Biology subjects

Zhan, Y.

Publications and source records attributed to Zhan, Y..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Genetic variation modulates susceptibility to aberrant DNA hypomethylation and imprint deregulation in naive pluripotent stem cells

Naive pluripotent stem cells (nPSC) frequently undergo pathological and not readily reversible loss of DNA methylation marks at imprinted gene loci. This abnormality poses a hurdle for using pluripotent cell lines in biomedical applications and underscores the need to identify the causes of imprint instability in these cells. We show that nPSCs from inbred mouse strains exhibit pronounced strain-specific susceptibility to locus-specific deregulation of imprinting marks during reprogramming to pluripotency and upon culture with MAP kinase inhibitors, a common approach to maintain naive pluripotency. Analysis of genetically highly diverse nPSCs from the Diversity Outbred (DO) stock confirms that genetic variation is a major determinant of epigenome stability in pluripotent cells. We leverage the variable DNA hypomethylation in DO lines to identify several trans-acting quantitative trait loci (QTLs) that determine epigenome stability at either specific target loci or genome-wide. Candidate factors encoded by two multi-target QTLs on chromosomes 4 and 17 suggest specific transcriptional regulators that contribute to DNA methylation maintenance in nPSCs. We propose that genetic variants represent candidate biomarkers to identify pluripotent cell lines with desirable properties and might serve as entry points for the targeted engineering of nPSCs with stable epigenomes. HighlightsO_LINaive pluripotent stem cells from distinct inbred mouse strains exhibit variable DNA methylation levels at imprinted gene loci. C_LIO_LIThe vulnerability of pluripotent stem cells to loss of genomic imprinting caused by MAP kinase inhibition strongly differs between inbred mouse strains. C_LIO_LIGenetically diverse pluripotent stem cell lines from Diversity Outbred mouse stock allow the identification of quantitative trait loci controlling DNA methylation stability. C_LIO_LIGenetic variants may serve as biomarkers to identify naive pluripotent stem cell lines that are epigenetically stable in specific culture conditions. C_LI

developmental biology↗

bioRxiv2024

Aging limits stemness and tumorigenesis in the lung by reprogramming iron homeostasis

Aging is associated with a decline in the number and fitness of adult stem cells1-4. Aging-associated loss of stemness is posited to suppress tumorigenesis5,6, but this hypothesis has not been tested in vivo. Here, using physiologically aged autochthonous genetically engineered mouse models and primary cells7,8, we demonstrate aging suppresses lung cancer initiation and progression by degrading stemness of the alveolar cell of origin. This phenotype is underpinned by aging-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, leading to a functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1--lipocalin-2 axis or iron supplementation rescue stemness and promote tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1-- lipocalin-2 axis is detrimental to young alveolar cells via induction of ferroptosis. We find that aging-associated DNA hypomethylation at specific enhancer sites associates with elevated NUPR1 expression, which is recapitulated in young alveolar cells by inhibition of DNA methylation. We uncover that aging drives a functional iron insufficiency, which leads to loss of stemness and tumorigenesis, but promotes resistance to ferroptosis. These findings have significant implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate in young individuals, revealing a critical window for such cancer prevention efforts.

cancer biology↗

bioRxiv2024

LETSmix: a spatially informed and learning-based domain adaptation method for cell-type deconvolution in spatial transcriptomics

Spatial transcriptomics (ST) has revolutionized our understanding of gene expression patterns by incorporating spatial context. However, many ST technologies operate on heterogeneous cell mixtures due to limited spatial resolution. To resolve cell type composition at each sequencing spot, several deconvolution methods have been proposed. Yet, these approaches often underutilize spatial context inherent in ST data and paired histopathological images, meanwhile overlooking domain variances between ST and reference single-cell RNA sequencing (scRNA-seq) data. Here, we present LETSmix, a novel deconvolution method that enhances spatial correlations within ST data using a tailored LETS filter, and employs a mixup-augmented domain adaptation strategy to address domain shifts. The performance of LETSmix was validated across diverse ST platforms and tissue types, including 10x Visium human dorsolateral prefrontal cortex, ST human pancreatic ductal adenocarcinoma, 10x Visium mouse liver, and Stereo-seq mouse olfactory bulb datasets. Our findings demonstrate that the proposed method accurately estimates cell type proportions and effectively maps them to the expected regions, establishing a new record among current state-of-the-art models. LETSmix is expected to serve as a robust tool for advancing studies on cellular composition and spatial architecture in spatial transcriptomics. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=149 SRC="FIGDIR/small/591425v2_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1b264cborg.highwire.dtl.DTLVardef@f77e8forg.highwire.dtl.DTLVardef@9609ddorg.highwire.dtl.DTLVardef@61af58_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2024

Tumor Stroma Content Regulates Penetration and Efficacy of Tumor-targeting Bacteria

Bacteria-based cancer therapy (BBCT) strains grow selectively in primary tumors and metastases, colonize solid tumors independent of genetics, and kill cells resistant to standard molecular therapy. Clinical trials of BBCT in solid tumors have not reported any survival advantage yet, partly due to the limited bacterial colonization. Collagen, abundant in primary and metastatic solid tumors, has a well-known role in hindering intratumoral penetration of therapeutics. Nevertheless, the effect of collagen content on the intratumoral penetration and antitumor efficacy of BBCT is rarely unexplored. We hypothesized that the presence of collagen limits the penetration and, thereby, the antitumor effects of tumor-selective Salmonella. Typhimurium VNP20009 cheY+. We tested our hypothesis in low and high collagen content tumor spheroid models of triple-negative murine breast cancer. We found that high collagen content significantly hinders bacteria transport in tumors, reducing bacteria penetration and distribution by [~]7-fold. The higher penetration of bacteria in low collagen-content tumors led to an overwhelming antitumor effect ([~]73% increase in cell death), whereas only a 28% increase in cell death was seen in the high collagen-content tumors. Our mathematical modeling of intratumoral bacterial colonization delineates the role of growth and diffusivity, suggesting an order of magnitude lower diffusivity in the high collagen-content tumors dominates the observed outcomes. Finally, our single-cell resolution analysis reveals a strong spatial correlation between bacterial spatial localization and collagen content, further corroborating that collagen acts as a barrier to bacterial penetration despite S. Typhimurium VNP20009 cheY+ motility. Understanding the effect of collagen on BBCT performance could lead to engineering more efficacious BBCT strains capable of overcoming this barrier to colonization of primary tumors and metastases.

biophysics↗

bioRxiv2024

Chromosome-level Subgenome-aware de novo Assembly of Saccharomyces bayanus Provides Insight into Genome Divergence after Hybridization

Interspecies hybridization is prevalent in various eukaryotic lineages and plays important roles in phenotypic diversification, adaption, and speciation. To better understand the changes that occurred in the different subgenomes of a hybrid species and how they facilitated adaptation, we completed chromosome-level de novo assemblies of all 16 pairs chromosomes for a recently formed hybrid yeast, Saccharomyces bayanus strain CBS380 (IFO11022), using Nanopore MinION long-read sequencing. Characterization of S. bayanus subgenomes and comparative analysis with the genomes of its parent species, S. uvarum and S. eubayanus, provide several new insights into understanding genome evolution after a relatively recent hybridization. For instance, multiple recombination events between the two subgenomes have been observed in each chromosome, followed by loss of heterozygosity (LOH) in most chromosomes in nine chromosome pairs. In addition to maintaining nearly all gene content and synteny from its parental genomes, S. bayanus has acquired many genes from other yeast species, primarily through the introgression of S. cerevisiae, such as those involved in the maltose metabolism. In addition, the patterns of recombination and LOH suggest an allotetraploid origin of S. bayanus. The gene acquisition and rapid LOH in the hybrid genome probably facilitated its adaption to maltose brewing environments and mitigated the maladaptive effect of hybridization.

evolutionary biology↗

bioRxiv2024

The evolution of 5'UTR length was shaped by natural selection for its functional impact on gene expression

Transcription start site (TSS) marks the first DNA nucleotide of a gene transcribed into RNA. Accumulating evidence suggests that alternative TSS usage (ATU) is widespread across eukaryotes, in response to environmental changes and tissue-specific needs. However, how ATU is coordinated with changes in gene transcription activity and whether it represents a regulated process or merely transcription initiation errors, remains unclear. To address these questions, we conducted integrative analyses of high-resolution TSS maps and translation efficiency data from multiple eukaryotic organisms. Our results reveal that most ATU events co-occur with differential gene expression and that the direction of ATU is largely consistent with changes in transcription levels. These findings suggest that ATU likely works in concert with transcriptional activity to fine-tune protein production, modulating translation efficiency and mRNA stability through alterations in 5'UTR sequence and structural features. Given its functional importance, the evolution of TSS locations may have been shaped by natural selection, leading to heterogeneous 5'UTR lengths in genes with distinct expression demands. This study offers new insights into the complexity of gene regulation and provides a plausible explanation for the highly variable 5'UTR landscape observed within and among eukaryotic genes.

genomics↗

bioRxiv2024

Robust Neutralization of SARS-CoV-2 Variants Including JN.1 and BA.2.87.1 by Trivalent XBB Vaccine-Induced Antibodies

Newly emerged SARS-CoV-2 variants like JN.1, and more recently, the hypermutated BA.2.87.1, have raised global concern. We recruited two groups of participants who had BA.5/BF.7 breakthrough infection post three doses of inactivated vaccines: one group experienced subsequent XBB reinfection, while the other received the XBB-containing trivalent WSK-V102C vaccine. Our comparative analysis of their serum neutralization activities revealed that the WSK-V102C vaccine induced stronger antibody responses against a wide range of variants, notably including JN.1 and the highly escaped BA.2.87.1. Furthermore, our investigation into specific mutations revealed that fragment deletions in NTD significantly contribute to the immune evasion of the BA.2.87.1 variant. Our findings emphasize the necessity for ongoing vaccine development and adaptation to address the dynamic nature of SARS-CoV-2 variants.

microbiology↗

bioRxiv2024

Gating of Memory to Behavior by the Locus Coeruleus

An essential function of memory is to guide behavior for survival and adaptation. While considerable knowledge has been accumulated on memory formation, much less is understood about how retrieved memories direct behavior/action. In the auditory Pavolovian threat conditioning paradigm, retrieval of conditioned threat memory activates dorsomedial prefrontal (dmPFC) neurons exhibiting transient responses (T-neurons), which activate both dmPFC neurons exhibiting sustained responses (S-neurons) and locus coeruleus (LC) neurons. Auditory inputs to S-neurons enable the conversion from transient to sustained responses so that the freezing durations match those of the auditory cues. Activation of LC neurons is required for the conversion by enhancing S-neuron responses, which, interestingly, opens a short time window during which non-conditioned cues also lead to freezing. The transition from memory to behavior thus hinges on the integration of retrieved memory, sensory inputs, and emotional/body state cues to generate a selective, adequate, and finely tuned behavior. Significance statementThis study provides new insights into the neural circuitry and mechanisms of how retrieved memories direct the execution of behavior in response to conditioned threatening stimuli. It reveals how different neuron types in the dmPFC interact with LC neurons to determine and modulate the duration and intensity of defensive responses. It also shows that activation of LC neurons can induce the generalization of freezing to non-threatening cues, which may have implications for understanding anxiety disorders. This study contributes to the field of neuroscience by advancing the understanding of memory-behavior conversion and role of the dmPFC and LC in conditioned threat/fear behavior.

neuroscience↗

bioRxiv2024

Multi-omic characterization of allele-specific regulatory variation in hybrid pigs

Genetic variation in the regulation of gene expression contributes substantially to phenotypic variation. Understanding how variation in DNA sequences and epigentic modifications leads to gene expression variation remains a challenging task. In hybrid animals where cellular environments are homogeneous, differences between the expression of paternal and maternal alleles must be due to cis sequence or epigenic differences. Therefore, hybrid mapping is a powerful approach to efficiently identify and characterize genes under regulation through mechanisms in cis. In this study, using reciprocal crosses of the phenotypically divergent Duroc and Lulai pig breeds, we performed a comprehensive multi-omic characterization of regulatory variation across brain, liver, muscle, and placenta in four developmental stages. We produced one of the largest multi-omic datasets to date in pigs, including 16 whole genome sequenced genomes, 48 whole genome bisulfite sequencing, 168 ATAC-Seq and 168 RNA-Seq samples. We developed a novel read count-based method to reliably assess allele-specific methylation, chromatin accessibility, and RNA expression. We showed that tissue specificity was much stronger than developmental stage specificity in all of DNA methylation, chromatin accessibility, and gene expression. We identified 573 genes showing allele specific expression, including those influenced by parent-of-origin as well as allele genotype effects. By integrating methylation, chromatin accessibility, and gene expression data, many of these allele specific expression can be explained by allele specific methylation and/or chromatin accessibility. This study provides one of the most comprehensive characterizations of regulatory variation across multiple tissues and developmental stages in pigs and offers new opportunity of genetic improvement for this important food animal species.

developmental biology↗

bioRxiv2023

Three-step mechanism of promoter escape by RNA polymerase II

The transition from transcription initiation to elongation is highly regulated in human cells but remains incompletely understood at the structural level. In particular, it is unclear how interactions between RNA polymerase (Pol) II and initiation factors are broken to enable promoter escape. Here we reconstitute Pol II promoter escape in vitro, determine high-resolution structures of five transition intermediates, and show that promoter escape occurs in three major steps. First, the growing RNA transcript displaces the B-reader element of the initiation factor TFIIB without evicting TFIIB. Second, rewinding of the upstream edge of the growing DNA bubble evicts TFIIA, TFIIB and TBP and repositions parts of TFIIE and TFIIF. Third, binding of DSIF and NELF evicts TFIIE and TFIIH, establishing the paused elongation complex. This three-step model for promoter escape fills a gap in our understanding of the initiation-elongation transition of Pol II transcription.

biochemistry↗

bioRxiv2023

Integrated Hfq-interacting RNAome and transcriptomic analysis reveals complex regulatory networks of nitrogen fixation in root-associated Pseudomonas stutzeri A1501

The RNA chaperone Hfq acts as a global regulator of numerous biological processes, such as carbon/nitrogen metabolism and environmental adaptation in plant-associated diazotrophs; however, its target RNAs and the mechanisms underlying nitrogen fixation remain largely unknown. Here, we used enhanced UV cross-linking immunoprecipitation coupled with high-throughput sequencing (eCLIP-seq) to identify hundreds of Hfq-binding RNAs probably involved in nitrogen fixation, carbon substrate utilization, biofilm formation, and other functions. Collectively, these processes endow strain A1501 with the requisite capabilities to thrive in the highly competitive rhizosphere. Our findings revealed a previously uncharted landscape of Hfq target genes. Notable among these is nifM, encoding an isomerase necessary for nitrogenase reductase solubility; amtB, encoding an ammonium transporter; oprB, encoding a carbohydrate porin; and cheZ, encoding a chemotaxis protein. Furthermore, we identified more than one hundred genes of unknown function, which expands the potential direct regulatory targets of Hfq in diazotrophs. Our data showed that Hfq directly interacts with regulatory proteins (RsmA, AlgU, NifA), regulatory ncRNA RsmY, and other potential targets, thus revealing the mechanistic links in nitrogen fixation and other metabolic pathways. IMPORTANCENumerous experimental approaches often face challenges in distinguishing between direct and indirect effects of Hfq-mediated regulation. New technologies based on high-throughput sequencing are increasingly providing insight into the global regulation of Hfq in gene expression. Here, enhanced UV cross-linking immunoprecipitation coupled with high-throughput sequencing (eCLIP-seq) was employed to identify the Hfq-binding sites and potential targets in the root-associated P. stutzeri A1501, and identify hundreds of novel Hfq-binding RNAs that are predicted to be involved in metabolism, environmental adaptation, and nitrogen fixation. In particular, we have shown that Hfq interactions with various regulatory proteins and their potential targets at both the protein and RNA levels. This study not only enhances our understanding of Hfq regulation but, importantly, also provides a framework for addressing integrated regulatory network underlying root-associated nitrogen fixation.

microbiology↗

bioRxiv2023

Enhancer-driven local 3D chromatin domain folding modulates transcription in human mammary tumor cells

The genome is organized in functional compartments and structural domains at the sub-megabase scale. How within these domains interactions between numerous cis-acting enhancers and promoters regulate transcription remains an open question. Here, we determined chromatin folding and composition over several hundred kb around estrogen responsive genes in human breast cancer cell lines following hormone stimulation. Modeling of 5C data at 1.8 kb resolution was combined with quantitative 3D analysis of multicolor FISH measurements at 100 nm resolution and integrated with ChIP-seq data on transcription factor binding and histone modifications. We found that rapid estradiol induction of the progesterone gene (PGR) expression occurs in the context of pre-existing, cell type specific chromosomal architectures encompassing the 90 kb PGR coding region and an enhancer-spiked 5 300 kb upstream genomic region. In response to estradiol, interactions between estrogen-receptor (ER) bound regulatory elements are re-enforced. While initial enhancer - gene contacts coincide with RNA Pol 2 binding and transcription initiation, sustained hormone stimulation promotes ER accumulation creating a regulatory hub stimulating transcript synthesis. In addition to implications for estrogen receptor signaling, we uncover that preestablished chromatin architectures efficiently regulate gene expression upon stimulation without the need for de-novo extensive rewiring of long-range chromatin interactions.

cell biology↗

bioRxiv2023

A senescence-like state is beneficial for ovarian cancer treatment

High-grade serous ovarian carcinoma (HGSOC) commonly responds to initial therapy, but this response is rarely durable. Understanding cell fate decisions taken by HGSOC cells in response to treatment could guide new therapeutic opportunities. Here we find that tissue-derived primary HGSOC epithelial cultures reflecting the original disease primarily undergo therapy-induced senescence in response to DNA damage and first-line carboplatin/paclitaxel chemotherapy. Unlike previous observations using cell lines, primary HGSOC cell TIS displays a stable senescence proliferation arrest and p16INK4A expression, and is accompanied by persistent DNA damage, an inflammatory secretome, and senolytic sensitivity, suggesting new avenues for selective pharmacological manipulation of these cells. Whether cell senescence induced by cancer therapy is beneficial or detrimental to clinical outcomes remains unknown. Single cell comparison of pre- and post-chemotherapy patient HGSOC tissue samples revealed changes in physio-pathological senescence biomarkers supporting a post-treatment senescence-like state. Importantly, patients with stronger senescence signatures post-chemotherapy displayed better 5-year survival suggesting that senescence accounts, at least in part, for beneficial cellular responses to treatment. Given that ovarian cancer epithelial cells almost universally retain the capacity to undergo senescence and that senescence appears beneficial in this context, HGSOC senescence-centric therapeutic avenues should be further explored. Author SummaryWhether cancer therapy-induced cell fate decisions like senescence are good or bad for patient treatment outcome is unknown. We find that ovarian cancer cells almost universally retain senescence competence and that senescence in treated cancer tissues correlate with good clinical outcomes. This reveals that senescence is a relevant drug target in ovarian cancer.

cancer biology↗

bioRxiv2023

ChromaFold predicts the 3D contact map from single-cell chromatin accessibility

The identification of cell-type-specific 3D chromatin interactions between regulatory elements can help to decipher gene regulation and to interpret the function of disease-associated non-coding variants. However, current chromosome conformation capture (3C) technologies are unable to resolve interactions at this resolution when only small numbers of cells are available as input. We therefore present ChromaFold, a deep learning model that predicts 3D contact maps and regulatory interactions from single-cell ATAC sequencing (scATAC-seq) data alone. ChromaFold uses pseudobulk chromatin accessibility, co-accessibility profiles across metacells, and predicted CTCF motif tracks as input features and employs a lightweight architecture to enable training on standard GPUs. Once trained on paired scATAC-seq and Hi-C data in human cell lines and tissues, ChromaFold can accurately predict both the 3D contact map and peak-level interactions across diverse human and mouse test cell types. In benchmarking against a recent deep learning method that uses bulk ATAC-seq, DNA sequence, and CTCF ChIP-seq to make cell-type-specific predictions, ChromaFold yields superior prediction performance when including CTCF ChIP-seq data as an input and comparable performance without. Finally, fine-tuning ChromaFold on paired scATAC-seq and Hi-C in a complex tissue enables deconvolution of chromatin interactions across cell subpopulations. ChromaFold thus achieves state-of-the-art prediction of 3D contact maps and regulatory interactions using scATAC-seq alone as input data, enabling accurate inference of cell-type-specific interactions in settings where 3C-based assays are infeasible.

bioinformatics↗

bioRxiv2023

ScopeViewer: A Browser-Based Solution for Visualizing Spatial Transcriptomics Data

MotivationSpatial transcriptomics (ST) enables a high-resolution interrogation of molecular characteristics within specific spatial contexts and tissue morphology. Despite its potential, visualization of ST data is a challenging task due to the complexities in handling, sharing and visualizing large image datasets together with molecular information. ResultsWe introduce ScopeViewer, a browser-based software designed to overcome these challenges. ScopeViewer offers the following functionalities: (1) It visualizes large image data and associated annotations at various zoom levels, allowing for intricate exploration of the data; (2) It enables dual interactive viewing of the original images along with their annotations, providing a comprehensive understanding of the context; (3) It displays spatial molecular features with optimized bandwidth, ensuring a smooth user experience; and (4) It bolsters data security by circumventing data transfers. AvailabilityScopeViewer is available at: https://datacommons.swmed.edu/scopeviewer ContactXiaowei.Zhan@UTSouthwestern.edu, Guanghua.Xiao@UTSouthwestern.edu Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2023

Protein arginine methyltransferase 5 (Prmt5) localizes to chromatin loop anchors and modulates expression of genes at TAD boundaries during early adipogenesis

Protein arginine methyltransferase 5 (Prmt5) is an essential regulator of embryonic development and adult progenitor cell functions. Prmt5 expression is mis-regulated in many cancers, and the development of Prmt5 inhibitors as cancer therapeutics is an active area of research. Prmt5 functions via effects on gene expression, splicing, DNA repair, and other critical cellular processes. We examined whether Prmt5 functions broadly as a genome-wide regulator of gene transcription and higher-order chromatin interactions during the initial stages of adipogenesis using ChIP-Seq, RNA-seq, and Hi-C using 3T3-L1 cells, a frequently utilized model for adipogenesis. We observed robust genome-wide Prmt5 chromatin-binding at the onset of differentiation. Prmt5 localized to transcriptionally active genomic regions, acting as both a positive and a negative regulator. A subset of Prmt5 binding sites co-localized with mediators of chromatin organization at chromatin loop anchors. Prmt5 knockdown decreased insulation strength at the boundaries of topologically associating domains (TADs) adjacent to sites with Prmt5 and CTCF co-localization. Genes overlapping such weakened TAD boundaries showed transcriptional dysregulation. This study identifies Prmt5 as a broad regulator of gene expression, including regulation of early adipogenic factors, and reveals an unappreciated requirement for Prmt5 in maintaining strong insulation at TAD boundaries and overall chromatin organization.

genomics↗

bioRxiv2023

Co-engagement of TIGIT+ immune cells to PD-L1+ tumours by a bispecific antibody potentiates T-cell response and tumour control

Co-targeting PD-1/PD-L1 and TIGIT/CD226 is being pursued to broaden the efficacy of current immunotherapy. Here we demonstrate that a bispecific antibody (BsAb) targeting PD-L1 and TIGIT, HB0036, shows major advantages over the combination of the two parental monoclonal Abs (mAbs). We demonstrated that HB0036 co-engages PD-L1+ tumour cells and TIGIT+ T cells, and thereby upregulates CD226 on T cells and induces a greater T-cell proliferative response compared to the combination of the parental antibodies in vitro. In vivo, HB0036 recruits greater amounts of TIGIT antibody in PD-L1+ tumours but not in PD-L1- tumours, compared with therapy using the two parental antibodies. We also observed improved tumour control and favourable immunological signatures with HB0036 in syngeneic and xenograft tumour models. Collectively, these findings demonstrate that bispecific antibodies targeting PD-L1 and TIGIT offer superior benefits in cancer immunotherapy compared with therapy using the two parental antibodies. Based on these studies, a phase I clinical trial with HB0036 has been initiated in patients with solid tumours (NCT05417321).

immunology↗

bioRxiv2023

Targeting Sex Determination to Suppress Mosquito Populations

Each year, hundreds of millions of people are infected with arboviruses such as dengue, yellow fever, chikungunya, and Zika, which are all primarily spread by the notorious mosquito Aedes aegypti. Traditional control measures have proven insufficient, necessitating innovations. In response, here we generate a next generation CRISPR-based precision-guided sterile insect technique (pgSIT) for Aedes aegypti that disrupts genes essential for sex determination and fertility, producing predominantly sterile males that can be deployed at any life stage. Using mathematical models and empirical testing, we demonstrate that released pgSIT males can effectively compete with, suppress, and eliminate caged mosquito populations. This versatile species-specific platform has the potential for field deployment to effectively control wild populations of disease vectors.

bioengineering↗