and affects larger proportions of the population with estimates of T2D prevalence impacting 25% of the population. There is a paucity of microbiome data from Middle Eastern populations, and previous studies have been conducted on small sample sizes. Here we report on the first-ever characterization of gut microbiota T2D versus non-T2D and largest microbiome study ever conducted in a Middle Eastern country. The datasets from this study are important to create a regional reference T2D-microbiome catalogue which will propel the understanding of regional gut flora which are associated with T2D development. Based on T2D status and quantified glucose levels of Middle Eastern participants, relatively stable differences in stool composition were observed by differential abundance and alpha diversity measures. Comparing overlapping and varying patterns in gut microbiota with other studies is critical to assessing novel treatment options in light of a rapidly growing T2D health epidemic.

microbiology↗

bioRxiv2021

Emergent collective locomotion in an active polymer model of entangled worm blobs

Numerous worm and arthropod species form physically-connected aggregations in which interactions among individuals give rise to emergent macroscale dynamics and functionalities that enhance collective survival. In particular, some aquatic worms such as the California blackworm (Lumbriculus variegatus) entangle their bodies into dense blobs to shield themselves against external stressors and preserve moisture in dry conditions. Motivated by recent experiments revealing emergent locomotion in blackworm blobs, we investigate the collective worm dynamics by modeling each worm as a self-propelled Brownian polymer. Though our model is two-dimensional, compared to real three-dimensional worm blobs, we demonstrate how a simulated blob can collectively traverse temperature gradients via the coupling between the active motion and the environment. By performing a systematic parameter sweep over the strength of attractive forces between worms, and the magnitude of their directed self-propulsion, we obtain a rich phase diagram which reveals that effective collective locomotion emerges as a result of finely balancing a tradeoff between these two parameters. Our model brings the physics of active filaments into a new meso- and macroscale context and invites further theoretical investigation into the collective behavior of long, slender, semi-flexible organisms.

biophysics↗