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Biology subjects

Chan, L.

Publications and source records attributed to Chan, L..

At least 19 recordsLinked to original sources

Hierarchical Predictive Processing during Natural Reading

Key neural mechanisms underlying reading, especially in the context of sentences and texts, remain elusive. An influential theory states that the brain rapidly generates a hierarchy of probabilistic predictions about upcoming words at multiple levels of linguistic representation. When encountering a word, a reader integrates sensory input with the linguistic predictions, and rely on the resulting prediction error signals to achieve efficient comprehension. Here, we tested this hierarchical predictive account with a natural reading task while EEG and eye movements were simultaneously recorded. We find distinct prediction error signals attributable to word contextual, lexical, and orthographic levels of predictions. These prediction error signals exhibit a temporal order. Our results also indicate that context-based predictions rapidly constrain orthographic-level predictions. We thus provide evidence for a hierarchical predictive process central to efficient natural reading.

neuroscience↗

Whole-genome 3D architectural screen reveals modulators of brain DNA structure

Three-dimensional (3D) genome architecture is the foundation of gene regulation, and plays a critical role in normal physiology and disease. However, our understanding of its biochemical determinants has long been limited by technology: imaging-based screens only profile a small number of loci, while sequencing-based studies rarely exceed 100 samples or conditions. Here we present "in-plate chromosome conformation capture" (Plate-C), a high-throughput, cost-effective platform that profiles thousands of whole-genome architectures in a day. Plate-C enabled the first chemical screen for whole-genome structural changes--profiling 2,956 samples from 834 conditions across 5 neuronal and glial types, accompanied by 6,081 single cells using "easy diploid chromosome conformation capture" (Easy Dip-C) and 200,893 single-cell transcriptomes. We discovered that diverse, dose/time-dependent, and cell type/species-specific modes of DNA structural changes can be rapidly induced by manipulating epigenetic (HDAC, BET), metabolic (mTOR), proteostatic (UPR), developmental (GSK3/Wnt, Hedgehog), immune (cGAS/STING), and neurotransmission pathways. To validate our finding in vivo, we demonstrated in newborn mice that HDAC inhibition drives brain-wide genome rewiring within hours, highly correlated with changes in vitro and inducing a latent structural and transcriptional state orthogonal to normal differentiation. By enabling massively parallel profiling of whole-genome structures, Plate-C paves the way for systematic discovery of DNA folding principles to better understand and engineer the human genome in 3D.

genomics↗

PTPN1/2 inhibits alveolar macrophage-mediated control of lung metastasis

Metastasis remains the leading cause of cancer mortality, yet effective therapies are limited. While therapeutic responses are influenced by organ-specific immune microenvironments, strategies to pharmacologically modulate these niches remain poorly defined. Here, using the clinical-stage inhibitor ABBV-CLS-484 (AC484) as a chemical probe, we demonstrate that systemic PTPN1/2 inhibition remodels the pulmonary myeloid landscape, specifically activating alveolar macrophages (AMs) toward a tumoricidal state. Integrated single-cell/spatial transcriptomics and functional assays reveal that AC484 promotes AM accumulation within metastatic lesions, elevates their IFN{gamma} production and responsiveness, and enhances their tumor-killing activity. Depletion of AMs diminishes the anti-metastatic efficacy of AC484. Mechanistically, inhibiting PTPN1/2 by AC484 amplifies IFN{gamma}-STAT1 signaling in AMs, while disrupting this pathway impairs their tumor control capability. These findings delineate a distinct innate immune axis where PTPN1/2 acts as a molecular "brake" on AM activation, suggesting that pharmacologically unleashing tissue-resident macrophages offers a therapeutic strategy to overcome metastatic progression, particularly in microenvironments where adaptive immunity is insufficient. SignificanceAMs are potent anti-metastatic immune effectors functionally constrained by PTPN1/2. Pharmacologically inhibiting PTPN1/2 amplifies their IFN{gamma}-STAT1 signaling and tumoricidal activity, establishing a strategy to reactivate tissue-resident immunity against metastasis.

immunology↗

A periplasmic protein complex mediates cell envelope integrity and intrinsic multidrug resistance in Mycobacterium tuberculosis

The intrinsic drug resistance of Mycobacterium tuberculosis (Mtb) is a major barrier to effective tuberculosis (TB) treatment, largely due to its complex, impermeable cell envelope. We identified a periplasmic protein complex comprising FecB and Rv3035 that is essential for maintaining envelope integrity and mediating intrinsic multidrug resistance in Mtb. FecB interacts with Rv3035, forming a stable heterodimer that associates with the cell envelope biosynthesis protein AftB. We report the structures of Rv3035 alone and in complex with FecB and identify critical residues for complex formation and function. Co-essentiality and genetic interaction analyses support a functional link between FecB, Rv3035 and AftB, an arabinofuranosyltransferase which synthesizes arabinogalactan and lipoarabinomannan. Loss of FecB or Rv3035 disrupted AftB-mediated arabinan synthesis, suggesting that these proteins support AftBs enzymatic activity. Importantly, FecB is required for Mtb virulence in mice, underscoring its physiological relevance. These findings highlight FecB, Rv3035 and AftB as promising therapeutic targets.

microbiology↗

Platform-dependent effects of genetic variants on plasma APOL1 and their implications for kidney disease

Mutations in apolipoprotein L1 (APOL1) are strongly associated with protection against parasitic infections and increased risk of kidney disease in individuals of African ancestry. To better understand the mechanisms underlying APOL1-related pathologies, we examined genetic drivers of circulating APOL1 in individuals of African and European ancestry from four independent cohorts (UK Biobank, AASK, deCODE, and Health ABC) using three proteomic technologies (Olink, SomaLogic, and mass spectrometry). We found that disease-associated APOL1 G1 and G2 variants are strong cis-pQTLs for plasma APOL1 measured by Olink and SomaLogic, but not mass spectrometry. Critically, the direction of variant effects differed between proteomic platforms, being positive with Olink and negative with SomaLogic. We identified an additional APOL1 missense variant (rs2239785), common in Europeans, exhibiting the same platform-dependent directional discrepancy. Furthermore, variants in the kallikrein-kinin system (KKS), involving KLKB1, F12, and KNG1, and their genetic interactions showed strong trans-pQTL effects on APOL1 measured by Olink, but not SomaLogic. These platform-dependent discrepancies raise the possibility that both intrinsic APOL1 mutations and extrinsic KKS activity induce conformational changes in the APOL1 protein that are differentially recognized by the proteomic platforms.

genetics↗

Enhanced lentiviral gene delivery to mammalian cells via paired cell surface and viral envelope engineering

Lentiviral vectors that facilitate gene delivery to desired cell types have been widely used in routine laboratory research and therapeutic cell engineering. However, the lack of proper entry receptors on many cell types often results in poor gene delivery. Here, we present a simple paired virus-cell engineering approach that promotes lentiviral gene delivery into mammalian cells. Lentiviruses are dual-pseudotyped with VSV-G and a chimeric envelope protein specifically recognizing a small molecule fluorescein (FITC-Env), and target cells are transiently labelled with FITC to create surrogate receptors for lentivirus attachment. The synthetic interaction between FITC-labeled cells and FITC-binding LVs enables efficient LV docking, viral entry and stable transgene expression in a range of mammalian cell lines and primary T cells. We showed that this approach enabled efficient delivery of a CD19-targeted chimeric antigen receptor (CAR) into naive human T cells that are naturally refractory to conventional VSV-G LVs, which upon activation rapidly eradicated CD19+ leukemic cells. This paired cell surface and virus envelope engineering approach may serve as a universal method for engineering synthetic virus-cell interactions to improve lentiviral gene delivery to mammalian cells.

bioengineering↗

Sex differences and immune correlates of Long COVID development, persistence, and resolution

Sex differences have been observed in acute COVID-19 and Long COVID (LC) outcomes, with greater disease severity and mortality during acute infection in males and a greater proportion of females developing LC. We hypothesized that sex-specific immune dysregulation contributes to the pathogenesis of LC. To investigate the immunologic underpinnings of LC development and persistence, we used single-cell transcriptomics, single-cell proteomics, and plasma proteomics on blood samples obtained during acute SARS-CoV-2 infection and at 3 and 12 months post-infection in a cohort of 45 patients who either developed LC or recovered. Several sex-specific immune pathways were associated with LC. Specifically, males who would develop LC at 3 months had widespread increases in TGF-{beta} signaling during acute infection in proliferating NK cells. Females who would develop LC demonstrated increased expression of XIST, an RNA gene implicated in autoimmunity, and increased IL1 signaling in monocytes at 12 months post infection. Several immune features of LC were also conserved across sexes. Both males and females with LC had reduced co-stimulatory signaling from monocytes and broad upregulation of NF-{kappa}B transcription factors. In both sexes, those with persistent LC demonstrated increased LAG3, a marker of T cell exhaustion, reduced ETS1 transcription factor expression across lymphocyte subsets, and elevated intracellular IL-4 levels in T cell subsets, suggesting that ETS1 alterations may drive an aberrantly elevated Th2-like response in LC. Altogether, this study describes multiple innate and adaptive immune correlates of LC, some of which differ by sex, and offers insights toward the pursuit of tailored therapeutics. One Sentence SummaryThis multi-omic analysis of Long COVID reveals sex differences and immune correlates of Long COVID development, persistence, and resolution.

immunology↗

Chromosomal-level genome assembly and single-nucleotide polymorphism sites of black-faced spoonbill Platalea minor

Platalea minor, the black-faced spoonbill (Threskiornithidae) is a wading bird that is confined to coastal areas in East Asia. Due to habitat destruction, it has been classified by The International Union for Conservation of Nature (IUCN) as globally endangered species. Nevertheless, the lack of its genomic resources hinders our understanding of their biology, diversity, as well as carrying out conservation measures based on genetic information or markers. Here, we report the first chromosomal-level genome assembly of P. minor using a combination of PacBio SMRT and Omni-C scaffolding technologies. The assembled genome (1.24 Gb) contains 95.33% of the sequences anchored to 31 pseudomolecules. The genome assembly also has high sequence continuity with scaffold length N50 = 53 Mb. A total of 18,780 protein-coding genes were predicted, and high BUSCO score completeness (93.7% of BUSCO metazoa_odb10 genes) was also revealed. A total of 6,155,417 bi-allelic SNPs were also revealed from 13 P. minor individuals, accounting for [~]5% of the genome. The resource generated in this study offers the new opportunity for studying the black-faced spoonbill, as well as carrying out conservation measures of this ecologically important spoonbill species.

genomics↗

DIETARY REGULATION OF SILENT SYNAPSES IN THE DORSOLATERAL STRIATUM

Obesity and drugs of abuse share overlapping neural circuits and behaviors. Silent synapses are transient synapses that are important for remodeling brain circuits. They are prevalent during early development but largely disappear by adulthood. Drugs of abuse increase silent synapses during adulthood and may facilitate reorganizing brain circuits around drug-related experience, facilitating addiction and contributing to relapse during treatment and abstinence. Whether obesity causes alterations in the expression of silent synapses in a manner similar to drugs of abuse has not been examined. Using a dietary-induced obesity paradigm, mice that chronically consumed high fat diet (HFD) exhibited increased silent synapses in both direct and indirect pathway medium spiny neurons in the dorsolateral striatum. Both the time of onset of increased silent synapses and their normalization upon discontinuation of HFD occurs on an extended time scale compared to drugs of abuse. These data demonstrate that chronic consumption of HFD, like drugs of abuse, can alter mechanisms of circuit plasticity likely facilitating neural reorganization analogous to drugs of abuse.

neuroscience↗

Genome assembly of the edible jelly fungus Dacryopinax spathularia (Dacrymycetaceae)

The edible jelly fungus Dacryopinax spathularia (Dacrymycetaceae) is wood-decaying and can be commonly found worldwide. It has also been used in food additives given its ability to synthesize long-chain glycolipids. In this study, we present the genome assembly of D. spathularia using a combination of PacBio HiFi reads and Omni-C data. The genome size of D. spathularia is 29.2 Mb and in high sequence contiguity and completeness, including scaffold N50 of 1.925 Mb and 92.0% BUSCO score, respectively. A total of 11,510 protein-coding genes, and 474.7 kb repeats accounting for 1.62% of the genome, were also predicted. The D. spathularia genome assembly generated in this study provides a valuable resource for understanding their ecology such as wood decaying capability, evolutionary relationships with other fungus, as well as their unique biology and applications in the food industry.

genomics↗

Chromosomal-level genome assembly of the long-spined sea urchin Diadema setosum (Leske, 1778)

The long-spined sea urchin Diadema setosum is an algal and coral feeder widely distributed in the Indo-Pacific and can cause severe bioerosion on the reef community. Nevertheless, the lack of genomic information has hindered the study its ecology and evolution. Here, we report the chromosomal-level genome (885.8 Mb) of the long-spined sea urchin D. setosum using a combination of PacBio long-read sequencing and Omni-C scaffolding technology. The assembled genome contained scaffold N50 length of 38.3 Mb, 98.1 % of BUSCO (Geno, metazoa_odb10) genes, and with 98.6% of the sequences anchored to 22 pseudo-molecules/chromosomes. A total of 27,478 genes including 23,030 protein-coding genes were annotated. The high-quality genome of D. setosum presented here provides a significant resource for further understanding on the ecological and evolutionary studies of this coral reef associated sea urchin.

genomics↗

Genome assembly of the rare and endangered Grantham's camellia, Camellia granthamiana

The Granthams camellia (Camellia granthamiana Sealy) is a rare and endangered tea species that is endemic to southern China, and was first discovered in Hong Kong in 1955. Despite its high conservation value, genomic resources of C. granthamiana remain limited. Here, we present a chromosome-scale draft genome of the tetraploid C. granthamiana (2n = 4x = 60) using a combination of PacBio long read sequencing and Omni-C data. The assembled genome size is [~]2.4 Gb with most sequences anchored to 15 pseudochromosomes that resemble a monoploid genome. The genome is of high contiguity, with a scaffold N50 of 139.7 Mb, and high completeness with a 97.8% BUSCO score. Gene model prediction resulted in a total 76,992 protein-coding genes with a BUSCO score of 85.9%. 1.65 Gb of repeat content was annotated, which accounts for 68.48% of the genome. The Granthams camellia genome assembly provides a valuable resource for future investigations on its biology, ecology, phylogenomic relationships with other Camellia species, as well as set up a foundation for further conservation measures.

plant biology↗

Chromosome-level genome assembly of the common chiton, Liolophura japonica (Lischke, 1873)

Chitons (Polyplacophora) are marine molluscs that can be found worldwide from cold waters to the tropics, and play important ecological roles in the environment. Nevertheless, there remains only two chiton genomes sequenced to date. The chiton Liolophura japonica (Lischke, 1873) is one of the most abundant polyplacophorans found throughout East Asia. Our PacBio HiFi reads and Omni-C sequencing data resulted in a high-quality near chromosome-level genome assembly of [~]609 Mb with a scaffold N50 length of 37.34 Mb (96.1% BUSCO). A total of 28,233 genes were predicted, including 28,010 protein-coding genes. The repeat content (27.89%) was similar to the other Chitonidae species and approximately three times lower than in the genome of the Hanleyidae chiton. The genomic resources provided in this work will help to expand our understanding of the evolution of molluscs and the ecological adaptation of chitons.

genomics↗

Genome assembly of the milky mangrove Excoecaria agallocha

The milky mangrove Excoecaria agallocha is a latex-secreting mangrove that are distributed in tropical and subtropical regions. While its poisonous latex is regarded as a potential source of phytochemicals for biomedical applications, the genomic resources of E. agallocha remains limited. Here, we present a chromosomal level genome of E. agallocha, assembled from the combination of PacBio long-read sequencing and Omni-C data. The resulting assembly size is 1,332.45 Mb and has high contiguity and completeness with a scaffold N50 of 58.9 Mb and a BUSCO score of 98.4 %. 73,740 protein-coding genes were also predicted. The milky mangrove genome provides a useful resource for further understanding the biosynthesis of phytochemical compounds in E. agallocha.

genomics↗

Chromosomal-level genome assembly of golden birdwing Troides aeacus (Felder & Felder, 1860)

Troides aeacus, the golden birdwing (Lepidoptera, Papilionidae) is a large swallowtail butterfly widely distributed in Asia. Despite its occurrence, T. aeacus has been assigned as a major protective species in many places given the loss of their native habitats under urbanisation and anthropogenic activities. Nevertheless, the lack of its genomic resources hinders our understanding of their biology, diversity, as well as carrying out conservation measures based on genetic information or markers. Here, we report the first chromosomal-level genome assembly of T. aeacus using a combination of PacBio SMRT and Omni-C scaffolding technologies. The assembled genome (351 Mb) contains 98.94% of the sequences anchored to 30 pseudo-molecules. The genome assembly also has high sequence continuity with scaffold length N50 = 12.2 Mb. A total of 28,749 protein-coding genes were predicted, and high BUSCO score completeness (98.9% of BUSCO metazoa_odb10 genes) was also revealed. This high-quality genome offers a new and significant resource for understanding the swallowtail butterfly biology, as well as carrying out conservation measures of this ecologically important lepidopteran species.

genomics↗

Nucleic acid sequence contributes to remodeler-mediated targeting of histone H2A.Z

The variant histone H2A.Z is inserted into nucleosomes immediately downstream of promoters and is important for transcription. The site-specific deposition of H2A.Z is catalyzed by SWR, a conserved chromatin remodeler with affinity for promoter-proximal nucleosome depleted regions (NDRs) and histone acetylation. By comparing the genomic distribution of H2A.Z in wild-type and SWR-deficient cells, we found that SWR is also responsible for depositing H2A.Z at thousands of non-canonical sites not directly linked to NDRs or histone acetylation. To understand the targeting mechanism of H2A.Z, we presented SWR with a library of nucleosomes isolated from yeast and characterized those preferred by SWR. We found that SWR prefers nucleosomes associated with intergenic over coding regions, especially when polyadenine tracks are present. Insertion of polyadenine sequences into recombinant nucleosomes near the H2A-H2B binding site stimulated the H2A.Z insertion activity of SWR. Therefore, the genome is encoded with information contributing to remodeler-mediated targeting of H2A.Z.

molecular biology↗

Huntingtin Over-Expression Does Not Alter Overall Survival in Murine Cancer Models

A reduced incidence of various forms of cancer has been reported in Huntingtons disease (HD) patients and may be due to pro-apoptotic effects of mutant huntingtin. We tested this hypothesis by assessing the effects of huntingtin protein over-expression on survival in two murine cancer models. We generated yeast artificial chromosome (YAC) HD mice containing human huntingtin transgenes with various CAG tract lengths (YAC18, YAC72, YAC128) on either an Msh2 or p53 null background, which have increased cancer incidence. In both mouse models of cancer, the over-expression of either mutant or wild-type huntingtin had no significant effect on overall survival. These results do not support the hypothesis that mutant huntingtin expression is protective against cancer.

cancer biology↗

Rapid, Reference-Free Human Genotype Imputation with Denoising Autoencoders

Genotype imputation is a foundational tool for population genetics. Standard statistical imputation approaches rely on the co-location of large whole-genome sequencing-based reference panels, powerful computing environments, and potentially sensitive genetic study data. This results in computational resource and privacy-risk barriers to access to cutting-edge imputation techniques. Moreover, the accuracy of current statistical approaches is known to degrade in regions of low and complex linkage disequilibrium. Artificial neural network-based imputation approaches may overcome these limitations by encoding complex genotype relationships in easily portable inference models. Here we demonstrate an autoencoder-based approach for genotype imputation, using a large, commonly-used reference panel, and spanning the entirety of human chromosome 22. Our autoencoder-based genotype imputation strategy achieved superior imputation accuracy across the allele-frequency spectrum and across genomes of diverse ancestry, while delivering at least 4-fold faster inference run time relative to standard imputation tools.

bioinformatics↗