Search bioRxiv⌕ Search

Biology subjects

Xia, X.

Publications and source records attributed to Xia, X..

At least 37 records · Page 2Linked to original sources

FEDRANN: effective overlap graph construction based on dimensionality reduction and approximate nearest neighbors

Overlap detection is a key step in de novo genome assembly pipelines based on the Overlap-Layout-Consensus (OLC) paradigm. However, existing methods for overlap detection either rely on heuristic seed-and-extension strategies or locality-sensitive hashing (LSH), both of which struggle to handle repetitive genomic regions and the computational burden of large-scale datasets. Here, we present FEDRANN, a novel strategy for overlap graph construction that integrates feature extraction, dimensionality reduction (DR), and approximate nearest neighbor (ANN) search. We find the pipeline combining inverse document frequency (IDF) transformation, sparse random projection (SRP), and NNDescent enables accurate detection of overlaps across diverse datasets. We developed an efficient open-source implementation of this pipeline named Fedrann (https://github.com/jzhang-dev/fedrann). Through systematic benchmarking on real long-read sequencing data, we demonstrate that Fedrann produces overlap graphs comparable to or better than those generated by existing state-of-the-art tools, including MECAT2, minimap2, and wtdbg2, while maintaining competitive runtime. Despite being implemented primarily in Python, Fedrann achieves performance on par with tools written in compiled languages, owing to matrix-based representations and C-accelerated numerical libraries. Our results suggest that DR and ANN techniques offer a promising new direction for scalable and accurate overlap detection in long-read assembly and broader sequence similarity search tasks.

bioinformatics↗

CryoEM structure of the central apparatus of the Trypanosoma brucei flagellum

Axonemes are cylindrical bundles of microtubule filaments that typically follow a 9+n pattern (where n ranges from 0 to 4). However, variations exist across species and cell types, including architectures with fewer (e.g., 3+0, 6+0) or more than nine doublet microtubules (e.g., 9+9+0, 9+9+3), reflecting diverse structural adaptations of cilia and flagella in eukaryotes. Trypanosoma brucei, the causative agent of African trypanosomiasis, relies on its single 9+2 flagellum to navigate through environments within the mammalian host and insect vector. Central to the T. brucei flagellums function is a canonical central apparatus (CA), composed of two--C1 and C2-- singlet microtubules, which regulates flagellar beating and ensures efficient movement. Despite its crucial mechanoregulatory role in flagellar beating, the molecular structure and interactions governing T. brucei CA assembly and function remain poorly understood. In this study, we employed cryogenic electron microscopy (cryoEM) to uncover structural details of the T. brucei CA. We identified conserved and stably C1/C2-associated protein densities, including the armadillo repeat protein PF16, which serves as a structural scaffold critical for CA assembly and axonemal asymmetry. Our analysis also revealed pronounced molecular flexibility of the CA and uncovered T. brucei-specific densities, suggesting lineage-specific adaptations for parasite motility. These findings provide critical insights into the structural foundations of T. brucei motility. They also highlight potential therapeutic targets to disrupt the parasites ability to cause disease, offering new avenues for the treatment of African trypanosomiasis. Comparison of CAs in this canonical 9+2 axoneme and non-canonical 9+n axonemes offers general insights into the assembly and diverse functions of CAs across a wide range of species. SignificanceThe flagellum of Trypanosoma brucei, the parasite causing African trypanosomiasis, drives motility essential for host infection and disease transmission. Our cryogenic electron microscopy study reveals the molecular architecture of its central apparatus, identifying PF16 as a key scaffold that stabilizes axonemal asymmetry and imparts flexibility critical for flagellar beating. We uncover conserved proteins and T. brucei- specific adaptations, highlighting evolutionary divergence underlying the parasites distinctive motility. These structural results offer insights about how the central apparatus regulates T. bruceis bihelical motion and unveil potential therapeutic targets to disrupt flagellar function and combat African trypanosomiasis. Comparison among the central apparatus of canonical and non-canonical axonemes allow us to suggest broader principles underlying their central roles in ciliary functions across eukaryotes.

microbiology↗

A Universal 6iL/E4 Culture System for Deriving and Maintaining Embryonic Stem Cells Across Mammalian Species

The derivation of authentic embryonic stem cells (ESCs) from diverse mammalian species offers valuable opportunities for advancing regenerative medicine, studying developmental biology, and enabling species conservation. Here, we report the development of a robust, serum-free culture system, termed 6iL/E4 that enables the derivation and long-term self-renewal of ESCs from multiple mammalian species, including mouse, rat, bovine, rabbit, and human. Using systematic signaling pathway analysis, we identified key regulators--including GSK3, STAT3, PDGFR, BRAF, and LATS--critical for ESC maintenance across species. Additionally, inducible expression of KLF2 and NANOG enhances the naive pluripotency and chimeric potential of bovine ESCs. The E4 medium also supports stable ESC growth while minimizing lineage bias. These findings reveal conserved principles underlying ESC self-renewal across divergent mammalian species and provide a universal platform for cross-species stem cell research, disease modeling, and biotechnology applications. In BriefWang et al. developed 6iL/E4, a serum-free system sustaining ESCs from mouse, rat, bovine, rabbit, and human. These findings reveal conserved fundamental mechanisms governing ESC self-renewal across diverse mammalian species. HighlightsO_LIDeveloped 6iL/E4 system for ESC derivation across five mammalian species. C_LIO_LIPDGFR signaling inhibition as critical for ESC derivation across species. C_LIO_LIE4 medium improves ESC maintenance and avoids neural bias of traditional N2B27. C_LIO_LIInducible KLF2/NANOG enhances naive pluripotency and chimera formation in bovine. C_LI

cell biology↗

Atomic Structure and Phospholipid Binding Properties of the Francisella Type VI Secretion System Effector Protein PdpC

Francisella tularensis, a gram-negative facultative intracellular pathogen, causes tularemia, a potentially fatal infection. The Francisella pathogenicity island (FPI) encodes a type VI secretion system (T6SS), critical for the bacteriums ability to replicate within host cells and cause disease. PdpC, an FPI-encoded T6SS effector protein, is essential for phagosomal escape, intracellular replication, and virulence in animals, yet its structure and function remain poorly understood. Here, we expressed PdpC recombinantly and determined the cryoEM structure of PdpC at 3.4 [A] resolution, revealing a monomeric 156 kDa protein with a seahorse-shaped architecture (80 [A] x 75 [A] x 120 [A]). PdpC comprises five domains: an N-terminal domain (NTD) forming a prominent lateral head lobe, a central body domain, a C-terminal tail domain, a small wedge domain at the groove between the body and tail, and an unmodeled "mouth" domain that completes the seahorse-like shape. Functional studies demonstrate that PdpC binds specific host cell phospholipids, including phosphatidylinositol-3-phosphate. These findings provide a foundation for elucidating PdpCs mechanism of action and developing strategies to prevent or treat tularemia.

microbiology↗

Macrophage Migration Inhibitory Factor Suppresses Natural Killer Cell Response and Promotes Hypoimmunogenic Stem Cell Engraftment Following Spinal Cord Injury

Human induced pluripotent stem cells (iPSCs) offer immense potential as a source for cell therapy in spinal cord injury (SCI) and other diseases. The development of hypoimmunogenic, universal cells that could be transplanted to any recipient without requiring a matching donor, could significantly enhance their therapeutic potential and accelerate clinical translation. To create off-the-shelf hypoimmunogenic cells, we used CRISPR-Cas9 to delete B2M (HLA class I) and CIITA (master regulator of HLA class II). Double-knockout (DKO) iPSC-derived neural progenitor cells (NPCs) evaded T cell-mediated immune rejection in vitro and after grafting into the injured spinal cord of athymic rats and humanized mice. However, loss of HLA class I heightened susceptibility to host natural killer (NK) cell attack, limiting graft survival. To counter this negative effect, we engineered DKO NPCs to overexpress macrophage migration inhibitory factor (MIF), an NK cell checkpoint ligand. MIF expression markedly reduced NK cell-mediated cytotoxicity and improved long-term engraftment and integration of NPCs in the animal models for spinal cord injury. These findings demonstrate that MIF overexpression, combined with concurrent B2M and CIITA deletion, generates hiPSC neural derivatives that escape both T- and NK-cell surveillance. This strategy provides a scalable route to universal donor cells for regenerative therapies in SCI and potentially other disorders.

cell biology↗

Krüppel Regulates Cell Cycle Exit and Limits Adult Neurogenesis of Mushroom Body Neural Progenitors in Drosophila

In many organisms, including Drosophila and humans, neural progenitors exit the cell cycle and are eliminated by the end of development, thereby restricting adult neurogenesis to specific brain regions. Here, we identify the evolutionarily conserved transcription factor Kruppel (Kr) as a lineage-specific regulator of cell cycle exit and elimination of mushroom body neuroblasts (MBNBs), which generate the learning and memory centre of the Drosophila brain, a structure functionally analogous to the mammalian hippocampus. Neuroblast-specific Kr RNAi and the Irregular facet (KrIf-1) mutation prolong MBNB lifespan, enabling continued neurogenesis in the adult brain. Although Kr is expressed only at low levels in postembryonic MBNBs, its pupal stage-specific depletion or misexpression is sufficient to cause MBNB retention, revealing a previously unrecognised postembryonic function distinct from its established role in embryonic neurogenesis. Mechanistically, persistent MBNBs maintain expression of the early temporal factor IGF2 mRNA-binding protein (Imp) and fail to fully induce the late temporal factors Syncrip (Syp) and Eip93F (E93). Co-depletion of Imp suppresses MBNB retention caused by Kr depletion, demonstrating that Imp is a key downstream effector of Kr. In parallel, Kruppel homolog 1 (Kr-h1), another Kr family transcription factor and a well-established mediator of hormone-responsive transcription, functionally antagonises Kr by suppressing E93 expression: Kr-h1 knockdown partially rescues the Kr depletion phenotype, whereas Kr-h1 overexpression drives tumour-like neuroblast overgrowth. Together, our findings establish Kr as an MBNB-specific coordinator that integrates intrinsic temporal programmes with extrinsic signalling pathways to coordinate neural stem cell termination and neuronal fate transitions, with potential parallels in other organisms.

developmental biology↗

Proteasome-derived antimicrobial peptides discovered via deep learning

Recent computational discoveries have identified numerous bioactive peptides within the human proteome, as well as across the broader tree of life, which were previously unrecognized for their roles in host immunity. These findings have led us to propose the "cross-talk hypothesis", suggesting that many molecules, such as proteins and peptides, traditionally viewed as extraneous to immune function may in fact actively contribute to immunity. Building on our earlier studies, which uncovered proteasome-derived peptides with putative antimicrobial activity in the human proteome, here we systematically interrogated the proteasome, a large protein complex responsible for degrading and recycling damaged or surplus proteins, for additional antimicrobial peptides. Using deep learning, we systematically mined ProteasomeDB, a curated repository of proteasomal cleavage and splicing events, to predict antibiotic activity against 11 clinically relevant pathogens. This deep learning approach uncovered 59 candidate peptides ("proteasomins") with a median minimum inhibitory concentration (MIC) of [≤]64LmolLLL1. Refinement yielded 21 sequence-diverse proteasomins, which were characterized for their physicochemical properties. These peptides were enriched in cationic residues and exhibit enhanced amphiphilicity, key attributes for disrupting microbial membranes. Dimensionality reduction via UMAP further showed that proteasomins are sequence-distinct from known antimicrobial peptides, underscoring their novelty and potential for unique mechanisms of action. Moreover, comparative analyses revealed that cis- and trans-spliced proteasomins exhibit similar predicted antimicrobial activities, suggesting that critical structural determinants remain conserved irrespective of splicing modality. Collectively, these findings expand our understanding of the proteasome, underscore the extensive, previously unrecognized repertoire of innate immune peptides, and provide a promising foundation for developing innovative therapeutics to combat multidrug-resistant pathogens.

microbiology↗

Disruption of a side portal pathway permits closed-state inactivation by BK β subunit N-termini

Cytosolic N-termini of several BK channel {beta} regulatory subunits mediate rapid inactivation. However, in contrast to Kv channels, inactivation does not occur via a simple, open channel block mechanism, but involves two steps, an association step in which ion permeation is maintained (O*), then followed by inactivation (I). To produce inactivation, BK {beta} subunit N-termini enter the central cavity through a lateral entry pathway ("side portal") separating the transmembrane pore-gate-domain and cytosolic gating ring. Comparison of BK conformations reveals an aqueous pathway into the central cavity in the open structure, while in the closed structure three sequential basic residues (R329K330K331) in S6 occlude central cavity access. We probed the impact of mutations of the RKK motif (RKK3Q, RKK3E, and RKK3V) on inactivation mediated by the {beta}3a N-terminus. All three RKK-mutated constructs differentially reduce depolarization-activated outward current, prolong {beta}3a-mediated tail current upon repolarization, and produce a persistent inward current at potentials down to -240 mV. With depolarization channels are driven into O*-I inactivated states and, upon repolarization, slow tails and persistent inward currents reflect slow changes in O*-I occupancy. However, evaluation of closed state occupancy prior to depolarization and at the end of slow tails reveals that some fraction of closed states at negative potentials corresponds to resting closed states in voltage-independent equilibrium with N-terminal-occluded closed-states. Thus, disruption of the RKK triplet both stabilizes the {beta}3a-N-terminus in its position of inactivation and permits access of that N-terminus to its blocking position in closed states. SummaryThe role of BK S6 residues R329K330K331 and E321/E324 in {beta} subunit-mediated inactivation is probed. WT R329K330K331 hinders inactivation in closed states, while RKK mutations stabilize inactivated states even under conditions where channels are otherwise closed. E321/E324 mutations do not permit closed-state inactivation.

biophysics↗

Fast, accurate parsing of antibody structures and antibody-antigen interactions enables a comprehensive structural antibody database

Antibody (Ab) structures and antibody-antigen interactions (AAIs) are essential for understanding immune recognition and designing Ab therapeutics. While existing structural Ab databases provide valuable insights, they still have notable limitations. Here, we present SAAINT-parser, an computational workflow for rapid, accurate, and robust extraction of Ab and AAI information from the Protein Data Bank (PDB). SAAINT-parser features precise detection of Ab chains, accurate pairing of Ab chains, and reliable identification of AAIs. The resulting SAAINT-DB contains 18,031 data entries from 9,373 PDB structures, offering a comprehensive and up-to-date resource. Detailed analyses of SAAINT-DB reveals its advantages over the most widely used SAbDab database, particularly in terms of data accuracy and completeness. Furthermore, SAAINT-DB provides nearly twice as many nonredundant, manually curated Ab-Ag binding affinity data compared to SAbDab. Both SAAINT-parser and SAAINT-DB are available as open-source resources, aimed at advancing Ab-related research and benefiting the broader scientific community.

bioinformatics↗

Unraveling the mechanism of 1-deoxynojirimycin (DNJ) accumulation: the role of SWEET3 in mulberry chloroplasts

Transporters are crucial for the accumulation and secretion of plant metabolic products. 1-Deoxynojirimycin (DNJ), a natural compound widely distributed in nature and known for its medicinal properties, has production limitations in microorganisms and herbaceous plants. Mulberry leaves, being easy to harvest and growing rapidly, are the main source of DNJ. However, the current production from mulberry is insufficient to meet the demand. Improving DNJ content in mulberry and thereby reducing production costs is a significant challenge. We first used a green fluorescent tag to visualize the localization of DNJ and found that DNJ highly accumulates in the chloroplasts of mulberry leaves but not in callus tissue. The sugar transporter gene SWEET3, which is highly expressed in mulberry leaves but not in callus, was shown to have DNJ transport capability. Molecular docking analysis revealed that the acidic amino acid residues E68 and D126 in the SWEET3 protein are potential binding sites for DNJ, and both neutral and basic mutations at these sites significantly reduced the ability to DNJ-transporting ability of SWEET3. Furthermore, transient overexpression or RNA interference of SWEET3 in mulberry leaves significantly increased or decreased DNJ content, respectively. Similarly, stable overexpression of the SWEET3 in mulberry hairy roots led to an enhancement in DNJ content within the roots. Our results demonstrated that SWEET3 is essential for DNJ accumulation in mulberry. The study represents a breakthrough in increasing DNJ yield in mulberry through the key role of transporters and identify specific molecular targets required for developing mulberry germplasm with increased DNJ levels.

plant biology↗

Brucella proline racemase protein A targets Tpl2 to promote IL-10 secretion for establishment of chronic infection

IL-10, an anti-inflammatory cytokine, plays a crucial role in limiting immune responses to pathogens, preventing host damage. However, the mechanisms underlying Brucella-mediated IL- 10 production remain incompletely understood. In this study, we demonstrate that the proline racemase protein A (PrpA) of Brucella melitensis M5-90 induces macrophages to secrete IL-10 by activating the Tpl2-ERK signaling pathway, thereby promoting chronic infection. Moreover, Tpl2 deletion impairs macrophage bactericidal ability, accompanied by reduced TNF- and IL-1{beta} but unaffected IL-10 levels. Additionally, Trp309, Glu103, and Glu129 of PrpA participate in interaction with Tpl2, but these residues do not influence PrpA-mediated IL-10 production in macrophages. PrpA deletion enhances IFN-{gamma} levels, specific anti-Brucella IgG, and CD4+ and CD8+ T cell numbers in mice. Furthermore, the Brucella melitensis M5-90 prpA mutant provides higher protection than the parental strain against virulent Brucella melitensis M28 infection in mice. Our findings suggest that Brucella PrpA promotes IL-10 secretion by macrophages through Tpl2 activation for bacterial survival and persistent infection, making the Brucella melitensis M5-90 prpA mutant a promising vaccine for enhanced protection. Author SummaryIL-10, an anti-inflammatory cytokine, is exploited by Brucella for survival. We identified Brucella PrpA as a potent IL-10 inducer, activating the Tpl2-ERK signaling pathway. Tpl2 deletion increased Brucella survival in macrophages, accompanied by reduced TNF- and IL-1{beta} but unaffected IL-10 secretion. Residues (Trp309, Glu103, and Glu129) of PrpA were crucial for interaction with Tpl2, yet did not impact PrpA-mediated IL-10 production. The B. melitensis M5-90 prpA mutant induced higher anti-Brucella IgG, IFN-{gamma}, and CD4+ and CD8+ T cell numbers in mice, providing better protection than B. melitensis M5-90. These findings unveil PrpAs role in IL-10 production and highlight the potential of the B. melitensis M5-90 prpA mutant as a promising vaccine for further evaluation.

microbiology↗

Improving American chestnut resistance to two invasive pathogens through genome-enabled breeding

Over a century after two introduced pathogens decimated American chestnut populations, breeding programs continue to incorporate resistance from Chinese chestnut to recover self-sustaining populations. Due to complex genetics of chestnut blight resistance, it is challenging to obtain trees with sufficient resistance and competitive growth. We developed high quality reference genomes for Chinese and American chestnut and leveraged large disease phenotype and genotype datasets to develop accurate genomic selection. Inoculation and simulation results indicate that resistance may be substantially increased in trees that inherited 70% to 100% of their genome from American chestnut. To facilitate gene editing, we integrated multiple lines of evidence to discover candidate alleles for blight resistance and susceptibility. These genomic resources provide a strong foundation to accelerate restoration of this iconic tree.

genomics↗

Suppression of PCBP1 Enhances PPARgamma via TAK1 Modulation to Improve Glycemic and Lipid Metabolism Disorders in Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) affects the health of pregnant women and their fetuses. Poly(C)-binding protein 1 (PCBP1), a multifunctional RNA-binding protein, is pivotal in maintaining cytosolic iron homeostasis. This study sheds light on the role and mechanism of PCBP1 in glucose and lipid metabolism dysregulation in GDM via a high-fat diet-induced GDM mouse model and a palmitic acid (PA)-triggered insulin resistance(IR) model in HepG2 cells. Glucose tolerance and insulin tolerance tests were performed in GDM mice, with lipid metabolism evaluated via hematoxylin-eosin (HE) staining, Oil Red O staining, as well as biochemical assay kits. Glucose content was quantified using the glucose oxidase method, while cell viability was evaluated trough the CCK-8 assay. Apoptotic activity was examined through TUNEL staining, and the expression levels of key proteins, including phosphorylated AKT (p-AKT), phosphorylated IRS1 (p-IRS1), PCBP1, TAK1, and PPAR{gamma}, were analyzed through Western blotting. The results demonstrated that GDM mice exhibited profound glucose and lipid metabolism disorders, characterized by significant lipid droplet accumulation in hepatic cells and disrupted insulin signaling pathways. Furthermore, hepatic expression of PCBP1 and TAK1 was notably upregulated, whereas PPAR{gamma} expression was significantly reduced. In vitro experiments revealed that silencing PCBP1 alleviated glucose and lipid metabolism abnormalities and improved insulin signaling in PA-induced insulin-resistant HepG2 (IR-HepG2) cells. This intervention also enhanced cell viability and suppressed apoptosis. Further mechanistic studies indicated that inhibition of TAK1 expression facilitated PPAR{gamma} upregulation, while TAK1 overexpression negated these effects. Additionally, silencing PPAR{gamma} in TAK1-silenced cells reversed the metabolic improvements in IR-HepG2 cells, whereas overexpression of PPAR{gamma} mitigated the adverse effects of PCBP1 overexpression. The foregoing findings demonstrate that PCBP1 exerts its effects on glucose and lipid metabolism in GDM via the TAK1/PPAR{gamma} signaling axis. Our study highlights the important function of the PCBP1/TAK1/PPAR{gamma} signaling pathway in mediating glucose and lipid metabolism in GDM, providing valuable insights into possible therapeutic targets for GDM treatment.

cell biology↗

OPUS-GO: An interpretable protein/RNA sequence annotation framework based on biological language model

Accurate annotation of protein and RNA sequences is essential for understanding their structural and functional attributes. However, due to the relative ease of obtaining whole sequence-level annotations compared to residue-level annotations, existing biological language model (BLM)-based methods often prioritize enhancing sequence-level classification accuracy while neglecting residue-level interpretability. To address this, we introduce OPUS-GO, which exclusively utilizes sequence-level annotations to provide both sequence-level and residue-level classification results. In other words, OPUS-GO not only provides the sequence-level annotations but also offers the rationale behind these predictions by pinpointing their corresponding most critical residues within the sequence. Our results show that, by leveraging features derived from BLMs and our modified Multiple Instance Learning (MIL) strategy, OPUS-GO exhibits superior sequence-level classification accuracy compared to baseline methods in most downstream tasks. Furthermore, OPUS-GO demonstrates robust interpretability by accurately identifying the residues associated with the corresponding labels. Additionally, the OPUS-GO framework can be seamlessly integrated into any language model, enhancing both accuracy and interpretability for their downstream tasks.

bioinformatics↗

Clathrins are involved in the endocytosis of host cytosol in the malaria parasite

In eukaryotic cells, clathrins interact with adaptor protein complexes to regulate key intracellular trafficking events. Specifically, they are associated with the adaptor protein (AP) complex-2 (AP2) to facilitate endocytosis and AP1 to mediate secretion and trafficking between endosome and Golgi. In Plasmodium falciparum, recent studies revealed that the Kelch domain-containing protein 13 and AP2 participate in hemoglobin uptake via cytostomes. However, clathrins appear not to be involved in this process because they primarily associate with AP1. To investigate the roles of clathrins in P. falciparum, we characterized the clathrin heavy chain (PfCHC), the clathrin light chain (PfCLC), and the AP1 {gamma} subunit (PfAP1 {gamma}). Extensive interactome analyses confirmed the major association of clathrins with AP1 components alongside proteins involved in cytostome formation. Live-cell imaging and protein colocalization studies showed that PfCHC, PfCLC, and PfAP1 {gamma} are localized in the parasite cytoplasm, predominantly at the parasite periphery and near the cis-Golgi. Ultrastructural studies using ascorbate peroxidase 2- based electron microscopy confirmed their presence at coated vesicle-like structures at the parasite periphery and, unexpectedly, at the collars of cytostomes. Consistent with these observations, the knockdown of PfCHC led to the formation of abnormally long cytostome tubes and impaired hemoglobin digestion. This study demonstrates that clathrins are essential for proper cytostome formation in P. falciparum, highlighting their critical role in the parasites hemoglobin uptake and digestion processes. IMPORTANCEMalaria is still one of the most severe public health problems worldwide and understanding how malaria parasites obtain hemoglobin from their host cells, red blood cells (RBCs), is critical for identifying targets for antimalarials. In this study, affinity purification revealed that clathrins (PfCHC and PfCLC) were not only mainly associated with AP1 complex but also marginally interacted with proteins that participated in hemoglobin uptake. Localization analysis demonstrated that clathrins and AP1 coated the clusters of vesicles at the parasite periphery and at the neck of the cytostome, an organelle for hemoglobin uptake. Consistently, the knockdown of PfCHC caused the formation of abnormally long cytostome tubes and reduced hemoglobin digestion. Collectively, this study demonstrates that clathrins play a critical role in the parasites hemoglobin uptake.

microbiology↗

Aurora kinase A promotes trained immunity via regulation of endogenous S-adenosylmethionine metabolism

Innate immune cells can acquire a memory phenotype, termed trained immunity, but the mechanism underlying the regulation of trained immunity remains largely elusive. Here, we demonstrate that inhibition of Aurora kinase A (AurA) dampens trained immunity induced by {beta}-glucan. ATAC-seq and RNA-seq analysis reveals that AurA inhibition restricts chromatin accessibility of genes associated with inflammatory pathways such as JAK-STAT, TNF and NF-{kappa}B pathways. Specifically, AurA inhibition promotes nuclear localization of FOXO3 and the expression of glycine N-methyltransferase (GNMT), a key enzyme responsible for S-adenosylmethionine (SAM) consumption. Metabolomic analysis confirms a reduction in SAM level upon AurA inhibition. As a result of SAM deficiency, trained mouse macrophages exhibit decreased H3K4me3 and H3K36me3 enrichment on gene regions of Il6 and Tnf. Additionally, the tumor inhibition effect of {beta}-glucan is notably abolished by AurA inhibition. Together, our findings identify an essential role of AurA in regulating trained immunity via a methylation-dependent manner by maintaining endogenous SAM level through mTOR-FOXO3-GNMT axis.

immunology↗

SARS-CoV-2 JN.1 reveals attenuated pathogenicity and airborne transmission

JN.1 is a subvariant of SARS-CoV-2 Omicron BA.2.86 lineage that was predominant worldwide in early 2024, of which the in vivo characteristics are largely unknown. Our results demonstrated that the replication of JN.1 was more efficient than that of the parental BA.2 in Vero cells, which demonstrated low dependence on TMPRSS2. Compared to Omicron variants BA.2 and XBB EG.5.1, JN.1 replicated less efficiently in hACE2 mouse lungs of which the intranasal infection was not lethal to hACE2 mice and led to weaker immune dysregulation. On a more sensitive, aged hACE2 hamster model, JN.1 led to a lower mortality rate and no weight loss, corresponding well with the low preference in lower airways. Lower amounts of viruses in nasal washes and exhaled aerosols were detected in JN.1 infected wildtype hamsters than EG.5.1, and consistently, JN.1 also exhibited largely reduced airborne transmission. Moreover, the poor transmission was also clearly demonstrated even by using hamsters expressing hACE2 receptors in the whole airway. Thus both pathogenicity and airborne transmission of JN.1 were demonstrated to be largely attenuated. ImportanceCurrently, SARS-CoV-2 JN.1 and its subvariants have fully replaced the previous dominant XBB lineage around the world. Although the strong immune evasion of JN.1 has been distinctly revealed, its in vivo pathogenicity and airborne transmission remained unclear. By using multiple Omicron-sensitive rodent models, our findings demonstrated that the pathogenicity of JN.1 was largely attenuated. The weak airborne transmission of JN.1 in wildtype and hACE2 hamsters was consistent with the reported relative lower transmissibility in human, and the using of airway-expressing hACE2 hamsters ulteriorly eliminates the potential bias in viral transmission studies induced by receptor divergence between animal models and human. These findings uncover the in vivo virological characteristics of SARS-CoV-2 novel lineage, providing insights for communicable disease control.

microbiology↗

Exploring The Association of Student Perceptions of Their Teachers' Science Instruction and Emotional Engagement and The Variance between Grade Level

AbstractPrevious research has consistently shown students have higher learning interests attitudes, and motivation toward science in elementary compared to middle and high school. However, the key predictors behind the observed differences in engagement levels across grade levels remain unclear. This study aims to identify the association between students perceptions of science instruction and their emotional engagement, as well as examine the differences across various educational stages. A multilevel random effect model was employed to investigate this association. In addition, the analysis examined whether the associations vary between grade levels. A sample of 6465 students from 25 schools participated in the study. This study shows that students in higher grades have significantly lower emotional engagement compared to third-grade students. Similarly, students in higher grades have significantly lower values on perceptions of science instruction of interesting science and understandable science decrease compared to third grade. Findings reveal significant associations between students perceptions of science instruction, both in perceiving interesting science instruction and understandable science instruction, and their emotional engagement in science learning. The interaction term (Perception of Interesting Science Instruction x Grade) of Grades four, six through eight, and grade 12 are statistically significantly related to emotional engagement, indicating that more positive slopes correspond to high-grade level than third-grade students. The increase in students perception of interesting science has the steepest slope of improvement in students emotional engagement in 6th grade. We find no statistically significant difference between grades in students perception of understandable science and emotional engagement. Interesting and understandable science classes have positive correlations with students emotional engagement in science learning. For future studies, it is worth exploring science instruction during transition grades to better address and mitigate the observed difference in emotional engagement.

scientific communication and education↗