Biology subjects

Huang, W.

Publications and source records attributed to Huang, W..

At least 127 records · Page 7Linked to original sources

bioRxiv2025

7-ketocholesterol contributes to microglia-driven increases in astrocyte reactive oxygen species in Alzheimer's disease

Oxidative stress is a prominent feature of Alzheimers disease. Within this context, cholesterol undergoes oxidation, producing the pro-inflammatory product 7-ketocholesterol (7-KC). In this study, we observe elevated levels of 7-KC in the brains of the 3xTg mouse model of AD. To further understand the contribution of 7-KC on the oxidative environment, we developed a method to express a genetically encoded fluorescent hydrogen peroxide (H2O2) sensor in astrocytes, the primary source of cholesterol in the brain. With this sensor, we discovered that 7-KC increases H2O2 levels in astrocytes in vivo, but not when directly applied to astrocytes in vitro. Interestingly, when 7-KC was applied to a microglia cell line alone or mixed astrocyte and microglia cultures, it resulted in microglia activation and increased oxidative stress in astrocytes. Depletion of microglia from 3xTg mice resulted in reduced 7-KC in the brains of these mice. Taken together, these findings suggest that 7-KC, acting through microglia, contributes to increased astrocyte oxidative stress in AD. This study sheds light on the complex interplay between cholesterol oxidation, microglia activation, and astrocyte oxidative stress in the pathogenesis of AD.

neuroscience↗

bioRxiv2025

GENETIC ANALYSIS OF ARABIDOPSIS AUTOPHAGY-RELATED 8 FAMILY PROTEINS REVEALS THEIR REDUNDANT AND REGULATORY ROLES IN PLANT AUTOPHAGY

Autophagy, a critical process for the vacuolar degradation of proteins and organelles, is governed by multiple conserved autophagy-related (ATG) proteins. The central component of the ATG machinery is the ubiquitin-like protein ATG8, which is essential for multiple steps of the autophagy process, including phagophore expansion, autophagosome closure, trafficking and fusion with the lysosome/vacuole, and selective cargo recruitment. Currently, our understanding of the roles of ATG8 in plant autophagy and the functional specialization of ATG8 family members is limited due to genetic redundancy. To assess the roles of ATG8 genes in plant autophagy, here we used CRISPR/Cas9 technology to systematically knockout the Arabidopsis ATG8 genes. By analyzing the atg8 mutants, we found that in contrast to mammalian ATG8s, in which the LC3s and GABARAP subfamilies play distinct roles in the autophagic process, Arabidopsis ATG8s perform an overlapping function in controlling autophagic flux. Combinatorial mutations of Clade I and Clade II ATG8s resulted in severely impaired autophagy under nutrient-starved conditions. Furthermore, we found that RABG3 proteins, members of the RAB7/RABG GTPase family, interact with ATG8s through AIM-LDS interfaces, and that such interaction is essential for the association of RABG3 proteins with the autophagosomal membrane and probably for the fusion of autophagosome with the vacuole, but is not required for endosomal trafficking. With the collection of multiple high-order atg8 mutants generated in this study, we now provide a venue to study the roles of ATG8 genes in canonical autophagy and non-canonical autophagy in Arabidopsis.

plant biology↗

bioRxiv2024

Neurodevelopmental deviations in schizophrenia: Evidences from multimodal connectome-based brain ages

BackgroundPathologic schizophrenia process originate early in brain development, leading to detectable brain alterations via structural and functional magnetic resonance imaging (MRI). Recent MRI studies have sought to characterize disease effects from a brain age perspective, but developmental deviations from the typical brain age trajectory in youths with schizophrenia remain unestablished. AimThis study investigated brain development deviations in early-onset schizophrenia (EOS) patients by applying machine learning algorithms to structural and functional MRI data. MethodsMultimodal MRI data, including T1-weighted MRI (T1w-MRI), diffusion MRI, and resting-state functional MRI (rs-fMRI) data, were collected from 80 antipsychotic-naive first-episode EOS patients and 91 typically developing (TD) controls. The morphometric similarity connectome (MSC), structural connectome (SC), and functional connectome (FC) were separately constructed by using these three modalities. According to these connectivity features, eight brain age estimation models were first trained with the TD group, the best of which was then used to predict brain ages in patients. Individual brain age gaps (BAGs) were assessed as brain ages minus chronological ages. ResultsBoth the SC and MSC features performed well in brain age estimation, whereas the FC features did not. Compared with the TD controls, the EOS patients presented widened structural BAGs, with opposite trends between childhood and adolescence. These increased absolute BAG scores for EOS patients were positively correlated with the severity of their clinical symptoms. ConclusionThese findings from a multimodal brain age perspective suggest that advanced BAGs exist early in youths with schizophrenia.

neuroscience↗

bioRxiv2024

MCM2 mediates post-MI cardioprotection by promoting the pro-angiogenic cardiosome signaling

AbstractO_ST_ABSBackgroundC_ST_ABSIn the past decade, induced cardiac rejuvenation has emerged as a leading approach to repair cardiac injury. Recent studies demonstrate that promoting cell cycle reentry in adult cardiomyocytes (CM) enhances cardiac rejuvenation by influencing paracrine signaling. We previously demonstrated that the inhibition of two cell cycle inhibitors, Retinoblastoma 1 (Rb1) and Meis homeobox 2 (Meis2), in the adult CM enhances angiogenesis and cardiac function following ischemic injury, but the underlying mechanisms have yet to be elucidated. The goal of this study is to determine the mechanisms by which inhibition of Rb1 and Meis2 promotes cardiac rejuvenation in a mouse model of myocardial infarction. MethodsMyocardial infarction was induced in adult C57/Bl6 mice via permanent LAD occlusion followed by direct injection of either control or Rb1+Meis2 siRNA cocktail to the ischemic myocardium. MCM2 overexpression done via direct myocardial injection of an MCM2-plasmid DNA expression cassette. Cardiac function and LV wall motion was assessed via echocardiography, and fibrosis and CM hypertrophy were assessed via histology. RNA-sequencing was performed on isolated adult murine CMs with siRNA-mediated Rb1+Meis2 knockdown to delineate the downstream mechanisms. Further identification of Rb1, Meis2, and MCM2-dependent mechanisms were done using in vitro techniques in isolated CMs and HUVEC cells. ResultsWe show that siRNA-mediated knockdown of Rb1 and Meis2 in vivo reduces pathological LV remodeling and preserves cardiac structure and function in adult mouse hearts post-MI. RNA-seq analyses revealed MCM2 as a potential downstream target of Rb1/Meis2 to enhance protective paracrine signaling in primary adult CMs. Indeed, re-expression of MCM2, which is developmentally lost from neonatal to adult CM in the heart, improves cardiac function and LV wall motion while reducing myocyte hypertrophy and fibrotic scar size post-MI. Mechanistically, re-expression of MCM2 promotes the secretion of pro- angiogenic factors from adult CM, and transfer of conditioned media from MCM2 expressing CM induced vasculogenesis in HUVEC cells. Proteomic analysis of the MCM2 interactome confirmed a significant enrichment of angiogenic mediators and suggests an MCM2-dependent protein packaging of pro- angiogenic factors in CM-derived small extracellular vesicles (cardiosomes). ConclusionRe-expression of MCM2 in adult CM promotes the secretion of pro-angiogenic cardiosomes that induce paracrine revascularization of endothelial cells and mitigates cardiac injury post-MI. SUMMARY DIAGRAM O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/628232v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@17eaeforg.highwire.dtl.DTLVardef@40f0f5org.highwire.dtl.DTLVardef@18b7664org.highwire.dtl.DTLVardef@109cb1c_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2024

RetS senses neurotransmitter norepinephrine and adrenergic agents to regulate Pseudomonas aeruginosa virulence

Bacterial cells employ diverse mechanisms to perceive and respond to host-associated molecules, coordinate intracellular signal transduction, and engage in interkingdom communications. In this study, we firstly discovered that the adrenergic antagonist dronedarone (DDR) effectively suppresses quorum sensing (QS) and pathogenesis of the opportunistic pathogen P. aeruginosa. Further analysis revealed that DDR targets RetS, an bacterial surface receptor critical for suppressing the GacS/GacA two-component regulatory system (TCS). Interestingly, the adrenergic agonist norepinephrine (NE) was found to exert opposite effects against RetS, thereby reversing DDR-induced phenotypes in P. aeruginosa. Moreover, we identified the hinge region of RetSDISMED2 serves as a binding pocket of NE and DDR, which provides potential mechanisms of the antagonistic effect of NE and DDR. Our study demonstrated that NE promotes P. aeruginosa infections while DDR can serve as an anti-virulence compound against P. aeruginosa infections. Thus, RetS might serve as a bacterial adrenergic receptor which keeps the NE under constant surveillance. SignificanceSensing and recognition of host-derived molecules, as well as therapeutic drugs, are crucial for the survival of pathogens during infection process. The adrenergic drugs are well known to affect virulence and pathogenesis of the opportunistic pathogen Pseudomonas aeruginosa (P. aeruginosa). In this work, we have provided in-depth characterization of a Norepinephrine (NE) receptor in P. aeruginosa, the RetS membrane protein. NE is the-adrenergic agonist known as a stress hormone, exerts its activity through interaction with mammalian adrenergic receptors (AR). It has been shown that increased NE concentration during early sepsis can stimulate the growth of various Gram-negative and Gram-positive bacteria, including P. aeruginosa. We revealed that both adrenergic agonist NE and another adrenergic antagonist dronedarone (DDR) are able to interfering the RetS-GacS/GacA signaling cascade of P. aeruginosa and execute opposite impact on the pathogenesis of P. aeruginosa during infections.

microbiology↗

bioRxiv2024

The metabolic pathways underlying dynamic heterosis for plant height are robust biomarkers in rice

The development of robust biomarkers enables accurate prediction of complex phenotypes. However, the dynamic nature of biomarkers is often underestimated since their quantitative changes during development are directly connected to phenotypic transformations, influencing both crop agronomic traits and human diseases. Here, we performed network analysis of untargeted metabolite profiles to investigate height heterosis in rice, which is dynamic that varies during development and is a key determinant of yield heterosis. We found that the levels of pyruvaldehyde were predictive of height heterosis specific at the seedling stage, while 4-hydroxycinnamic acid positively correlated with height heterosis across four developmental stages. We identified metabolic pathways associated with height heterosis and found that metabolomic changes during the elongation stage had a greater impact than those in other stages. Finally, 11 heterosis-associated pathways were developed into metabolomic biomarkers through random forest analysis, successfully predicting height heterosis in an independent population under different growth conditions. This study elucidates the metabolomic landscape of dynamic height heterosis in rice and develops pathway biomarkers for complex phenotypes, demonstrating robustness across diverse populations, environments, and developmental stages.

systems biology↗

bioRxiv2024

Single-cell atlas of developing mouse palates reveals cellular and molecular transitions in periderm cell fate

Cleft palate is one of the most common congenital craniofacial disorders that affects childrens appearance and oral functions. Investigating the transcriptomics during palatogenesis is crucial for comprehending the etiology of this disorder and facilitating prenatal molecular diagnosis. However, there is limited knowledge about the single-cell differentiation dynamics during mid- and late-palatogenesis, specifically regarding the subpopulations and developmental trajectories of periderm, a rare but critical cell population. Here we explore the single-cell landscape of mouse developing palates from E10.5 to E16.5. We systematically depict the single-cell transcriptomics of mesenchymal and epithelial cells during palatogenesis, including subpopulations and differentiation dynamics. Additionally, we identify four subclusters of palatal periderm and construct two distinct trajectories of cell fates for periderm cells. Our findings reveal that Claudins and Arhgap29 play a role in the non-stick function of the periderm before the palatal shelves contact, and Pitx2 mediates the adhesion of periderm during the contact of opposing palatal shelves. Furthermore, we demonstrate that epithelial-mesenchymal transition (EMT), apoptosis, and migration collectively contribute to the degeneration of periderm cells in the medial epithelial seam. Taken together, our study suggests a novel model of periderm development during palatogenesis and delineates the cellular and molecular transitions in periderm cell determination.

genomics↗

bioRxiv2024

Structural variations contribute to genetic diversity and heterosis in rice

Yield heterosis has been extensively exploited in hybrid breeding, with inter-subspecies hybrids often exhibiting the most pronounced effects. However, developing elite hybrids remains a laborious and time-consuming process. The genetic basis of heterosis has been debated for over a century, hindered largely by the lack of high-quality genomes. Here, we assembled genomes for 12 representative indica and japonica rice accessions. Using sequence variants of the Phr1 gene, we functionally validated two deletions responsible for phenol reaction variation between the subspecies. Comparative genomic analyses revealed extensive sequence variation among these inbred lines and highlighted the pivotal role of structural variants (SVs) in rice subspeciation. Importantly, the number of SVs between parental inbred lines significantly correlated with heterosis across 17 agronomic traits, with distinct correlation patterns for intra- and inter-subspecific F1 hybrids. We identified SVs associated with S5-ORF5 and OsBZR1 and validated their function to heterosis for seed setting rate and yield heterosis, respectively, underscoring the importance of SVs in breeding inter-subspecific hybrids. The genomic SVs altered gene expression and these transcriptional changes effectively explained the variances in heterosis. Furthermore, translocations outperformed other SVs and their heterozygous haplotypes exhibited heterosis over homozygous ones. Our findings establish SVs as pivotal drivers in subspeciation and highlight the overdominance model for harnessing rice heterosis.

plant biology↗

bioRxiv2024

Extrachromosomal DNA driven oncogene spatial heterogeneity and evolution in glioblastoma

Oncogene amplification on extrachromosomal DNA (ecDNA) is strongly associated with treatment resistance and shorter survival for patients with cancer, including patients with glioblastoma. The non-chromosomal inheritance of ecDNA during cell division is a major contributor to intratumoral genetic heterogeneity. At present, the spatial dynamics of ecDNA, and the impact on tumor evolutionary trajectories, are not well understood. Here, we investigate the spatial-temporal evolution of ecDNA and its clinical impact by analyzing tumor samples from 94 treatment-naive human IDH-wildtype glioblastoma patients. We developed a spatial-temporal computational model of ecDNA positive tumors ( SPECIES) that integrates whole-genome sequencing, multi-region DNA FISH, and nascent RNAscope, to provide unique insight into the spatial dynamics of ecDNA evolution. Random segregation in combination with positive selection of ecDNAs induce large, predictable spatial patterns of cell-to-cell ecDNA copy number variation that are highly dependent on the oncogene encoded on the circular DNA. EGFR ecDNAs often reach high mean copy number (mean of 50 copies per tumor cell), are under strong positive selection (mean selection coefficient, s > 2) and do not co-amplify other oncogenes on the same ecDNA particles. In contrast, PDGFRA ecDNAs have lower mean copy number (mean of 15 copies per cell), are under weaker positive selection and frequently co-amplify other oncogenes on the same ecDNA. Evolutionary modeling suggests that EGFR ecDNAs often accumulate prior to clonal expansion. EGFR structural variants, including vIII and c-terminal deletions are under strong positive selection, are found exclusively on ecDNA, and are intermixed with wild-type EGFR ecDNAs. Simulations show EGFRvIII ecDNA likely arises after ecDNA formation in a cell with high wild-type EGFR copy number (> 10) before the onset of the most recent clonal expansion. This remains true even in cases of co-selection and co-amplification of multiple oncogenic ecDNA species in a subset of patients. Overall, our results suggest a potential time window in which early ecDNA detection may provide an opportunity for more effective intervention. HighlightsO_LIecDNA is the most common mechanism of focal oncogene amplification in IDHwt glioblastoma. C_LIO_LIEGFR and its variants on ecDNA are particularly potent, likely arising early in tumor development, providing a strong oncogenic stimulus to drive tumorigenesis. C_LIO_LIWild-type and variant EGFR ecDNA heteroplasmy (co-occurrence) is common with EGFRvIII or c-terminal deletions being derived from EGFR wild-type ecDNA prior to the most recent clonal expansion. C_LIO_LITumors with ecDNA amplified EGFR versus PDGFRA exhibit different evolutionary trajectories. C_LIO_LISPECIES model can infer spatial evolutionary dynamics of ecDNA in cancer. C_LIO_LIA delay between ecDNA accumulation and subsequent oncogenic mutation may give a therapeutic window for early intervention. C_LI

cancer biology↗

bioRxiv2024

The maintenance of multiple ecDNA types in single cancer cells

Extrachromosomal DNA (ecDNA) has emerged as a key driver of oncogene amplification and a major contributor to rapid intra-tumour heterogeneity, thereby promoting tumour progression and therapeutic resistance. This heterogeneity arises from pronounced cell-to-cell variability in ecDNA copy number, enabling complex ecDNA amplicon compositions within individual tumour cells. Approximately one-third of ecDNA-positive tumours harbour multiple co-selected ecDNA species. However, the mechanisms governing the heterogeneity and persistence of ecDNA variants -- beyond the presence of distinct ecDNA species -- remain less well understood. In particular, little is known about the maintenance of genetic or phenotypic diversity within a single ecDNA species. Here, we develop computational models to investigate the dynamics that enable the stable maintenance of tumour cells carrying multiple ecDNA variants ("mixed cells"). We explore how variant switching contributes to the persistence of ecDNA diversity under varying fitness regimes. Our results demonstrate that both a positive fitness of ecDNA+ cells and variant switching are required to maintain mixed cell subpopulations, whereas direct co-selection of mixed cells is not necessary. Notably, the fraction of mixed cells peaks at intermediate switching rates across fitness landscapes, a pattern reflected in subpopulation structures, transition probabilities between pure and mixed ecDNA states, and single-cell Shannon diversity indices.

cancer biology↗

bioRxiv2024

Cross-species protection suggests Entamoeba histolytica trogocytosis enables complement resistance through the transfer of negative regulators of complement activation

Entamoeba histolytica is a major cause of diarrheal disease. E. histolytica trophozoites ("amoebae") can invade the intestine and disseminate via the bloodstream, resisting complement lysis through unknown mechanisms. Amoebae kill human cells by performing trogocytosis. After performing trogocytosis, amoebae display human proteins on their own surface and are resistant to lysis by human serum. In this study we sought to further evaluate the mechanism by which amoebae resist complement. To test if complement is responsible for lysis of amoebae, C3-depleted serum was compared to replete serum, and C3 was required for lysis. Amoebae were allowed to perform trogocytosis of human cells and exposed to mouse serum. Although they had performed trogocytosis on a different species than the source of the serum, they were protected from lysis. To test if the protection from lysis by mouse serum was due to the functional interchangeability of human and mouse complement pathway proteins, human CD46 or CD55 (negative regulators of complement activation) were exogenously expressed. Amoebae that expressed human CD46 or CD55 were protected from lysis by mouse serum, indicating that display of human proteins was sufficient to inhibit mouse complement activation. Finally, amoebae were allowed to perform trogocytosis of a cell type in which the complement pathway is not conserved, and they did not become resistant to lysis. Overall, these findings are consistent with the model that trogocytosis enables amoebic acquisition and display of host proteins, including negative regulators of the complement pathway, that provide protection from complement lysis. Since other microbes can perform trogocytosis, this novel mechanism for complement resistance might apply to other infections.

microbiology↗

bioRxiv2024

Unraveling Integration-Segregation Imbalances in Schizophrenia Through Topological High-Order Functional Connectivity

BackgroundThe occurrence of brain disorders correlates with detectable dysfunctions in the specialization of brain connectomics. While extensive research has explored this relationship, there is a lack of studies specifically examining the statistical correlation between the integration and segregation of psychotic brain networks using high-order networks, given the limitations of low-order networks. Moreover, these dysfunctions are believed to be linked to information imbalances in brain functions. However, our understanding of how these imbalances give rise to specific psychotic symptoms remains limited. MethodsThis study aims to address this gap by investigating variations at the topological high-order level of the system with regard to specialization in both healthy individuals and those diagnosed with schizophrenia. By employing graph-theoretic brain network analysis, we systematically examine information integration and segregation to delineate system-level differences in the connectivity patterns of brain networks. ResultsThe findings indicate that topological high-order functional connectomics highlight differences in the connectome between healthy controls and schizophrenia, demonstrating increased cingulo-opercular task control and salience interactions, while the interaction between subcortical and default mode networks, dorsal attention and sensory/somatomotor mouth decreases in schizophrenia. Furthermore, we observed a reduction in the segregation of brain systems in healthy controls compared to individuals with schizophrenia, which means the balance between segregation and integration of brain networks is disrupted in schizophrenia, suggesting that restoring this balance may aid in the treatment of the disorder. Additionally, the increased segregation and decreased integration of brain systems in schizophrenia patients compared to healthy controls may serve as a novel indicator for early schizophrenia diagnosis. ConclusionWe discovered that topological high-order functional connectivity highlights brain network interactions compared to low-order functional connectivity. Furthermore, we observed alterations in specific brain regions associated with schizophrenia, as well as changes in brain network information integration and segregation in individuals with schizophrenia.

neuroscience↗

bioRxiv2024

Assessment of drive efficiency and resistance allele formation of a homing gene drive in the mosquito Aedes aegypti

Aedes aegypti, known for transmitting viruses such as dengue, zika, and yellow fever, poses a significant public health threat. Conventional insecticides give rise to a range of issues, including ecological contamination and insect resistance. Hence, there is a pressing demand for environmentally friendly, safer, and more efficacious strategies for mosquito control. With the rapid advancement of the CRISPR/Cas9 system in gene function exploration and pest population control, substantial progress has been achieved in utilizing CRISPR/Cas9-based gene drive systems across various mosquito species. Only a few studies on gene drive technology have been conducted in A. aegypti. In this study, we constructed two complete drives for A. aegypti with different Cas9 promoters, each targeting kmo. Our drive based on Pub-Cas9 had limited activity, but one with exu-Cas9 exhibited super-Mendelian inheritance rates of approximately 60%. We observed low but detectable somatic activity of the drive and no evidence of maternally deposited Cas9. Germline resistance allele formation rates were similar to drive conversion rates, but most wild-type alleles in the germline remained uncut. Injections into the exu-Cas9 drive line had 100% knockout efficiency among surviving offspring at three separate target genes. These results support the development and application of novel genetic pest control technologies aimed at combating A. aegypti.

genetics↗

bioRxiv2024

Whisker deprivation triggers a distinct form of cortical homeostatic plasticity that is impaired in the Fmr1 KO

Mouse models of Fragile X Syndrome (FXS) have demonstrated impairments in excitatory and inhibitory sensory-evoked neuronal firing. Homeostatic plasticity, which encompasses a set of mechanisms to stabilize baseline activity levels, does not compensate for these changes in activity. Previous work has shown that impairments in homeostatic plasticity are observed in FXS, including deficits in synaptic scaling and intrinsic excitability. Here, we aimed to examine how homeostatic plasticity is altered in vivo in an Fmr1 KO mouse model following unilateral whisker deprivation (WD). We show that WD in the wild type leads to an increase in the proportion of L5/6 somatosensory neurons that are recruited, but this does not occur in the KO. In addition, we observed a change in the threshold of excitatory neurons at a later developmental stage in the KO. Compromised homeostatic plasticity in development could influence sensory processing and long-term cortical organization.

neuroscience↗

bioRxiv2024

Novel regulator Fpr2 controls immune homeostasis via CCL4-dependent neutrophils

Polymorphonuclear leukocytes (PMNs) in Fpr2-deficient mice have significantly impaired bactericidal activity, yet the precise mechanism remains elusive. Our research unveiled the cellular heterogeneity of peripheral blood PMNs through single-cell RNA-sequencing (scRNA-seq) and identified two new neutrophil clusters related to bacterial infection, including a sterilization cluster named Neu_CSTA and a regulation cluster named Neu_CCL4. The lack of Fpr2 leads to an immune regulation imbalance of Neu_CCL4 on other clusters in uninfected conditions, resulting in persistent instability of PMNs in peripheral blood, elevated inflammatory factors, and increased NOX2 expression. Furthermore, our findings corroborate that the regulatory function of Neu_CCL4 on PMNs immune balance is closely tied to its high expression of the anti-inflammatory ligand Anxa1. Regulon analysis inferred by scRNA-seq and ChIP-seq data suggested that a specific transcription factor Elf4, could modulate the expression of Anxa1, thereby facilitating its regulatory impact on other clusters. In the infection state, there was a noted increase in intercellular interactions across different clusters, leading to a general improvement in the bactericidal activity of PMNs. In summary, our research revealed distinct functional cellular sub-populations of PMNs, discovered the potential regulatory mechanisms, and elucidated the essential roles of Fpr2 in their ability to resist infection.

immunology↗

bioRxiv2024

Metagenomic analyses of single phages and phage cocktails show instances of contamination with temperate phages and bacterial DNA

Increasing antibiotic resistance has led to renewed attention being paid to bacteriophage therapy. Commercial phage cocktails are available but often their contents of the phages are not well defined. Some metagenomic studies have been done to retrospectively characterise these cocktails, but little is known about the replication cycle of the included phages, or about the possible bacterial DNA contamination. In this study, published metagenomic sequences were reanalysed using recent advances in viromics tools. Signs of temperate phage contigs were found in all cocktail metagenomes, as well as host DNA, which could poses a risk as it may lead to horizontal gene transfer of virulence factors to commensals and pathogens. This suggests the need to implement further quality measures before using phage cocktails therapeutically.

microbiology↗

bioRxiv2024

Cancer-immune coevolution dictated by antigenic mutation accumulation

The immune system is one of the first lines of defence against cancer. When effector cells attempt to suppress tumour, cancer cells can evolve methods of escape or inhibition. Knowledge of this coevolutionary system can help to understand tumour-immune dynamics both during tumorigenesis and during immunotherapy treatments. Here, we present an individual-based model of mutation accumulation, where random mutations in cancer cells trigger specialised immune responses. Unlike previous research, we explicitly model interactions between cancer and effector cells and incorporate stochastic effects, which are important for the expansion and extinction of small populations. We find that the parameters governing interactions between the cancer and effector cells induce different outcomes of tumour progress, such as suppression and evasion. While it is hard to measure the cancer-immune dynamics directly, genetic information of the cancer may indicate the presence of such interactions. Our model demonstrates signatures of selection in sequencing-derived summary statistics, such as the single-cell mutational burden distribution. Thus, bulk and single-cell sequencing may provide information about the coevolutionary dynamics.

evolutionary biology↗

bioRxiv2024

scDrugAtlas: an integrative single-cell drug response atlas for unraveling tumor heterogeneity in therapeutic efficacy

Tumor heterogeneity often leads to substantial differences in responses to same drug treatment. The presence of pre-existing or acquired drug-resistant cell sub-populations within a tumor survive and proliferate, ultimately resulting in tumor relapse and metastasis. The drug resistance is the leading cause of failure in clinical tumor therapy. Therefore, accurate identification of drug-resistant tumor cell subpopulations could greatly facilitate the precision medicine and novel drug development. However, the scarcity of single-cell drug response data significantly hinders the exploration of tumor cell resistance mechanisms and the development of computational predictive methods. In this paper, we propose scDrugAtlas, a comprehensive database devoted to integrating the drug response data at single-cell level. We manually compiled more than 100 datasets containing single-cell drug responses from various public resources. The current version comprises large-scale single-cell transcriptional profiles and drug response labels from 1,023 samples (cell line, mouse, PDX models, patients and bacterium), across 78 unique drugs and 24 major cancer types. Particularly, we assigned a confidence level to each response label based on the tissue source (primary or relapse/metastasis), drug exposure time and drug-induced cell phenotype. We believe scDrugAtlas could greatly facilitate the Bioinformatics community for developing computational models and biologists for identifying drug-resistant tumor cells and underlying molecular mechanism. The scDrugAtlas database is available at: http://drug.hliulab.tech/scDrugAtlas/.

bioinformatics↗