Biology subjects

Zhu, F.

Publications and source records attributed to Zhu, F..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Pleiotropic functions of an antenna-specific odorant binding protein linking xenobiotic adaptation and olfaction in the Colorado potato beetle, Leptinotarsa decemlineata

The Colorado potato beetle, Leptinotarsa decemlineata, is the primary defoliator of potatoes and is notorious for its robust capability to develop resistance to various insecticides used to control it. As the initial interface between the environment and the insect olfactory system, odorant binding proteins (OBPs) solubilize and transport hydrophobic odorant molecules from the sensillar lymph to olfactory receptors. Recently, evidence has suggested that OBPs may also sequester excess harmful molecules such as insecticides in the perireceptor space, preventing them from reaching vulnerable olfactory sensory neuronal dendrites. In this study, we identified an antenna-specific OBP (LdecOBP33) that is 2.5-fold higher expressed in a neonicotinoid resistant strain than the susceptible one. Competitive displacement fluorescence binding assays revealed that LdecOBP33 protein binds to a wide range of compounds including various plant volatiles and insecticides. Next, we used RNA interference to knock down LdecOBP33 and combined with toxicological bioassays, behavioral, and electrophysiological assays to investigate functions of LdecOBP33 in insecticide resistance and host location. We found that LdecOBP33 silencing increased male beetles susceptibility to imidacloprid, suggesting its role in insecticide resistance. Additionally, LdecOBP33 aids in host location through enhancing the detection of stress-induced potato plant volatiles, increasing the efficacy of CPB adult foraging. Taken together, our study is the first to functionally characterize an OBP in CPB linked to insecticide resistance and host location. Our findings provide insight into a key molecular factor involved in CPBs response to environmental challenges, suggesting a potential link between insect adaptation to xenobiotics and olfactory processing.

molecular biology↗

bioRxiv2025

Single-Cell Pharmacogenomic Landscapes of Epigenetic Therapy in Gastric Cancer

Gene expression signatures ("molecular phenotypes") are extensively utilized in cancer research. To study how gastric cancer (GC) molecular phenotypes are shaped by cell-intrinsic genetic alterations interacting with cell-extrinsic therapeutic pressures, we performed direct capture Perturb-seq (dcPerturb-seq) to interrogate >200 GC-related genes across 4 distinct epigenetic drug classes in multiple gastric lines. We captured 17.7 million pharmocogenomic expression interactions in 625,866 cells representing baseline and post-therapeutic molecular phenotypes. This single-cell pharmacogenomic compendium confirmed previously known gene-driven molecular phenotypes, elucidated poorly characterized genes, and uncovered novel gene dosage-molecular phenotype relationships. Molecular phenotypes in post-therapeutic surviving cells revealed diverse gene perturbation-associated pathways causing convergent drug resistance (EMT plasticity, cell cycle alterations, metabolic reprogramming), highlighting combinatorial strategies for restoring sensitivity. Mapping of in vitro molecular phenotypes to primary human GCs imparted prognostic information and insights into spatial heterogeneity. Comparative analysis of gene perturbations across therapies and lines revealed both conserved and context-specific molecular alterations. Our results illustrate how Perturb-seq approaches can systematically map diverse cancer-associated molecular phenotypes across multiple gene/drug/cell line interactions, yielding translational insights.

cancer biology↗

bioRxiv2025

Identification of a neural basis for energy expenditure in the arcuate hypothalamus

Given the evolutionary instinct for caloric intake and the tendency for weight rebound after discontinuing dietary interventions or medications, increasing energy expenditure emerges as an alternative obesity treatment. However, neural regulation of energy expenditure remains poorly understood. Here, we report that a hypothalamic neuronal subtype, characterized by Crabp1 expression, establishes connections with multiple hypothalamic nuclei to regulate energy expenditure in mice. Inactivation of Crabp1 neurons reduces physical activity, body temperature, and adaptive thermogenesis, leading to an obese phenotype. Conversely, activation of these neurons increases energy expenditure and mitigates diet-induced obesity. Structural and functional analyses reveal that Crabp1 neurons promote energy metabolism through a "one-to-many" projection pattern. While Crabp1 neurons are rapidly activated by cold exposure and physical activity, prolonged light exposure abrogates their firing and may mediate light-induced metabolic disorder. Together, we reveal a neural basis that integrate various physiological and environmental stimuli to control energy expenditure and body weight.

neuroscience↗

bioRxiv2025

SARS-CoV-2 Exploits Host Translation and Immune Evasion Pathways via Viral RNA-Host Protein Interactions

RNA viruses, including SARS-CoV-2, Influenza A Virus (IAV), Zika Virus, and Dengue Virus (DENV) pose serious global health challenges by manipulating host cellular mechanisms. SARS-COV-2, in particular exploits host translational machinery to enhance replication and evade immune response. Here, we investigated how SARS-CoV-2 circumvents host immune defenses through RNA - host protein interactions. By integrating multiple datasets, ClusterProfiler, KEGG, Reactome, WikiPathways, and Gene Ontology, we performed functional enrichment analyses on host protein interactions with SARS-CoV-2 RNA. Our results identified key pathways involved in viral replication, translation regulation, and immune evasion. Comparing SARS-CoV-2 interactomes from IAV, Zika, and DENV, we uncovered a subset of 275 common host proteins serving as promising targets for broad-spectrum antiviral strategies. Network analysis highlighted critical translation factors (EEF1A1, EIF4A1, EIF3H) and RNA-binding proteins (NCL, ILF3) as key nodes in viral replication. These findings provide insights into RNA virus pathogenesis and support the development of targeted therapeutics.

immunology↗

bioRxiv2025

Transcriptomic plasticity is a hallmark of metastatic pancreatic cancer

Metastasis is the leading cause of cancer deaths; nonetheless, how tumor cells adapt to vastly different organ contexts is largely unknown. To investigate this question, we generated a transcriptomic atlas of primary tumor and diverse metastatic samples from a patient with pancreatic ductal adenocarcinoma who underwent rapid autopsy. Unsupervised archetype analysis identified both shared and site-specific gene programs, including lipid metabolism and gastrointestinal programs prevalent in peritoneum and stomach wall lesions, respectively. We developed a probabilistic approach for inferring clonal phylogeny from single-cell and matched whole-exome data. Distantly related genetic clones in the peritoneum express the lipid metabolism program, likely due to signaling by the adipocyte-rich peritoneum environment, and cells in most clones express multiple programs, suggesting that transcriptomic plasticity is a prevalent feature of metastatic cells. These deeply annotated analyses using a patient-centric platform provide a model for investigating metastatic mechanisms and plasticity in advanced cancer.

bioinformatics↗

bioRxiv2025

Single cell resolved spatial immune repertoire unveils spatial heterogeneity of lymphoid aggregates in human immune disorders

Adaptive immunity, mediated by T and B cell responses, is essential for defending against infections and cancers while also being implicated in autoimmune diseases. Tracking T and B cell repertoires in situ at single-cell resolution is essential for understanding adaptive immune responses. To address the lack of tools for in situ single-cell T/BCR (XCR) sequencing, we developed Stereo-XCR-seq, an efficient strategy for retrieving and sequencing TCR and BCR from Stereo-seq cDNA libraries at subcellular resolution. Stereo-XCR-seq provides unbiased full-length XCR reads alongside spatial transcriptomics, enabling the identification of heterogeneous lymphoid aggregates with distinct clonal activities in cancers and inflammatory bowel disease (IBD). We identified plasma cell aggregates that differ from tertiary lymphoid structures (TLSs) in both transcriptomic profiles and clonal activities, with spatial positioning potentially mediating unique immune responses. Collectively, Stereo-XCR-seq enables in situ single-cell profiling of T and B cell clonal activities within tissue microenvironments, providing insights into lymphocyte adaption to environmental stimuli. This technology provides potential for advancing our understanding of tissue immunity and the development of therapeutic strategies for immune disorders.

immunology↗

bioRxiv2024

TRAIT: A Comprehensive Database for T-cell Receptor-Antigen Interactions

Comprehensive and integrated resources on interactions between T-cell receptors and antigens are still lacking for adoptive T-cell-based immunotherapies, highlighting a significant gap that must be addressed to fully comprehend the mechanisms of antigen recognition by T-cells. In this study, we present TRAIT, a comprehensive database that profiles the interactions between T-cell receptors (TCRs) and antigens. TRAIT stands out due to its comprehensive description of TCR-antigen interactions by integrating sequences, structures and affinities. It provides nearly 8 million experimentally validated TCR-antigen pairs, resulting in an exhaustive landscape of antigen-specific TCRs. Notably, TRAIT emphasizes single-cell omics as a major reliable data source for TCR-antigen interactions and includes millions of reliable non-interactive TCRs. Additionally, it thoroughly demonstrates the interactions between mutations of TCRs and antigens, thereby benefiting affinity maturation of engineered TCRs as well as vaccine design. TCRs on clinical trials were innovatively provided. With the significant efforts made towards elucidating the complex interactions between TCRs and antigens, TRAIT is expected to ultimately contribute superior algorithms and substantial advancements in the field of T-cell-based immunotherapies. TRAIT is freely accessible at https://pgx.zju.edu.cn/traitdb.

immunology↗

bioRxiv2024

Inferring single-cell resolution spatial gene expression via fusing spot-based spatial transcriptomics, location and histology using GCN

Spatial transcriptomics technology allows for the detection of cellular transcriptome information while preserving the spatial location of cells. This capability enables researchers to better understand the cellular heterogeneity, spatial organization and functional interactions in complex biological systems. However, current technological methods are limited by low resolution, which reduces the accuracy of gene expression levels. Here, we propose scstGCN, a multimodal information fusion method based on Vision Transformer (ViT) and Graph Convolutional Network (GCN) that integrates histological images, spot-based spatial transcriptomics data and spatial location information to infer super-resolution gene expression profiles at single-cell level. We evaluated the accuracy of the super-resolution gene expression profiles generated on diverse tissue ST datasets with disease and healthy by scstGCN along with their performance in identifying spatial patterns, conducting functional enrichment analysis, and tissue annotation. The results show that scstGCN can predict super-resolution gene expression accurately, aid researchers in discovering biologically meaningful differentially expressed genes and pathways. Additionally, scstGCN can segment and annotate tissues at a finer granularity, with results demonstrating strong consistency with coarse manual annotations. Key PointsO_LIscstGCN combines multi-modal information including histology image, spot-based spatial transcriptomics (ST) data, and physical spatial location through deep learning methods to achieve single-cell resolution of spot-based ST data without requiring single-cell references. C_LIO_LIscstGCN employs GCN to capture complex relationships between neighboring cells, facilitating the integration of multimodal feature information based on single-cell level, and then accurately infers single-cell resolution spatial gene expression. C_LIO_LIscstGCN can infer single-cell resolution gene expression across the entire tissue region. Through transfer learning, gene expression in three-dimensional tissues can be characterized efficiently. Furthermore, it demonstrates outstanding performance in spatial patterns enhancement, functional enrichment analysis, and annotate tissues at the high-resolution. C_LI

bioinformatics↗

bioRxiv2024

Comprehensive sequencing of the lung neuroimmune landscape in response to asthmatic induction

Evidence demonstrates that sensory neurons respond to pathogenic/allergic infiltration and mediate immune responses, forming an integral part of host defense that become hypersensitized during allergy. Our objective was to investigate how asthmatic induction alters the pulmonary neuroimmune transcriptome. We hypothesized that asthmatic induction would upregulate genes in the vagal ganglia (nodose/jugular ganglia), which would be associated with asthmatic immunity, and that these would be clustered, primarily in nodose neurons. Furthermore, lungs would increase transcripts associated with nerve activation, and these would be centered in neural and neuroendocrine-like cells. Bulk RNA-seq revealed that genes related to allergen sensing were increased in asthmatic ganglia nodose/jugular ganglia compared to control ganglia. These genes were associated with nodose clusters as shown by single-nucleus RNA sequencing, and a distinct caudal-to-rostral spatial arrangement was presented as delineated by spatial transcriptomics. The distinct clusters closely match previous identification of nodose neuron clusters. Correspondingly, the lung transcriptome was altered with asthmatic induction such that transcripts associated with neural excitation were upregulated. The spatial distribution of these transcripts was revealed by spatial transcriptomics to illustrate that these were expressed in neuroendocrine-like cells/club cells, and neurons. These results show that the neuroimmune transcriptome is altered in response to asthmatic induction in a cell cluster and spatially distinct manner. Significance statementThis study provides a comprehensive transcriptomic map of the neuroimmune alterations in response to asthmatic induction.

immunology↗

bioRxiv2024

GPR30 in spinal cholecystokinin-positive neurons modulates neuropathic pain via mediating descending facilitation

Neuropathic pain, a major health problem affecting 7-10% of the global population, lacks effective treatment due to its elusive mechanisms. Cholecystokinin-positive (CCK+) neurons in the spinal dorsal horn (SDH) are critical for neuropathic pain, yet the underlying molecular mechanisms remain unclear. Here, we show that the membrane estrogen receptor G-protein coupled estrogen receptor (GPER/GPR30) in spinal neurons was significantly upregulated in chronic constriction injury (CCI) mice and that inhibition of GPR30 in CCK+ neurons reversed CCI-induced neuropathic pain. Furthermore, GPR30 in spinal CCK+ neurons was essential for the enhancement of AMPA-mediated excitatory synaptic transmission in CCI mice. Moreover, GPR30 was expressed in spinal CCK+ neurons that received direct projection from the primary sensory cortex (S1-SDH). Chemogenetic inhibition of S1-SDH post-synaptic neurons alleviated CCI-induced neuropathic pain. Conversely, chemogenetic activation of these neurons mimicked neuropathic pain symptoms, which were attenuated by spinal inhibition of GPR30. Finally, we confirmed that GPR30 in S1-SDH post-synaptic neurons was required for CCI-induced neuropathic pain. Taken together, our findings suggest that GPR30 in spinal CCK+ neurons and S1-SDH postsynaptic neurons is pivotal for neuropathic pain, thereby representing a promising therapeutic target for neuropathic pain.

neuroscience↗

bioRxiv2024

Sympathetic Nervous System Overactivation Induces Colonic Eosinophil-Associated Microinflammation and Contributes to the Pathogenesis of Irritable Bowel Syndrome

ObjectiveMucosal microinflammation is a characteristic clinical manifestation of irritable bowel syndrome (IBS), and its symptoms are often triggered by psychological stress. In the present study, we aimed to investigate the impact of early life stress-associated dysfunction of the sympathetic nervous system (SNS) on mucosal immune changes in the gastrointestinal tract (GI) and its contribution to IBS pathogenesis. DesignWe utilised a traditional animal model of IBS with maternal separation (MS) and evaluated colorectal hypersensitivity, immune alterations, and SNS activity in adult rats with MS. We conducted a series of experiments to manipulate peripheral SNS activity pharmacologically and chemogenetically to explore the interaction between SNS activity and GI events. ResultsThe MS-induced IBS model exhibited visceral hypersensitivity and eosinophilic infiltration in the colonic mucosa, along with SNS overactivation. Degeneration of the SNS using 6-OHDA neurotoxin decreased eosinophil infiltration and visceral hypersensitivity in the MS model. Notably, specific chemogenetic activation of the peripheral SNS induced eosinophil infiltration in the intestinal mucosa through the noradrenergic signalling-mediated release of eotaxin-1 from mesenchymal cells. ConclusionThis study highlights the critical role of SNS overactivation in eotaxin-1-driven eosinophil infiltration in the colon, leading to the development of visceral hypersensitivity in IBS. The results provide important insights into the mechanistic links among increased sympathetic activity, mucosal microinflammation, and visceral hypersensitivity in individuals with IBS, suggesting potential therapeutic approaches. What is already known on this topicO_LIA subgroup of patients with irritable bowel syndrome (IBS) presents with microinflammation in the gastrointestinal tract (GI). C_LIO_LIEarly life stress is recognised as a major risk factor for the development of IBS in adulthood. C_LIO_LIOveractivation of the sympathetic nervous system (SNS) is frequently associated with IBS. C_LI What this study addsO_LIMaternal separation (MS) stress induces eosinophil-associated microinflammation in the colonic mucosa of adult rats. C_LIO_LIInhibition of SNS activity suppresses eosinophil infiltration and mitigates visceral hypersensitivity in the MS model. C_LIO_LINoradrenergic signalling within the peripheral sympathetic activation stimulates mesenchymal cells to release eotaxin-1, leading to substantial eosinophil-predominant immune alterations in the colon. C_LI How this study might affect research, practice, or policyO_LITreatment with fibroblast-derived eotaxin-1 and targeting eosinophil-associated microinflammation could be a potential strategy to alleviate visceral pain in patients with IBS. C_LIO_LIThe chemogenomic method specifically manipulates peripheral SNS and provides a valuable tool for future research. C_LI

neuroscience↗

bioRxiv2024

Oriented nucleosome binding by the pioneer factor ELF2

Pioneer transcription factors are DNA-binding proteins that can bind to nucleosomes in closed chromatin regions, exposing enhancers and promoters of genes for transcription. The action of these factors underpin stem cell pluripotency, cell reprogramming and differentiation. ELF2 is an ETS family pioneer factor that has a strong preference for oriented binding on nucleosomes at a composite head-to-tail dimeric sequence motif with a 2 bp spacing between the GGAA core elements. In this study, we investigated the interaction between ELF2 and a nucleosome using single-particle cryo-electron microscopy (cryo-EM). The ELF2-nucleosome structure shows two ELF2 proteins bound to the nucleosome cooperatively at superhelical location +4. The recognition [a]4 helices of both ELF2 monomers dock into the major groove at the core GGAA motifs and unwrap approximately four helical turns of the DNA from the surface of the nucleosome. The unwrapping almost completely exposes one histone H2A:H2B dimer, which dissociates in a subset of particles to form an ELF2-bound hexasome. ChIP-seq combined with genome-wide motif mapping indicates that all unmethylated high-affinity ELF2 double motifs are occupied, indicating that ELF2 is able to use its binding energy to function as a pioneer factor both in vitro and in vivo. ELF2 binding is highly enriched downstream of transcription start sites (TSS) of highly expressed genes, with the motifs oriented in such a way that the TSS becomes accessible upon ELF2 binding. This mechanism is essential for cells, as mutation of ELF2 motifs result in decreased cell proliferation. Taken together, our results indicate that ELF2 can use its binding energy to open chromatin in an oriented fashion, facilitating nucleosome positioning and transcription initiation at transcription start sites.

biochemistry↗

bioRxiv2024

LucaOne: Generalized Biological Foundation Model with Unified Nucleic Acid and Protein Language

AbstractThe language of biology, encoded in DNA, RNA, and proteins, forms the foundation of life but remains challenging to decode due to its complexity. Traditional computational methods often struggle to integrate information across these molecules, limiting a comprehensive understanding of biological systems. Advances in Natural Language Processing (NLP) with pre-trained models offer new possibilities for interpreting biological language. Here, we introduce LucaOne, a pre-trained foundation model trained on nucleic acid and protein sequences from 169,861 species. Through large-scale data integration and semisupervised learning, LucaOne demonstrates an understanding of key biological principles, such as DNA-Protein translation. Using few-shot learning, it effectively comprehends the central dogma of molecular biology and performs competitively on tasks involving DNA, RNA, or protein inputs. Our results highlight the potential of unified foundation models to address complex biological questions, providing an adaptable framework for bioinformatics research and enhancing the interpretation of lifes complexity.

bioinformatics↗

bioRxiv2024

Spatially Resolved Tumor Ecosystems and Cell States in Gastric Adenocarcinoma Progression and Evolution

Gastric cancer (GC) is a major cause of global cancer mortality with high heterogeneity levels. To explore geospatial interactions in tumor ecosystems, we integrated 1,563 spatial transcriptomic regions-of-interest (ROIs) with 152,423 single-cell expression profiles across 130 GC samples from 70 patients. We observed pervasive expression-based intratumor heterogeneity, recapitulating tumor progression through spatially localized and functionally ordered subgroups with specific immune microenvironments and immune checkpoint profiles. Evolutionary phylogenetic analysis revealed two different evolutionary trajectories (branched evolution and diaspora evolution) associated with distinct molecular subtypes, clinical prognoses, stromal neighborhoods including VWF+ ACKR1+ endothelial cells, and genetic drivers such as SOX9. Spatial analysis of tumor-stromal interfaces across multiple GCs highlighted new ecosystem states not attributable to mere tumor/stroma admixture, landmarked by increased GREM1 expression. Our results provide insights into how the cellular ecosystems of individual GCs are sculpted by tumor intrinsic and extrinsic selective pressures, culminating in individualized patient-specific cancer cartographies.

cancer biology↗

bioRxiv2024

Regenerative clustering of Enteroblasts in the Drosophila midgut revealed by a morphometric analysis

Enteroblasts (EBs) are the cells responsible for the maintenance of the epithelium that lines the adult midgut in Drosophila. In response to cell death and damage, EBs undergo a Mesenchymal-Epithelial-Transition (MET) as they incorporate into the epithelium and differentiate into enterocytes (ECs). The morphogenetic mechanisms driving this MET process are not well understood. To improve phenotypic analysis of EBs, we established an analysis pipeline that uses machine learning segmentation to produce a reliable and automated quantification of cellular morphology and spatial distributions. EB morphology and fate is visualised using the Repressible Dual Differential stability cell Marker (ReDDM) approach. We show that wildtype EB cells exhibit a bimodal distribution pattern in which midguts fall into two categories: "quiescent" guts, in which EBs are evenly spaced out and newly formed ECs are uncommon, and "regenerative" guts, in which EBs are clustered and new ECs are prevalent. Using this system we first show that RNAi knockdown of Septate Junction proteins disrupts normal EB morphology and spatial distribution. With time-lapse imaging, we have also established that EBs are motile in nature, and when artificial tissue damage was introduced, exhibited increased cytoplasmic movements, and formed distinct clusters. We then demonstrate the utility of our pipeline in a small candidate screen for genes that might mediate EB clustering. Based on our results, we propose a working model that links the dynamic behaviour of EBs with midgut regeneration.

developmental biology↗

bioRxiv2024

Sensory neurons regulate stimulus-dependent humoral immunity

Sensory neurons sense pathogenic infiltration, informing immune coordination of host defense. However, sensory neuron-immune interactions have been predominantly shown to drive innate immune responses. Humoral memory, whether protective or destructive, is acquired early in life - as demonstrated by both early exposure to streptococci and allergic disease onset. Our study further defines the role of sensory neuron influence on humoral immunity in the lung. Using a murine model of Streptococcus pneumonia pre-exposure and infection and a model of allergic asthma, we show that sensory neurons are required for B-cell and plasma cell recruitment and antibody production. In response to S. pneumoniae, sensory neuron depletion resulted in a larger bacterial burden, reduced B-cell populations, IgG release, and neutrophil stimulation. Conversely, sensory neuron depletion reduced B-cell populations, IgE, and asthmatic characteristics during allergen-induced airway inflammation. The sensory neuron neuropeptide released within each model differed. With bacterial infection, vasoactive intestinal polypeptide (VIP) was preferentially released, whereas substance P was released in response to asthma. Administration of VIP into sensory neuron-depleted mice suppressed bacterial burden and increased IgG levels, while VIP1R deficiency increased susceptibility to bacterial infection. Sensory neuron-depleted mice treated with substance P increased IgE and asthma, while substance P genetic ablation resulted in blunted IgE, similar to sensory neuron-depleted asthmatic mice. These data demonstrate that the immunogen differentially stimulates sensory neurons to release specific neuropeptides that specifically target B-cells. Targeting sensory neurons may provide an alternate treatment pathway for diseases involved with insufficient and/or aggravated humoral immunity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/574231v3_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1a96e0org.highwire.dtl.DTLVardef@1a75c97org.highwire.dtl.DTLVardef@afd6f8org.highwire.dtl.DTLVardef@4a6666_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Interfacial water confers transcription factors with dinucleotide specificity

Transcription factors bind to DNA by recognizing specific bases within their binding motifs. Binding to each DNA mononucleotide within the motif often contributes independently to total binding energy. However, some transcription factors (TFs) can bind to DNA more specifically than predicted by this model, by directly recognizing DNA dinucleotides. To understand this process, we have solved the structures of the basic helix-loop-helix protein MYF5, and the homeodomain protein BARHL2 together with DNA containing a set of dinucleotides that have different affinities to the proteins at high resolution (< 1 [A]). We observe that dinucleotides can be recognized either enthalpically by an extensive water network that connects the adjacent bases to the TF, or entropically by formation of a hydrophobic patch that maintains water mobility at the protein-DNA interface. The two distinct thermodynamic signatures of the two equally optimal sites also confer differential temperature sensitivity to the optimal sites, with implications for thermal regulation of gene expression. Our results uncover the enigma of how TFs can recognize more complex local features than mononucleotides, and demonstrate that water-mediated recognition is important in predicting affinities of macromolecules from their sequence.

biochemistry↗

bioRxiv2023

Proportionality-based association metrics in count compositional data

MotivationCompositional data comprise vectors that describe the constituent parts of a whole. Data arising from various -omics platforms such as 16S and RNA-sequencing are compositional in nature. However, correlations between features on raw counts have no meaningful interpretation. Metrics of proportionality were formulated to address this problem. However, there is an inherent bias that arises when calculating these metrics empirically on count-based measures due to variability in read depths. ResultsWe quantify the bias introduced by empirically calculating proportionality-based association metrics in count data. Additionally, we propose a means of estimating these metrics within a logit-normal multinomial model in pursuit of more accurate estimates. The model-based estimates are shown to outperform empirical estimates in simulated data, and are additionally applied to a mouse embryonic stem-cell single-cell sequencing dataset as well as a pediatric-onset multiple sclerosis metagenomic dataset. Availability and ImplementationAn R package is available at https://CRAN.R-project.org/package=countprop. Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗