Biology subjects

Zhang, J.-Y.

Publications and source records attributed to Zhang, J.-Y..

12 recordsLinked to original sources

bioRxiv2026

Novel conserved RNA structural motifs regulate genome cyclization of yellow fever virus

The long-range RNA-RNA interaction between the termini of a flavivirus genome is controlled by multiple local RNA secondary and tertiary structures. However, a complete picture of this essential genome cyclization process is still elusive. Herein, by using selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE), SHAPE and mutational profiling, in vitro RNA binding assays, and reverse genetics approaches, we demonstrated that the hairpin 2 in the capsid-coding region (cHP2) is required for efficient replication of yellow fever virus and functionally interacts with the 3'-small hairpin (sHP) during genome cyclization. Interestingly, through a combination of multidimensional chemical probing and functional characterization assays, it was discovered that the sHP forms previously unknown tertiary interactions with an immediately upstream GACG region embedded within the 3'-cyclization sequence. This crucial tertiary RNA motif accounts for a potential negative regulatory mechanism of genome cyclization and is universally conserved among the mosquito-borne-related flaviviruses, which constitute a major phylogenetic branch within the subgenus Euflavivirus, genus Orthoflavivirus. Our study highlights the intricacy of RNA-based regulation in flaviviruses.

biochemistry↗

bioRxiv2025

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↗

bioRxiv2025

Unprecedented Number of Recurrent Mutations Drive the Rapid Evolution of Pesticide Resistance in a Notorious Pest

The genetic basis of pesticide resistance has been widely studied, but the exact nature of this evolutionary process in the field is often unclear, particularly when a limited number of populations is considered and when there is a lag between the evolutionary event and its investigation. We showed that an unprecedented number of recurrently evolved mutations in an arthropod pest, the two-spotted spider mite Tetranychus urticae, drive the rapid evolution of resistance to a recently commercialized acaricide, cyetpyrafen. We first observed high levels of resistance that appeared and became widespread within three years. Genome scans revealed genetic heterogeneity of resistance among populations and identified 15 target mutations, including six mutations on five amino acid residues of subunit sdhB, and nine mutations on three amino acid residues of subunit sdhD of the pesticide target succinate dehydrogenase, with as many as five substitutions on one residue. No mutations were present in 2666 screened historical specimens, suggesting that mutations arose rapidly through de novo substitutions or from very rare segregating mutations. Identical mutations recurrently appeared in different genetic backgrounds, increasing the likelihood of resistance evolution. The high number of mutational options available for the evolution of target site resistance in this pest challenges resistance management practices.

evolutionary biology↗

bioRxiv2024

A single-molecule nanopore sequencing platform

Nanopore sequencing, a third-generation sequencing technology, has revolutionized the gene sequencing industry with its advantages of long reads, fast speed, real-time sequencing and analysis, and potential in detecting base modifications. This technology allows researchers to sequence longer DNA fragments in a single read, providing more comprehensive genomic information compared to previous methods. Nanopore sequencing operates on electrical signals generated by a nanopore embedded in a membrane separating two electrolyte-filled chambers. When single-stranded DNA (ssDNA) passes through the nanopore, it creates variations in the current that correspond to different DNA bases. By analyzing these current fluctuations with machine learning algorithms, the DNA sequence can be determined. In this study, we introduced several improvements to nanopore sequencing, including nanopore local chemistry sequencing, novel motor and pore proteins, chip design, and basecalling algorithms. Our new nanopore sequencing platform, CycloneSEQ, demonstrated long-duration sequencing (107 hours) on a single chip with high yield (>50 Gb). In human genomic DNA sequencing, CycloneSEQ was able to produce long reads with N50 33.6 kb and modal identity 97.0%. Preliminary findings on human whole-genome de novo assembly, variant calling, metagenomics sequencing, and single-cell RNA sequencing have further highlighted CycloneSEQs potential across different areas of genomics.

genomics↗

bioRxiv2024

The prion-like protein Doppel: A soluble biomarker steering ovarian cancers peritoneal to circulatory dissemination

Detecting ovarian cancer (OC) early using existing biomarkers, e.g., cancer antigen 125 (CA125), is challenging due to its ubiquitous expression in many tissues. Doppel, a prion-like protein, expresses in male reproductive organ but absent in female reproductive systems and healthy tissues, but plays an important role in neoangiogenesis. Here, we have shown two platforms, soluble Doppel in sera/ascites and Doppel expressed circulating tumor cells (Dpl+CTC) in the whole blood, to detect subsets of epithelial OC (EOC). Increased level of Doppel in the sera of OC patients, in three different cohorts, confirm Doppel as OC specific biomarker. Serum Doppel level distinguishes EOC subtypes and early stages HGSOCs from non-cancerous conditions with high sensitivity and specificity. Stratifying the EOCs based on Doppel level, we categorized them into Doppel-high (Dplhi) and Doppel-low (Dpllow) groups. Using ascites-derived organoids and single cell sequencing of whole ascites of Dplhi and Dpllow patients, we identify that Doppel induces epithelial-mesenchymal transition (EMT) and creates an immunosuppressive microenvironment, respectively. Doppel levels in the sera/ascites correlate with the changes of Dpl+CTC number in whole blood, highlighting the association of Doppel-induced EMT with CTC dissemination in circulation. Thus, Doppel-based detection of EOC subtypes could be a promising platform as clinical biomarker and link Doppel-axis with OC dissemination.

cancer biology↗

bioRxiv2023

A conserved protein inhibitor brings under check the activity of RNase E in cyanobacteria

RNase E is a major ribonuclease for RNA metabolism in bacteria. Because it has a large substrate spectrum and poor substrate specificity, its activity must be well controlled under different conditions. Only a few regulators of RNase E are known in bacteria, limiting our understanding on the posttranscriptional regulatory mechanisms operating in these organisms. Here we show that, RebA, a protein universally present in cyanobacteria, interacts with RNase E in the filamentous cyanobacterium Anabaena PCC 7120. Distinct from those known regulators of RNase E, RebA interacts with the 5 sensor domain in the catalytic region of RNase E, and suppresses the cleavage activities of RNase E for all tested RNA substrates irrespective of their 5-end status. Consistent with the inhibitory function of RebA on RNase E, conditional depletion of RNase E and overproduction of RebA caused formation of elongated cells, whereas the absence of RebA and overproduction of RNase E resulted in a shorter-cell phenotype. We further showed that the morphological changes caused by altered levels of RNase E or RebA are dependent on their physical interaction. The action of RebA represents a new mechanism, highly conserved in cyanobacteria, for RNase E regulation. Our findings provide insights into the regulation and the function of RNase E, and demonstrate the importance of balanced RNA metabolism in bacteria.

microbiology↗

bioRxiv2022

Microglia are involved in regulating histamine dependent and non-dependent itch transmissions with distinguished signal pathways

Although itch and pain have many similarities, they are completely different in perceptual experience and behavioral response. In recent years, we have a deep understanding of the neural pathways of itch sensation transmission. However, there are few reports on the role of non-neuronal cells in itch. Microglia are known to play a key role in chronic neuropathic pain and acute inflammatory pain. It is still unknown whether microglia are also involved in regulating the transmission of itch sensation. In the present study, we used several kinds of transgenic mice to specifically deplete CX3CR1+ central microglia and peripheral macrophages together (whole depletion), or selectively deplete central microglia alone (central depletion). We observed that the acute itch responses to histamine, compound 48/80 and chloroquine were all significantly reduced in mice with either whole or central depletion. Spinal c-fos mRNA assay and further studies revealed that histamine and compound 48/80, but not chloroquine elicited primary itch signal transmission from DRG to spinal Npr1- and somatostatin-positive neurons relied on microglial CX3CL1-CX3CR1 pathway. Our results suggested that central microglia were involved in multiple types of acute chemical itch transmission, while the underlying mechanisms for histamine dependent and non-dependent itch transmission were different that the former required the CX3CL1-CX3CR1 signal pathway.

neuroscience↗

bioRxiv2021

Dopamine enhanced auditory perceptual learning in humans via long-term memory consolidation

Dopamine is known to modulate sensory plasticity in animal brain, but how it impacts perceptual learning in humans remains largely unknown. In a placebo-controlled, double-blinded training experiment with young healthy adults (both male and female), oral administration of Madopar, a dopamine precursor, during each of multiple training sessions was shown to enhance auditory perceptual learning, particularly in late training sessions. Madopar also enhanced learning and transfer to working memory when tested outside the time widow of drug effect, which appeared to retain for at least 20 days. To test whether such learning modulation was mediated by the dopaminergic working memory network, the same dopamine manipulation was applied to working memory training, but to little influence on learning or transfer. Further, a neural network model of auditory perceptual learning revealed distinctive behavioural modulation patterns for proposed dopaminergic functions in the auditory cortex: trial-by-trial reinforcement signals (reward/reward prediction error and expected reward) and across-session memory consolidation. Only the memory consolidation simulations matched experimental observations. The results thus demonstrate that dopamine modulates human perceptual learning, mostly likely via enhancing memory consolidation over extended time scales.

neuroscience↗

bioRxiv2021

Enhanced genetic analysis of type 1 diabetes by selecting variants on both effect size and significance, and by integration with autoimmune thyroid disease

For polygenic traits, associations with genetic variants can be detected over many chromosome regions, owing to the availability oflarge sample sizes. Most variants, however, have small effects on disease risk and, therefore, unravelling the causal variants, target genes, and biology of these variants is challenging. Here, we define the Bigger or False Discovery Rate (BFDR) as the probability that either a variant is a false-positive or a randomly drawn, true-positive association exceeds it in effect size. Using the BFDR, we identified 302 previously unreported signals with larger effect associations with type 1 diabetes and autoimmune thyroid disease. Out of 239 genome-wide significant signals in both diseases, only 66 (28%) show evidence for having a large effect using the BFDR, further demonstrating how using a combination of effect size and significance, rather than significance alone, is important in identifying SNPs and candidate genes for further investigation.

genetics↗

bioRxiv2021

Using de novo assembly to identify structural variation of complex immune system gene regions

Driven by the necessity to survive environmental pathogens, the human immune system has evolved exceptional diversity and plasticity, to which several factors contribute including inheritable structural polymorphism of the underlying genes. Characterizing this variation is challenging due to the complexity of these loci, which contain extensive regions of paralogy, segmental duplication and high copy-number repeats, but recent progress in long-read sequencing and optical mapping techniques suggests this problem may now be tractable. Here we assess this by using long-read sequencing platforms from PacBio and Oxford Nanopore, supplemented with short-read sequencing and Bionano optical mapping, to sequence DNA extracted from CD14+ monocytes and peripheral blood mononuclear cells from a single European individual identified as HV31. We use this data to build a de novo assembly of eight genomic regions encoding four key components of the immune system, namely the human leukocyte antigen, immunoglobulins, T cell receptors, and killer-cell immunoglobulin-like receptors. Validation of our assembly using k-mer based and alignment approaches suggests that it has high accuracy, with estimated base-level error rates below 1 in 10 kb, although we identify a small number of remaining structural errors. We use the assembly to identify heterozygous and homozygous structural variation in comparison to GRCh38. Despite analyzing only a single individual, we find multiple large structural variants affecting core genes at all three immunoglobulin regions and at two of the three T cell receptor regions. Several of these variants are not accurately callable using current algorithms, implying that further methodological improvements are needed. Our results demonstrate that assessing haplotype variation in these regions is possible given sufficiently accurate long-read and associated data; application of these methods to larger samples would provide a broader catalogue of germline structural variation at these loci, an important step toward making these regions accessible to large-scale genetic association studies.

bioinformatics↗

bioRxiv2020

HetF protein is a new divisome component in a filamentous and developmental cyanobacterium

Bacterial cell division, with a few exceptions, is driven by FtsZ through a treadmilling mechanism to remodel and constrict the rigid peptidoglycan (PG) layer. Yet, different organisms may differ in the composition of the cell-division complex (divisome). In the filamentous cyanobacterium Anabaena PCC 7120, hetF is required for the initiation of the differentiation of heterocysts, cells specialized in N2-fixing cells under combined nitrogen deprivation. In this study, we demonstrate that hetF is expressed in vegetative cells and necessary for cell division in a conditional manner. Under non-permissive conditions, cells of a {Delta}hetF mutant stop dividing, consistent with increased level of HetF under similar conditions in the wild type. Furthermore, HetF is a membrane protein located at midcell and cell-cell junctions. In the absence of HetF, FtsZ rings are still present in the elongated cells; however, PG remodelling is abolished. This phenotype is similar to that observed with the inhibition of septal PG synthase FtsI. We further reveal that HetF is recruited to or stabilized at the divisome by interacting with FtsI and this interaction is necessary for HetF function in cell division. Our results indicate that HetF is a member of the divisome, and reveal distinct features of the cell-division machinery in cyanobacteria that are of high ecological and environmental importance. Significance StatementCyanobacteria shaped the Earths evolutionary history, and are still playing important roles for elementary cycles in different environments. They are consisted of highly diverse species with different cell shape, size and morphology. Although these properties are strongly affected by the process of cytokinesis, the mechanism remains largely unexplored. Using different approaches, we demonstrate that HetF is a new component of the cell division machinery in the filamentous cyanobacterium Anabaena PCC 7120. The common and diverged characteristics of cell division in prokaryotes reflect the evolutionary history of different bacteria, as an adaptive measure to proliferate under certain environmental conditions. As a protein for cell differentiation, the recruitment of HetF to the septum illustrates such an adaptive mechanism for cyanobacteria.

microbiology↗

bioRxiv2020

Single-cell landscape of immunological responses in COVID-19 patients

In COVID-19 caused by SARS-CoV-2 infection, the relationship between disease severity and the host immune response is not fully understood. Here we performed single-cell RNA sequencing in peripheral blood samples of five healthy donors and 13 COVID-19 patients including moderate, severe and convalescent cases. Through determining the transcriptional profiles of immune cells, coupled with assembled T cell receptor and B cell receptor sequences, we analyzed the functional properties of immune cells. Most cell types in COVID-19 patients showed a strong interferon-alpha response, and an overall acute inflammatory response. Moreover, intensive expansion of highly cytotoxic effector T cell subsets, such as CD4+ Effector-GNLY (Granulysin), CD8+ Effector-GNLY and NKT CD160, was associated with convalescence in moderate patients. In severe patients, the immune landscape featured a deranged interferon response, profound immune exhaustion with skewed T cell receptor repertoire and broad T cell expansion. These findings illustrate the dynamic nature of immune responses during the disease progression.

immunology↗