Biology subjects

Nguyen, C.

Publications and source records attributed to Nguyen, C..

At least 73 records · Page 4Linked to original sources

bioRxiv2021

Gene regulatory networks underlying human microglia maturation

The fetal period is a critical time for brain development, characterized by neurogenesis, neural migration, and synaptogenesis1-3. Microglia, the tissue resident macrophages of the brain, are observed as early as the fourth week of gestation4 and are thought to engage in a variety of processes essential for brain development and homeostasis5-11. Conversely, microglia phenotypes are highly regulated by the brain environment12-14. Mechanisms by which human brain development influences the maturation of microglia and microglia potential contribution to neurodevelopmental disorders remain poorly understood. Here, we performed transcriptomic analysis of human fetal and postnatal microglia and corresponding cortical tissue to define age-specific brain environmental factors that may drive microglia phenotypes. Comparative analysis of open chromatin profiles using bulk and single-cell methods in conjunction with a new computational approach that integrates epigenomic and single-cell RNA-seq data allowed decoding of cellular heterogeneity with inference of subtype- and development stage-specific transcriptional regulators. Interrogation of in vivo and in vitro iPSC-derived microglia models provides evidence for roles of putative instructive signals and downstream gene regulatory networks which establish human-specific fetal and postnatal microglia gene expression programs and potentially contribute to neurodevelopmental disorders.

genomics↗

bioRxiv2021

Parasitic nematode fatty acid- and retinol-binding proteins compromise host immunity by interfering with host lipid signaling pathways

Parasitic nematodes cause significant morbidity and mortality globally. Excretory/secretory products (ESPs) such as fatty acid- and retinol- binding proteins (FARs) are hypothesized to suppress host immunity during infection, yet little is known about their interactions with host tissues. Leveraging the insect parasitic nematode, Steinernema carpocapsae, we provide the first in vivo study that shows FARs modulate animal immunity, causing an increase in susceptibility to bacterial infection. Next we determined that FARs dampen various aspects of the fly immune response including the phenoloxidase cascade and antimicrobial peptide (AMP) production. Finally, we found that FARs deplete lipid signaling precursors in vivo as well as bind to these fatty acids in vitro, suggesting that FARs elicit their immunomodulatory effects by altering the availability of lipid signaling molecules necessary for a functional immune response. Collectively, these data reveal a complex role for FARs in immunosuppression and provide detailed mechanistic insight into parasitism in phylum Nematoda. SignificanceA central aspect of parasitic nematode success is their ability to modify host biology, including evasion and/or subversion of host immunity. Modulation of host biology and the pathology caused by parasitic nematodes is largely effected through the release of proteins and small molecules. There are hundreds of proteins released by nematodes during an infection and few have been studied in detail. Fatty acid- and retinol-binding proteins (FARs) are a unique protein family released during infection. We report that nematode FARs from S. carpocapsae, C. elegans and A. ceylanicum dampen fly immunity decreasing resistance to infection. Mechanistically, this is achieved through modulation of the phenoloxidase cascade and antimicrobial peptide production. Furthermore, FARs alter the availability of lipid immune signaling precursors in vivo and show binding specificity in vitro. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=187 SRC="FIGDIR/small/436866v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@48f582org.highwire.dtl.DTLVardef@1ee4292org.highwire.dtl.DTLVardef@1548248org.highwire.dtl.DTLVardef@13574d6_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

molecular biology↗

bioRxiv2021

Neither wood ash application nor phosphorus-fertilisation mitigated the negative effects of whole-tree harvesting on a temperate oligotrophic forest.

Background and AimsConcerns about climate change and carbon economy have prompted the promotion of alternative energy sources, including forest-based bioenergy. An evaluation of the environmental consequences of intensive harvests (stumps and roots, and also branches and foliage) for energy wood supply, and use of wood-ash recycling as a compensatory practice, helps in the evaluation of the use of forest biomass for energy production. MethodsWe made use of records from a split-plot experimental site crossing four different intensities of biomass harvesting (Stem-Only Harvest [SOH], Aboveground Additional Harvest [AAH], Belowground Additional Harvest [BAH], and Whole-Tree Harvest [WTH]) and three compensation methods (control [C], wood ash application [A] and phosphorus fertilisation [P]) to evaluate, in the 11-years-old stand (maritime pine: Pinus pinaster) that followed the biomass exports of the former stand, their effects on nutrient budgets, tree growth, soil fertility, chemical properties and soil carbon. This site is located in a forest on a poor soil, under a warm temperate climate (SW France). Key resultsDespite their low additional biomass exports (+10% for AAH to +34% for WTH), the non-conventional harvest practices exported much higher quantities of nutrients than the conventional SOH technique (for example +145% for N and K in WTH). Consequently, these treatments had negative effects on the soil nutritive status. Additional biomass harvests impacted the soil organic matter content, with negative effects on P-organic, soil cation exchange capacity, exchangeable Ca, and most extractible nutrients. However, data suggested that tree growth and foliage nutrient content had not yet been significantly impacted by harvest treatments, whereas tree nutritional status was improved by P-fertiliser or wood ash. As expected, we observed a positive effect of wood ash application on soil pH and nutrient content but, like additional harvests, wood ash application decreased the pool of soil organic carbon (~10% of the initial stock with ~7% of N-total losses). ConclusionsOverall, this factorial experiment showed that exporting more forest biomass due to the additional harvesting of tree canopies, stumps and roots had negative consequences on the ecosystem biogeochemistry. Additional harvests have aggravated the poverty of the already oligotrophic soil, and decreased the soil organic carbon content. Importantly, applying nutrients as fertiliser or wood ash did not compensate for all the negative impacts of biomass exports and the method of wood ash recycling in forests could even decrease the soil organic carbon.

ecology↗

bioRxiv2021

RBPMS2 is a conserved regulator of alternative splicing that promotes myofibrillar organization and optimal calcium handling in cardiomyocytes

RationaleThe identification of novel cardiomyocyte-intrinsic factors that support heart function will expand the number of candidate genes and therapeutic options for heart failure, a leading cause of death worldwide. ObjectiveTo identify and characterize conserved regulators of cardiomyocyte function. Methods and ResultsWe report that the RNA-binding protein RBPMS2 is required for myofibril organization and the regulation of intracellular calcium dynamics in both zebrafish embryos and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). A differential expression screen in zebrafish uncovered enrichment of rbpms2 paralogs, rbpms2a and rbpms2b, in the myocardium. Double knock-out (rbpms2-null) embryos suffer from compromised ventricular filling during the relaxation phase of the cardiac cycle, which significantly reduces cardiac output. Whole transcriptome sequencing and validation studies revealed differential alternative splicing of several genes linked to cardiomyopathies in humans, including myosin binding protein C3 (mybpc3) and phospholamban (pln), consistent with a role in causing the observed ventricular deficiencies. Further, RBPMS2-null hiPSC-CMs exhibit myofibril and calcium handling defects that are highly analogous to those observed in the rbpms2-null zebrafish ventricle. ConclusionsTaken together, our data identify RBPMS2 as a conserved and essential regulator of alternative splicing that is required for myofibrillar organization and optimal calcium handling from zebrafish to humans.

developmental biology↗

bioRxiv2021

Comprehensive Assessment of Somatic Copy Number Variation Calling Using Next-Generation Sequencing Data

Copy number variation (CNV) is a common type of mutation that often drives cancer progression. With advances in next-generation sequencing (NGS), CNVs can be detected in a detailed manner via newly developed computational tools but quality of such CNV calls has not been carefully evaluated. We analyzed CNV calls reported by 6 cutting-edge callers for 91 samples which were derived from the same cancer cell line, prepared and sequenced by varying the following factors: type of tissue sample (Fresh vs. Formalin Fixed Paraffin Embedded (FFPE)), library DNA amount, tumor purity, sequencing platform (Whole-Genome Sequencing (WGS) versus Whole-Exome Sequencing (WES)), and sequencing coverage. We found that callers greatly determined the pattern of CNV calls. Calling quality was drastically impaired by low purity (<50%) and became variable when WES, FFPE, and medium purity (50%-75%) were applied. Effects of low DNA amount and low coverage were relatively minor. Our analysis demonstrates the limitation of benchmarking somatic CNV callers when the real ground truth is not available. Our comprehensive analysis has further characterized each caller with respect to confounding factors and examined the consistency of CNV calls, thereby providing guidelines for conducting somatic CNV analysis.

bioinformatics↗

bioRxiv2021

Chronic nicotine increases midbrain dopamine neuron activity and biases individual strategies towards reduced exploration in a foraging task.

Long-term exposure to nicotine alters brain circuits and induces profound changes in decision-making strategies, affecting behaviors both related and unrelated to drug seeking and consumption. Using an intracranial self-stimulation reward-based foraging task, we investigated the impact of chronic nicotine on the trade-off between exploitation and exploration, and the role of ventral tegmental area (VTA) dopamine (DA) neuron activity in decision-making unrelated to nicotine-seeking. Model-based and archetypal analysis revealed a substantial inter-individual variability in decision-making strategies, with mice passively exposed to chronic nicotine visiting more frequently options associated with higher reward probability and therefore shifting toward a more exploitative profile compared to non-exposed animals. We then mimicked the effect of chronic nicotine on the tonic activity of VTA DA neurons using optogenetics, and found that photo-stimulated mice had a behavioral phenotype very close to that of mice exposed to nicotine, suggesting that the dopaminergic control of the exploration/exploitation balance is altered under nicotine exposure. Our results thus reveal a key role of tonic midbrain DA in the exploration/exploitation trade-off and highlight a potential mechanism by which nicotine affects decision-making.

neuroscience↗

bioRxiv2021

DeepStrain: A Deep Learning Workflow for the Automated Characterization of Cardiac Mechanics

Myocardial strain analysis from cinematic magnetic resonance imaging (cine-MRI) data could provide a more thorough characterization of cardiac mechanics than volumetric parameters such as left-ventricular ejection fraction, but sources of variation including segmentation and motion estimation have limited its wide clinical use. We designed and validated a deep learning (DL) workflow to generate both volumetric parameters and strain measures from cine-MRI data, including strain rate (SR) and regional strain polar maps, consisting of segmentation and motion estimation convolutional neural networks developed and trained using healthy and cardiovascular disease (CVD) subjects (n=150). DL-based volumetric parameters were correlated (>0.98) and without significant bias relative to parameters derived from manual segmentations in 50 healthy and CVD subjects. Compared to landmarks manually-tracked on tagging-MRI images from 15 healthy subjects, landmark deformation using DL-based motion estimates from paired cine-MRI data resulted in an end-point-error of 2.9 {+/-} 1.5 mm. Measures of end-systolic global strain from these cine-MRI data showed no significant biases relative to a tagging-MRI reference method. On 4 healthy subjects, intraclass correlation coefficient for intra-scanner repeatability was excellent (>0.95) for strain, moderate to excellent for SR (0.690-0.963), and good to excellent (0.826-0.994) in most polar map segments. Absolute relative change was within ~5% for strain, within ~10% for SR, and <1% in half of polar map segments. In conclusion, we developed and evaluated a DL-based, end-to-end fully-automatic workflow for global and regional myocardial strain analysis to quantitatively characterize cardiac mechanics of healthy and CVD subjects based on ubiquitously acquired cine-MRI data.

bioinformatics↗

bioRxiv2020

Variation in pyrethroid resistance phenotypes in Anopheles darlingi from residual malaria transmission area: warning on suspected resistance built-up in French Guiana.

Anopheles darlingi is the major vector of malaria in South America. In French Guiana, malaria transmission occurs inland and along the rivers with a particular reemergence in the lower Oyapock area. Control against malaria vector is performed using deltamethrin indoor residual spraying and long lasting impregnated bednets. For four years, the level of resistance to pyrethroids was monitored using CDC bottle tests in An. darlingi populations. Resistance built-up was suspected in a mosquito population in malaria endemic area but did not sustained, supposably due to the reintroduction of susceptible alleles. No mutation on the insecticide target genes was found, metabolic resistance is then suspected.

zoology↗

bioRxiv2020

Putative Pseudolysogeny-Dependent Phage Gene Implicated in the Superinfection Resistance of Cutibacterium acnes

BackgroundBacteriophage therapy is a promising option to minimize the risk of treatment-associated antibiotic resistance in Cutibacterium acnes. A novel phage (Aquarius) was isolated and analyzed to explore characteristics of C. acnes phages that may confer lysis-evasion properties. Materials and MethodsPhage superinfection resistance assays were performed with a range of C. acnes phages, which were assayed for pseudolysogeny via phage release assays and episome PCR. Bioinformatics and qRT-PCR were used to identify candidate genes related to observed phenotypes. ResultsAssay findings indicated that infected C. acnes strains were broadly resistant to superinfection and were capable of forming stable pseudolysogens. A conserved Ltp family-like gene contained protein signatures which may be contributing to phage-mediated superinfection resistance in a pseudolysogeny-dependent manner. ConclusionsC. acnes bacteria are capable of harboring phage pseudolysogens, and this phenomenon may result in superinfection resistance, necessitating consideration in targeting optimization of C. acnes phage-based therapy.

microbiology↗

bioRxiv2020

Functional Landscape of SARS-CoV-2 Cellular Restriction

A deficient interferon response to SARS-CoV-2 infection has been implicated as a determinant of severe COVID-19. To identify the molecular effectors that govern interferon control of SARS-CoV-2 infection, we conducted a large-scale gain-of-function analysis that evaluated the impact of human interferon stimulated genes (ISGs) on viral replication. A limited subset of ISGs were found to control viral infection, including endosomal factors that inhibited viral entry, nucleic acid binding proteins that suppressed viral RNA synthesis, and a highly enriched cluster of ER and Golgi-resident ISGs that inhibited viral translation and egress. These included the type II integral membrane protein BST2/tetherin, which was found to impede viral release, and is targeted for immune evasion by SARS-CoV-2 Orf7a protein. Overall, these data define the molecular basis of early innate immune control of viral infection, which will facilitate the understanding of host determinants that impact disease severity and offer potential therapeutic strategies for COVID-19.

microbiology↗

bioRxiv2020

Distinct dopamine circuits transmit the reinforcing and anxiogenic effects of nicotine

Nicotine, the addictive component of tobacco, stimulates dopamine (DA) neurons of the ventral tegmental area (VTA) to establish and maintain reinforcement. Nicotine also induces negative emotional states such as anxiety, yet through an unknown circuitry. Here we show that nicotine at reinforcing doses drives opposite functional responses on two distinct populations of VTA DA neurons with anatomically segregated projections: it activates those that project to the nucleus accumbens (NAc) while it inhibits those that project to the amygdala nuclei (Amg). We further show that nicotine, by acting on {beta}2 subunit-containing nicotinic acetylcholine receptors of the VTA, mediates both reinforcement and anxiety. Finally, using optogenetic experiments we dissociate the roles of the VTA-NAc excitation and VTA-Amg inhibition in reinforcement and anxiety-like behavior, respectively. We thus propose that the positive and negative behavioral outcomes of nicotine consumption involve distinct subpopulations of VTA DA neurons with opposite responses to nicotine.

neuroscience↗

bioRxiv2020

Identification of French Guiana anopheline mosquitoes by MALDI-TOF MS profiling using protein signatures from two body parts.

In French Guiana, the malaria, a parasitic infection transmitted by Anopheline mosquitoes, remains a disease of public health importance. To prevent malaria transmission, the main effective way remains Anopheles control. For an effective control, accurate Anopheles species identification is indispensable to distinguish malaria vectors from non-vectors. Although, morphological and molecular methods are largely used, an innovative tool, based on protein pattern comparisons, the Matrix Assisted Laser Desorption / Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) profiling, emerged this last decade for arthropod identification. However, the limited mosquito fauna diversity of reference MS spectra remains one of the main drawback for it large usage. The aim of the present study was then to create and to share reference MS spectra for the identification of French Guiana Anopheline species. A total of eight distinct Anopheles species, among which four are malaria vectors, were collected in 6 areas. To improve Anopheles identification, two body parts, legs and thoraxes, were independently submitted to MS for the creation of respective reference MS spectra database (DB). This study underlined that double checking by MS enhanced the Anopheles identification confidence and rate of reliable classification. The sharing of this reference MS spectra DB should made easier Anopheles species monitoring in endemic malaria area to help malaria vector control or elimination programs.

microbiology↗

bioRxiv2020

A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals

The emergence of novel SARS coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of severe pneumonia-like disease designated as coronavirus disease 2019 (COVID-19). To date, more than 2.1 million confirmed cases and 139,500 deaths have been reported worldwide, and there are currently no medical countermeasures available to prevent or treat the disease. As the development of a vaccine could require at least 12-18 months, and the typical timeline from hit finding to drug registration of an antiviral is >10 years, repositioning of known drugs can significantly accelerate the development and deployment of therapies for COVID-19. To identify therapeutics that can be repurposed as SARS-CoV-2 antivirals, we profiled a library of known drugs encompassing approximately 12,000 clinical-stage or FDA-approved small molecules. Here, we report the identification of 30 known drugs that inhibit viral replication. Of these, six were characterized for cellular dose-activity relationships, and showed effective concentrations likely to be commensurate with therapeutic doses in patients. These include the PIKfyve kinase inhibitor Apilimod, cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825, and ONO 5334, and the CCR1 antagonist MLN-3897. Since many of these molecules have advanced into the clinic, the known pharmacological and human safety profiles of these compounds will accelerate their preclinical and clinical evaluation for COVID-19 treatment.

microbiology↗

bioRxiv2020

Mechanosensation Mediates Long-Range Spatial Decision-Making in an Aneural Organism

The unicellular protist Physarum polycephalum is an important emerging model for understanding how aneural organisms process information toward adaptive behavior. Here, we reveal that Physarum can use mechanosensation to reliably make decisions about distant objects its environment, preferentially growing in the direction of heavier, substrate-deforming but chemically-inert masses. This long-range mass-sensing is abolished by gentle rhythmic mechanical disruption, changing substrate stiffness, or addition of a mechanosensitive transient receptor potential channel inhibitor. Computational modeling revealed that Physarum may perform this calculation by sensing the fraction of its growth perimeter that is distorted above a threshold strain - a fundamentally novel method of mechanosensation. Together, these data identify a surprising behavioral preference relying on biomechanical features and not nutritional content, and characterize a new example of an aneural organism that exploits physics to make decisions about growth and form. HighlightsO_LIThe aneural Physarum makes behavioral decisions by control of its morphology C_LIO_LIIt has a preference for larger masses, which it can detect at long range C_LIO_LIThis effect is mediated by mechanosensing, not requiring chemical attractants C_LIO_LIMachine learning reveals that it surveys environment and makes decision in < 4 hours C_LIO_LIA biophysical model reveals how its pulsations enable long-distance mapping of environmental features C_LI

animal behavior and cognition↗

bioRxiv2020

Diagnostic Cerebrospinal Fluid Biomarker Discovery and Validation in Patients with Central Nervous System Infections

BackgroundCentral nervous system (CNS) infections are common causes of morbidity and mortality worldwide. Rapid, accurate identification of the likely cause is essential for clinical management and the early initiation of antimicrobial therapy, which potentially improves clinical outcome. MethodsWe applied liquid chromatography tandem mass-spectrometry on 45 cerebrospinal fluid (CSF) samples from a cohort of adults with/without CNS infections to discover potential diagnostic protein biomarkers. We then validated the diagnostic performance of a selected biomarker candidate in an independent cohort of 364 consecutively treated adults with CNS infections admitted to a referral hospital in southern Vietnam. ResultsIn the discovery cohort, we identified lipocalin 2 (LCN2) as a potential biomarker of bacterial meningitis. The analysis of the validation cohort showed that LCN2 could discriminate bacterial meningitis from other CNS infections, including tuberculous meningitis, cryptococcal meningitis and viral/antibody-mediated encephalitis (sensitivity: 0.88 (95% confident interval (CI): 0.77-0.94), specificity: 0.91 (95%CI: 0.88-0.94) and diagnostic odd ratio: 73.8 (95%CI: 31.8-171.4)). LCN2 outperformed other CSF markers (leukocytes, glucose, protein and lactate) commonly used in routine care worldwide. The combination of LCN2 and these four routine CSF markers resulted in the highest diagnostic performance for bacterial meningitis (area under receiver-operating-characteristic-curve 0.96; 95%CI: 0.93-0.99). ConclusionsOur results suggest that LCN2 is a sensitive and specific biomarker for discriminating bacterial meningitis from a broad spectrum of CNS infections. A prospective study is needed to further assess the diagnostic utility of LCN2 in the diagnosis and management of CNS infections.

microbiology↗

bioRxiv2019

Tubular STAT3 limits renal inflammation in autosomal dominant polycystic kidney disease

The inactivation of the ciliary proteins polycystin 1 or 2 leads to autosomal dominant polycystic kidney disease (ADPKD), the leading genetic cause of chronic kidney disease. Both cilia signaling and interstitial inflammation play a critical role in the disease. Yet, the reciprocal interactions between immune and tubular cells are not well characterized. The transcription factor STAT3, which is suspected to fuel ADPKD progression, is involved in crosstalks between immune and non-immune cells in various tissues and is a component of the cilia proteome. Here, we explore how STAT3 intersects with cilia signaling, renal inflammation and cyst growth using conditional murine models of post-developmental Pkd1, Stat3 and cilia ablation. Our results indicate that, although primary cilia directly modulate STAT3 activation in vitro, the bulk of STAT3 activation in polycystic kidneys occurs through an indirect mechanism in which primary cilia trigger macrophage recruitment to the kidney, which in turn promotes STAT3 activation. Surprisingly, while disrupting Stat3 in Pkd1 deficient tubules slightly reduced cyst burden, it resulted in a massive infiltration of the cystic kidneys by macrophages and T cells, precluding any improvement of kidney function. Mechanistically, STAT3 represses the expression of the inflammatory chemokines CCL5 and CXCL10 in polycystic kidneys and cultured tubular cells. These results demonstrate that STAT3 is not a critical driver of cyst growth in ADPKD but plays a major role in the crosstalk between immune and tubular cells that shapes disease expression.

pathology↗

bioRxiv2019

ExpansionHunter Denovo: A computational method for locating known and novel repeat expansions in short-read sequencing data

Expansions of short tandem repeats are responsible for over 40 monogenic disorders, and undoubtedly many more pathogenic repeat expansions (REs) remain to be discovered. Existing methods for detecting REs in short-read sequencing data require predefined repeat catalogs. However recent discoveries have emphasized the need for detection methods that do not require candidate repeats to be specified in advance. To address this need, we introduce ExpansionHunter Denovo, an efficient catalog-free method for genome-wide detection of REs. Analysis of real and simulated data shows that our method can identify large expansions of 41 out of 44 pathogenic repeats, including nine recently reported non-reference REs not discoverable via existing methods. ExpansionHunter Denovo is freely available at https://github.com/Illumina/ExpansionHunterDenovo

bioinformatics↗

bioRxiv2019

Social status influences normal and pathological behaviors in mice, a role for dopamine and stress signaling

The rules leading to the emergence of a social organization and the role of social hierarchy on normal and pathological behaviours remain elusive. Here we show that groups of four isogenic male mice rapidly form enduring social ranks in a dominance hierarchy. Highest ranked individuals display enhanced anxiety and working memory, are more social and more susceptible to stress-related maladaptive behaviours. Are these differences causes or consequences to social life? We show that anxiety emerges from life in colony whereas sociability is a pre-existing trait. Strikingly, highest ranked individuals exhibit lower bursting activity of VTA dopamine neurons. Both pharmacogenetic inhibition of this neuronal population and the genetic inactivation of glucocorticoid receptor signalling in dopamine-sensing brain areas promote the accession to higher social ranks. Altogether, these results indicate that the shaping of social fate relies upon the interplay of dopamine system and stress response, impacting individual behaviour and potentially mental health.

animal behavior and cognition↗