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Nguyen, H. T.

Publications and source records attributed to Nguyen, H. T..

At least 19 recordsLinked to original sources
bioRxiv2026

Urban Vietnam at the microbiome transition: Co-existing enterotypes reflect the global industrialization patterns

Vietnam's rapid socioeconomic and dietary transition offers a rare window into how industrialization is reflected in the gut microbiome, yet Vietnamese populations remain underrepresented in global reference datasets. We investigated whether healthy Vietnamese adults in Hanoi harbor microbial community configurations associated with different stages of industrialization. Metagenomic data from stool samples of 183 clinically screened participants in Hanoi were analyzed alongside 629 publicly available metagenomic datasets from populations in low to middle income (LMI) and high income (HI) countries. Species-level taxonomic composition and gene-content-based metabolic pathways were characterized using community clustering and multivariable association analyses. Rather than forming a single population profile, the Vietnamese cohort separated into two enterotypes that mirrored the global industrialization gradient. Enterotype 1 more closely resembled populations from LMICs and showed greater microbial richness and diversity, whereas Enterotype 2 aligned with taxonomic and functional profiles observed in HICs. Both taxonomic and functional potential shows similar trajectories. Diet and lifestyle patterns describe some of the variance between enterotypes, supporting an association between contemporary exposures and microbiome structure without establishing causation. Antibiotic resistance profiles also varied between enterotypes, suggesting that the transition may encompass functions relevant to antimicrobial exposure. Together, these findings position urban Vietnam at a microbiome transition, where community states associated with different levels of industrialization coexist within a single population. This Vietnamese reference cohort expands representation in global metagenomic research and provides a baseline for tracking how rapid socioeconomic change may reshape microbial ecology, metabolic capacity, and antimicrobial resistance.

microbiology↗
bioRxiv2026

Treeline ecotone habitat loss and upward shift is driven by land abandonment rather than climate change in the Italian Alps

1. Plant populations at high elevation persist near their physiological limits, and treeline position is one of the clearest expressions of this constraint. In many mountain regions, however, this limit reflects historical land use as much as climate. Treeline shift is most often tracked as the displacement of a boundary line (1D) overlooking structural changes only visible when the ecotone is analysed as a surface (2D). 2. We reconstructed treeline ecotone dynamics at nine sites in the Italian Alps using aerial imagery from 1954 and 2017. At each site we detected the timberline and tree species line, quantified elevational displacement, and measured ecotonal surface change, relating them to climatic, land-use, and topographic predictors. 3. Both boundaries advanced upslope at all nine sites, with timberlines shifting faster (1.6 m/yr) than tree species lines (1.1 m/yr). This decoupled velocity caused the ecotonal surface to contract by ~17%. Land-use variables consistently explained more variance than climatic ones. 4. Land-use legacy and abandonment have a major role in shaping treeline dynamics. Boundary displacement reveals vegetation advance at both margins, while the surface view reveals concurrent narrowing of the habitat available for tree establishment. Both perspectives are needed to fully characterize how plant populations respond to shifting limiting factors at the treeline ecotone.

ecology↗
bioRxiv2026

Molecular origins of heterogeneous aging and spatial organization in RNA condensates

The molecular origins of aging of biomolecular condensates, which play a central role in cellular organization, is poorly understood. Here, we use coarse-grained molecular simulations to investigate how RNA sequence and chain connectivity govern condensate aging over extended timescales. Condensates formed by CAG-repeat RNA undergo pronounced aging characterized by progressive dynamical slowing, loss of ergodicity, and the emergence of two distinct relaxation timescales. Aging proceeds heterogeneously in space, giving rise to a dynamically arrested, solid-like core surrounded by a more fluid shell. We demonstrate that aging is driven by sequence-encoded base pairing that favors RNA expansion, alignment and the formation of a dense interchain interaction network. These structural changes lead to increased topological entanglement, stabilizing long-lived conformations and reinforcing dynamic arrest in the condensate interior. Strikingly, a scrambled sequence with identical composition remains largely liquid-like. Our results establish RNA sequence patterning as a key determinant not only of phase separation but also of condensate aging and spatial organization. These findings provide a molecular framework for understanding the persistence and solidification of repeat RNA assemblies observed in diseases and suggest general physical principles by which entangled polymer networks drive aging in biomolecular condensates.

biophysics↗
bioRxiv2026

Cell-type-resolved transcriptional reprogramming in resistant soybean roots reveals cambial activation and early syncytium initiation upon nematode infection

Soybean cyst nematode (SCN) is the most destructive pathogen of soybean, yet the cellular basis of host resistance remains poorly understood. Here, we present a high-quality, cell-type-resolved atlas of root responses during early SCN infection in the highly resistant genotype PI437654, capturing transcriptional states across all major tissues, including rare syncytial cells. Our analyses reveal that resistance is mediated not by a localized defense but by coordinated, multicell reprogramming spanning invasion layers, vascular tissues, and feeding site-associated cells. We identify the vascular cambium as the primary cellular origin of SCN-induced syncytia, resolving a long-standing question in nematology. Mechanistically, resistance arises from disruption of key processes required for feeding site establishment, secretory stress via imbalanced vesicle trafficking, suppression of endoreduplication to prevent hypertrophic syncytial growth, and activation of autophagy to maintain cellular homeostasis. Spatially organized hormone signaling networks, including jasmonic acid, salicylic acid, and ethylene pathways, further reinforce defense, with GmJAZ1 functioning as a central regulator of JA-SA crosstalk. Collectively, PI437654 enforces resistance by targeting host cell identity, nutrient sink formation, and sustained parasitism, deploying a multilayered, tissue-specific defense strategy. This study provides a mechanistic, systems-level framework for SCN resistance and establishes a single-cell resource capturing rare root cell states, offering actionable targets for engineering durable nematode resistance. Key pointsO_LISoybean cyst nematode (SCN) is the most destructive pathogen of soybean worldwide, yet the cellular basis of early host responses and feeding site initiation remains poorly understood. C_LIO_LIUsing single-nucleus RNA sequencing (snRNA-seq), we generated a cell-type-resolved atlas of early SCN infection in roots of a unique and highly resistant soybean genotype PI437654. Trajectory analysis integrated with syncytium marker genes revealed that cambium cells are selectively targeted as the cellular origin of syncytium formation. C_LIO_LISCN infection triggers extensive cell-type-specific transcriptional reprogramming, particularly in vascular tissues (xylem, phloem, and cambium), involving pathways related to cell cycle and endoreduplication, vesicle trafficking, autophagy, and phytohormone signaling. C_LIO_LIFunctional validation demonstrated enhanced autophagy activation in infected roots via increased GFP-GmATG8a-labeled autophagic puncta, while overexpression of the jasmonic acid regulator GmJAZ1 significantly enhanced SCN resistance in susceptible soybean. C_LIO_LITogether, these findings define the cellular origin of SCN-induced syncytia and reveal coordinated cell-type-specific defense programs, providing a mechanistic framework for engineering durable resistance to SCN. C_LI

plant biology↗
bioRxiv2026

Next-Generation Soybean Haplotype Map as A Genomic Resource for Enhanced Trait Discovery and Functional Analysis

We present a global soybean haplotype map generated from whole-genome sequencing of 1,278 Glycine max and Glycine soja accessions, comprising 11.37 million SNPs and 2.05 million short insertions and deletions. This map (GmHapMap-II) captures unprecedented worldwide genetic diversity, reflecting the broad extent of the global soybean gene pool. Population structure analyses revealed six geographically distinct subpopulations that affected the linkage and shaped the recombination. The haplotype variation map was used to identify novel genomic regions associated with crude protein content on chromosome 15 that were not detected by a lower SNP density array. LD-based haplotype analysis revealed a superior haplotype for crude protein content. The constructed haplotype map enabled detailed characterization of haplotype diversity and copy number polymorphism at the SCN-associated rhg-1 and Rhg-4 loci, revealing both novel haplotype structures and germplasm lines with elevated CNV relative to previously characterized genotypes. We employed the HapMap matrix for a multi-class variations ML-based genomic prediction approach to predict phenotypes for SCN and catalogued the gene-centric haplotypes in a user-friendly database. The analysis revealed the extent of deleterious alleles present in the soybean germplasm and how breeders have deployed beneficial alleles and purged deleterious ones. The haplotype map will serve as a major genomic resource for trait-based mapping, enhancing efforts in the genomics-enabled development of improved cultivars.

genomics↗
bioRxiv2026

Discovery of a cluster in the PRRSV Nsp1α leader protease reveals host-virus interplay in its downstream functions

Porcine reproductive and respiratory syndrome virus (PRRSV; Betaarterivirus suid) is a major global threat to swine production, yet effective antiviral therapies are lacking. The leader protease Nsp1 is essential for viral replication and innate immune suppression, and its N-terminal zinc-finger (ZF) domain is critical for function, although its molecular role remains unclear. Here, we show that the ZF domain plays only a minor role in protease activity and that Nsp1 is largely inactive following release from the polyprotein. Using Mossbauer and UV/visible spectroscopy combined with chemoproteomics, we demonstrate that the ZF site binds not only Zn but also a [4Fe-4S] cluster. Notably, the Fe-S cluster, but not Zn, allosterically modulates residual protease activity. Nsp1 directly engages the cytosolic iron-sulfur cluster assembly machinery via CIAO1 and competes with the Fe-S carrier CIAO3, establishing the [4Fe-4S] cluster as a bona fide cofactor. These findings redefine Nsp1 as an Fe-S-dependent viral protein and reveal new opportunities for metal-targeted antiviral strategies.

biochemistry↗
bioRxiv2025

De novo Cyclic Peptides Allow Visualisation of the Monomeric and Functional Amyloid Conformations of the Kinase RIPK3

Receptor Interacting Protein Kinase 3 (RIPK3) is a central regulator of necroptosis and a key mediator of inflammatory signaling. Its function is orchestrated through RIP Homotypic Interaction Motif (RHIM)-dependent interactions with other RHIM-containing adapter proteins, forming amyloid-structured necrosomes that trigger kinase activation and subsequently lead to immunogenic cell lysis. Necroptosis eliminates infected or damaged cells and provokes a strong inflammatory response. Dysregulated necroptosis is implicated in chronic inflammatory diseases and associated with ischaemic injury. Despite separate structural elucidation of the isolated RIPK3 kinase domain and the amyloid fibrils formed by the RIPK3 RHIM-containing region, visualizing full-length human RIPK3 in live cells remains challenging due to a lack of specific tools. To address this, we employed Random Non-standard Peptide Integrated Discovery (RaPID) mRNA display to identify cyclic peptides that bind the RHIM-containing region of RIPK3 during its assembly into amyloid fibrils. Three peptides were selected for characterisation and demonstrate utility in visualizing RIPK3 in human cells. These peptides represent promising tools for probing RIPK3 localisation and modulating its function.

biochemistry↗
bioRxiv2025

Characterization of full-length and cytoplasmic tail-truncated envelope glycoproteins incorporated into human immunodeficiency virus (HIV-1) virions and virus-like particles

During transport to the surface of infected cells, the human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer is cleaved to produce the mature functional Env trimer ((gp120/gp41)3). Env cleavage stabilizes the pretriggered Env conformation (PTC), the major target for broadly neutralizing antibodies. Although the mature Env is relatively enriched in virions and virus-like particles (VLPs), conformationally flexible uncleaved Envs typically contaminate preparations of these particles. In non-permissive cells, the long [~]149-residue gp41 cytoplasmic tail (CT) is necessary for Env incorporation into virions. In a minority of HIV-1 strains, the gp41 CT is clipped in virions by the viral protease. Here, we compare Envs with CT truncations and CT alterations that increase or decrease protease clipping in permissive cells. Changes in protease clipping affected amphotericin B sensitivity, but did not alter other viral phenotypes. By contrast, a corresponding CT truncation (L748STOP) increased cell-surface and virion Env levels, cell-cell fusion, and virus infectivity and cytotoxicity. Notably, in diverse HIV-1 strains, the ratio of cleaved/uncleaved Envs in preparations of virions and extracellular vesicles was increased by this CT truncation. ESCRT and ALIX-binding region (EABR) vesicles incorporated significantly more uncleaved CT-truncated Env than HIV-1 VLPs. Env CT deletion/truncation did not qualitatively alter the viral neutralization profile; however, increased antibody concentrations were required to neutralize viruses with the higher levels of cleaved Env that resulted from CT truncation. Specific CT truncations provide a means of enriching the PTC and limiting the incorporation of nonfunctional and conformationally heterogeneous uncleaved Envs into preparations of virions and VLPs. IMPORTANCEThe human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer mediates entry of the virus into host cells. The pretriggered conformation (PTC) of Env is the major target for protective broadly neutralizing antibodies, but the PTC is unstable and therefore difficult to study. The cleavage of the flexible Env precursor stabilizes the PTC. Therefore, the presence of uncleaved Env compromises the purity of the PTC in Env preparations. We found that certain truncations of the Env cytoplasmic tail resulted in improved ratios of cleaved:uncleaved Env in preparations of HIV-1 viruses or virus-like particles. In some contexts, cytoplasmic tail truncation increased the level of Env in virus preparations. Although higher concentrations of antibodies were required to neutralize these viruses, Envs with specific truncations of the cytoplasmic tail retained the PTC. Thus, cytoplasmic tail truncation could assist efforts to purify and characterize the Env PTC on the viral membrane.

microbiology↗
bioRxiv2025

Machine Learning-Driven Identification of Virulence Determinants in Borrelia burgdorferi Associated with Human Dissemination

Lyme disease, the most common tick-born infectious diseases in the United States, presents with highly variable clinical outcomes, ranging from localized erythema migrans to severe disseminated complications affecting the heart, joints, and nervous system. The bacterial determinants underlying this phenotypic variation remain largely unknown, limiting our ability to predict disease progression and optimize treatment strategies. Here, we applied machine learning (ML) approaches to identify specific amino acid residues within surface-exposed virulence factors that predict human dissemination phenotypes. Utilizing the whole genome sequences from 299 clinical Bb isolates, we extracted and characterized variants of seven known virulence factors (BB_0406, BBK32, DbpA, OspA, OspC, P66, and RevA). Protein variants were classified based on their association with disseminated versus localized infections using clinical metadata. Cramers V analysis revealed strong associations between dissemination phenotypes and five adhesins: BBK32, DbpA, OspC, P66, and RevA. We developed ML models using five algorithms with multiple feature selection strategies, achieving robust predictive performance for DbpA, OspC, and RevA variants (all performance metrics >0.7). Feature importance analysis identified key predictive amino acid residues for DbpA, OspC, and RevA. Notably, B-cell epitope prediction revealed significant enrichment of ML-identified residues within predicted epitope regions for OspC and RevA, suggesting these residues may influence immune recognition and bacterial persistence. This study establishes the first computational framework linking Borrelia burgdorferi protein sequence variants to clinical dissemination phenotypes, providing molecular insights into Lyme disease pathogenesis that may inform development of improved diagnostics and therapeutic targets.

microbiology↗
bioRxiv2025

A single-cell fixed RNA profiling of liver fibrosis progression and regression reveals SEMA4D and LMCD1 as key mediators of fibrogenesis

Liver fibrosis progression and regression are dynamic processes involving diverse hepatic and immune cell populations. Here, we utilize single-cell fixed RNA profiling (FLEX) of a TAA-induced mouse liver cirrhosis model, with and without a recovery phase, to depict the cellular landscape and molecular mechanisms of fibrosis resolution. The regression phase was characterized by the emergence of pericentral hepatocytes enriched in detoxification and antioxidant genes (e.g., Cyp2e1, Txn1), which secreted Rarres2 to modulate hepatic stellate cell (HSC) function. This was accompanied by the upregulation of scar-resolving genes (Mmp14, Ctsl), restoration of fenestrae in liver sinusoidal endothelial cells, anti-inflammatory phenotypes of Kupffer cells, a decrease in fibrogenic cholangiocyte subsets, and recovery-associated signatures in NK/T cells, B cells, and neutrophils. In contrast, SEMA4D secreted by monocyte-derived macrophages during fibrosis progression activated Plxnb2 HSCs, and its blockade attenuated fibrosis in vivo. Furthermore, LMCD1 was identified as a novel marker for HSC activation and regulation. This single-cell atlas reveals key transcriptional programs and intercellular signaling pathways dependent on the fibrotic condition, offering new therapeutic targets for liver cirrhosis.

cell biology↗
bioRxiv2025

RNA structural complexity dictates its ion atmosphere

Electrostatic interactions mediated by the surrounding ions govern virtually every facet of RNA behavior. Most studies have focused on rigid, well-folded motifs, leaving the structurally heteregeneous, and biologically ubiquitous, flexible RNAs underexplored. To address this gap, we performed molecular dynamics simulation of three RNAs spanning the structural continuum: an unstructured poly-uridylic tract (rU30), a semiflexible cytosine-adenine-guanine (CAG) repeat, and the tightly folded Beet Western Yellow Virus (BWYV) pseudoknot. Despite carrying nearly identical net charge, their ion atmospheres diverge strikingly. rU30 envelops itself in a diffuse Mg2+ environment retained through two or more hydration shells, whereas the CAG repeat and pseudoknot favor more localized outer-sphere Mg2+ binding. In contrast, Ca2+ tends to form inner-sphere contacts with all three RNAs, regardless of their folds. Remarkably, the diffuse ion clouds around unstructured RNAs extend farther into solution than that of the folded RNAs, significantly broadening their electrostatic sphere of influence. Nonetheless, the ion exchange kinetics remain virtually unchanged, demonstrating a surprising decoupling between spatial distribution and dynamical turnover. Our findings reveal RNA structural flexibility as a powerful lever for tuning ionic screening, with important implications for biomolecular recognition, RNA-driven phase separation, and physical properties of RNA-rich condensate. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=149 SRC="FIGDIR/small/654961v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@12e78aborg.highwire.dtl.DTLVardef@1f4328borg.highwire.dtl.DTLVardef@122561dorg.highwire.dtl.DTLVardef@143c5ff_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗
bioRxiv2025

Embolization-on-a-chip: Novel Vascularized Liver Tumor Model for Evaluation of Cellular and Cytokine Response to Embolic Agents

BackgroundEmbolization is a well-established treatment modality for liver cancer. However, traditional embolization agents are limited by inefficient delivery and aggregation in blood vessels. Novel shear-thinning hydrogels (STH) have been developed to address the need for safer and more effective local delivery of embolic agents and therapeutics. ObjectiveWe aim to evaluate the efficacy of novel embolic agents such as STH using a human-relevant in vitro model that recapitulates human hepatocellular carcinoma capillary networks. MethodsA vascularized human liver-tumor-on-a-chip model was developed to assess embolic agent performance. The effects of drug-eluting STH (DESTH) on tumor cell viability, surface marker expression, vasculature morphology, and cytokine responses were evaluated. To study the effects of embolization on microvasculature morphology independent of the chemotherapy compound, we assessed the effect of different drug-free embolic agents on the vascular tumor microenvironment under flow conditions. ResultsDESTH treatment induced tumor cell death, downregulated the expression of Epithelial Cell Adhesion Molecules (EpCAM) in HepG2, increased levels of cytokines such as Interleukin-4 (IL-4), Granulocyte-macrophage colony-stimulating factor (GM-CSF), and Vascular Endothelial Growth Factor (VEGF), and decreased albumin secretion. Furthermore, different embolic agents exert distinct effects on microvascular morphology, with STH causing complete regression of the microvascular networks. ConclusionThis vascularized liver tumor-on-a-chip model enables human-relevant, real-time assessment of embolic agent efficacy and vascular response, paving the way for the development of innovative and effective embolization therapies for liver cancer.

bioengineering↗
bioRxiv2025

Perilysosomal Ca2+ overload impairs autophagic degradation in β-cell lipotoxicity

Saturated fatty acids impose lipotoxic stress on pancreatic {beta}-cells, leading to {beta}-cell failure and diabetes. In this study, we investigate the critical role of organellar Ca2+ disturbance on defective autophagy and {beta}-cell lipotoxicity. Palmitate, a saturated fatty acid, induced perilysosomal Ca2+ elevation, sustained mTORC1 activation on the lysosomal membrane, suppression of the lysosomal transient receptor potential mucolipin 1 (TRPML1) channel, and accumulation of undigested autophagosomes in {beta}-cells. These Ca2+ aberrations with autophagy defects by palmitate were prevented by a mTORC1 inhibitor or a mitochondrial superoxide scavenger. To alleviate perilysosomal Ca2+ overload, strategies such as lowering extracellular Ca2+, employing voltage-gated Ca2+ channel blocker or ATP-sensitive K+ channel opener effectively abrogated mTORC1 activation and preserved autophagy. Furthermore, redirecting perilysosomal Ca2+ into the endoplasmic reticulum (ER) with an ER Ca2+ ATPase activator, restores TRPML1 activity, promotes autophagic flux, and improves survival of {beta}-cells exposed to palmitate-induced lipotoxicity. Our findings suggest oxidative stress-Ca2+ overload-mTORC1 pathway involves in TRPML1 suppression and defective autophagy during {beta}-cell lipotoxicity. Restoring perilysosomal Ca2+ homeostasis emerges as a promising therapeutic strategy for metabolic diseases.

physiology↗
bioRxiv2025

The Lipidome Landscape of Amiodarone Toxicity: An in vivo Lipid-centric Multi-Omics Study

Amiodarone is an effective therapy for arrhythmias, its prolonged management may lead to significant adverse drug reactions. Amiodarone-induced hepatoxicity is described by phospholipidosis, hepatic steatosis, cholestatic hepatitis, and cirrhosis. However, the systemic and hepatic lipidome disturbances and underlying toxicological mechanisms remain comprehensively elucidated. Untargeted lipidomics were utilized to analyze serum and liver samples from the rats orally administered a daily dose of amiodarone of either 100 or 300 mg/kg for one week. Changes in the expression of hepatic lipid-related genes were also examined utilizing transcriptomics. We found a higher magnitude of lipidome alterations in the 300 mg/kg than those in the 100 mg/kg groups. Treated animals showed elevated abundances of phosphatidylcholines, ether-linked phosphatidylcholines, sphingomyelins, and ceramides, and decreased levels of triacylglycerols, ether-linked triacylglycerols, and fatty acids. We also found 199 lipid-related differentially expressed hepatic genes between the 300 mg/kg group versus controls, implying lipid metabolism and signaling pathways disturbances. Specifically, elevation of serum phosphatidylcholines and ether-linked phosphatidylcholines, as well as hepatic bismonoacylglycerophosphates were associated with reduced expression of phospholipase genes and elevated expression of glycerophospholipid biosynthesis genes, possibly driving phospholipidosis. Perturbations of sphingolipid metabolism might also be the key events for amiodarone-induced toxicity. Alterations in gene expression levels related to lipid storage and metabolism, mitochondria functions, and energy homeostasis were also found. Collectively, our study characterized the sophisticated perturbations in the lipidome and transcriptome of amiodarone-treated rats and suggested potential mechanisms responsible for amiodarone-induced hepatotoxicity.

pharmacology and toxicology↗
bioRxiv2024

RNA encodes physical information

Most amino acids are encoded by multiple codons, making the genetic code degenerate. Synonymous mutations affect protein translation and folding, but their impact on RNA itself is often neglected. We developed a genetic algorithm that introduces synonymous mutations to control the diversity of structures sampled by an mRNA. The behavior of the designed mRNAs reveals a physical code layered in the genetic code. We find that mRNA conformational heterogeneity directs physical properties and functional outputs of RNA-protein complexes and biomolecular condensates. The role of structure and disorder of proteins in biomolecular condensates is well appreciated, but we find that RNA conformational heterogeneity is equally important. This feature of RNA enables both evolution and engineers to build cellular structures with specific material and responsive properties.

biophysics↗
bioRxiv2024

Stoichiometry of HIV-1 Envelope Glycoprotein Protomers with Changes That Stabilize or Destabilize the Pretriggered Conformation

During human immunodeficiency virus (HIV-1) entry into host cells, binding to the receptors, CD4 and CCR5/CXCR4, triggers conformational changes in the metastable envelope glycoprotein (Env) trimer ((gp120-gp41)3). CD4 binding induces Env to make transitions from its pretriggered conformation (PTC) to more "open" conformations that are sensitive to inhibition by antibodies, CD4-mimetic compounds (CD4mcs) and exposure to cold. Changes in functional membrane Envs have been identified that either stabilize or destabilize the PTC. Here, we investigate the stoichiometric requirements for the PTC-stabilizing and -destabilizing changes in the Env protomers. To this end, we generated viruses bearing Envs with mixed protomers exhibiting different degrees of PTC stability and determined the sensitivity of the viruses to cold (0{degrees}C) and, in some cases, to a CD4mc. The number of stabilized Env protomers required to achieve stabilization of the PTC was inversely related to the degree of PTC stabilization that resulted from the introduced Env change. For strongly stabilizing Env changes, modification of a single protomer was sufficient to achieve PTC stabilization; given adequate stability, the modified protomer can apparently constrain the conformation of the other two protomers to maintain the PTC. Weakly stabilizing Env changes needed to be present in all three protomers to achieve efficient stabilization of the PTC. In many cases, the PTC was disrupted when destabilizing changes were present in only a single protomer. These complementary results suggest that conformational symmetry among the protomers of the functional Env trimer is conducive to the integrity of the PTC. IMPORTANCEThe human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer consists of three protomers. In response to receptor binding, the flexible Env changes its conformation to mediate virus entry into host cells. The shape-shifting ability of Env also contributes to HIV-1s capacity to evade the host immune system. The pretriggered (State-1) conformation (PTC) of Env is an important target for virus entry inhibitors and host antibodies, but is unstable and therefore incompletely characterized. Changes in Env amino acids that either stabilize or destabilize the PTC have been identified. Here, we define how many Env protomers need to be modified by these changes to achieve stabilization or destabilization of the PTC. These results can guide the placement of changes in the HIV-1 Env protomers to control the movement of the Env trimer from the PTC, allowing better characterization of this elusive conformation and testing of its utility in vaccines.

microbiology↗
bioRxiv2024

Disentangling plant response to biotic and abiotic stress using HIVE, a novel tool to perform unpaired multi-omics integration

All organisms are subjected to multiple stresses usually occurring at the same time, requiring the activation of the appropriate signalling pathways to respond to all or by prioritizing the response to one stress factor. Plants, as sessile organisms, are particularly impacted by the constantly changing environment that is often unfavourable or even hostile. Because of the experimental complexity of studying the response of one organism to multiple stressors simultaneously, usually experiments are conducted considering one individual stress factor at the time. An alternative consists in performing in silico integration of those data on single stress response. Currently used methods to integrate unpaired experiments consist of performing meta-analysis or finding differentially expressed genes for each condition separately and then selecting the commonly regulated ones. Although these approaches allowed to find valuable results, they mainly identify specific signatures in response to one stress and very few signature responding to multiple stresses and lack those modulated differently in each condition. For this purpose, we developed HIVE (Horizontal Integration analysis using Variational AutoEncoders) to integrate multiple single-stress transcriptomics datasets composed of unpaired experiments. Briefly, we coupled a variational autoencoder, that alleviates batch effects, with a random forest regression and the SHAP explainer to select relevant genes modulated specifically in response to one or multiple stresses. We illustrate the functionality of HIVE to study the transcriptional changes of several different plants namely Arabidopsis thaliana, rice, maize, wheat, grapevine and peanut by collecting publicly available experiments on single stress, either biotic and/or abiotic, and jointly analyse them. HIVE performed better than the differential expression analysis, meta-analysis and the state-of-the-art tool for horizontal integration allowing to identify novel promising candidates responsible for triggering effective defence responses to multiple stresses.

plant biology↗