Biology subjects

Paul, K.

Publications and source records attributed to Paul, K..

18 recordsLinked to original sources

bioRxiv2026

Specialization of independently acquired flagellar FliC proteins in plant-associated Sphingomonas balances swimming and immunogenicity

Plants monitor their environment for microbial invaders using pattern-recognition receptors that detect microbe-associated molecular patterns (MAMPs). Flagellin, the main component of bacterial flagellum, contains the flg22 epitope recognized by the plant immune receptor FLS2. Immune recognition can create an evolutionary conflict, requiring bacteria to balance flagellar function and immune evasion. Here, we show that plant-associated Sphingomonads resolve this constraint by partitioning two flagellar functions, motility and colonization, across two divergent and independently acquired flagellin genes. Comparative genomics revealed widespread coexistence of FliC proteins expressing either an immunogenic variant (FliC-H) or a non-immunogenic variant (FliC-L). The non-immunogenic FliC-L is necessary and sufficient for full directional swimming, whereas FliC-H is dispensable for swimming, but sufficient for full attachment and colonization. Flagellin expression patterns mirror these functions. Thus, FLS2 recognizes the flagellar variant required for colonization rather than motility, potentially restricting colonizing bacteria from entering internal leaf and root tissues.

plant biology↗

bioRxiv2025

Identification of Pesticides Associated with an Increased Risk of Parkinson's Disease using a Multi-Screen Approach

Parkinsons Disease (PD) is a progressive neurodegenerative disease characterized by aggregation and transmission of alpha-synuclein (-syn) protein and loss of dopaminergic neurons. The etiology of PD is multifactorial involving both genetic and environmental factors. Pesticide exposure has been associated with PD, but it is still unclear which of the hundreds of chemically and structurally diverse pesticides confer this association. While there are numerous pesticides currently registered for use in the United States, in this study, we focused on 62 pesticides used in the California Central Valley. We used 2 cell-based screens and a recently developed pesticide-wide association study (PWAS) analysis to identify candidates that increase the risk of PD. One cell-based screen tested for pesticides that alter autophagy and the other tested for their effect on -syn transmission. To establish biological plausibility, pesticides that were positive in all 3 screens were tested for dopaminergic neurotoxicity in an in vivo zebrafish (ZF) model. The autophagy screen resulted in a total of 22 hits for alterations to either autophagosomes (16 hits) and lysosomes (14 hits) out of the 62 pesticides tested. The -syn transmission screen resulted in 29 hits, and the PWAS resulted in 34 hits. Six pesticides were positive in all 3 screens and four of these pesticides induced aminergic neuron loss in ZF larvae. The majority of the pesticides identified in our screens have not previously been implicated as risk factors for PD but should be considered in future studies.

pharmacology and toxicology↗

bioRxiv2025

Lost in a Large EEG Multiverse? Comparing Sampling Approaches for Representative Pipeline Selection

The multiplicity of defensible strategies for processing and analysing data has been implicated as a core contributor to the replicability crisis, creating uncertainty about the robustness of a result to variations in data processing choices. This issue is exacerbated where a large number of data processing pipelines are defensible, and where there is great heterogeneity in the pipelines applied in the literature, such as in processing and analysing electroencephalography (EEG) signals. In a multiverse analysis, equally defensible pipelines are computed and the robustness of the result to these variations is reported. However, a large number of defensible pipelines is sometimes infeasible to compute exhaustively, and researchers rely on sampling approaches. In these cases, pipelines are sampled from the full multiverse and the robustness is reported across these samples, assuming that they are representative for the entire multiverse. However, different sampling methods may yield different robustness results, introducing what we term multiverse sampling uncertainty. To illustrate, we computed a 528-pipeline multiverse analysis on EEG-recordings during an emotion classification task aiming to predict extraversion scores from the Late Positive Potential. We applied three sampling methods (random, stratified, and active learning) to sample 26 pipelines (5%), and evaluated the results in terms of the representativeness of the distribution of model fits to that of the full multiverse. Our results highlight variability in the representativeness of the distribution of model fits between samples. The active learning sample most closely represented the median model fit of the full multiverse. The need for representative pipeline sampling to mitigate bias in large multiverse analyses is discussed.

neuroscience↗

bioRxiv2025

CDDO-Imidazole regulates RBC alloimmunization to the KEL antigen by activating Nrf2

During red blood cell (RBC) transfusion, production of alloantibodies can promote significant hemolytic events. However, most transfusion recipients do not form anti-RBC alloantibodies. Identifying mechanisms that inhibit alloimmunization may lead to prophylactic interventions. One potential regulatory mechanism is activation of the transcription factor, nuclear factor erythroid-derived 2-like 2 (Nrf2), a master regulatory of antioxidant pathways. Pharmacologic Nrf2 activators improve sequelae of sickle cell disease in pre-clinical models. The Nrf2 activator, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), suppresses production of inflammatory cytokines including type 1 interferons (IFN/{beta}), which have been implicated in promoting RBC alloimmunization in transfusion models. Thus, we tested the hypothesis that the Nrf2 activator, CDDO-Im, regulates RBC alloimmunization. Here, we report that CDDO-Im induced Nrf2 activated gene expression and suppressed poly(I:C)-induced IFN/{beta}-stimulated gene (ISG) expression in human macrophages and murine blood leukocytes. In addition, following transfusion of wildtype mice with RBCs expressing the KEL antigen, CDDO-Im treatment inhibited poly(I:C)-induced anti-KEL IgG production and promoted post-transfusion recovery of KEL+ RBCs, but failed to do so in Nrf2-/- mice. Results indicate that activation of the Nrf2 antioxidant pathway regulates RBC alloimmunization to the KEL antigen in a pre-clinical model. If findings translate to other models and human studies, Nrf2 activators may represent a potential prophylactic intervention to inhibit alloimmunization. Key PointsO_LIThe antioxidant pathway, Nrf2, inhibits anti-RBC alloantibody responses in a pre-clinical transfusion model. C_LIO_LINrf2 activation may represent a prophylactic strategy to inhibit RBC alloimmunization in transfusion recipients. C_LI

immunology↗

bioRxiv2025

VISTA-induced tumor suppression by a four amino acid intracellular motif

VISTA is a key immune checkpoint receptor under investigation for cancer immunotherapy; however, its signaling mechanisms remain unclear. Here we identify a conserved four amino acid (NPGF) intracellular motif in VISTA that suppresses cell proliferation by constraining cell-intrinsic growth receptor signaling. The NPGF motif binds to the adapter protein NUMB and recruits Rab11 endosomal recycling machinery. We identify and characterize a class of triple-negative breast cancers with high VISTA expression and low proliferative index. In tumor cells with high VISTA levels, the NPGF motif sequesters NUMB at endosomes, which interferes with epidermal growth factor receptor (EGFR) trafficking and signaling to suppress tumor growth. These effects do not require canonical VISTA ligands, nor a functioning immune system. As a consequence of VISTA expression, EGFR receptor remains abnormally phosphorylated and cannot propagate ligand-induced signaling. Mutation of the VISTA NPGF domain reverts VISTA-induced growth suppression in multiple breast cancer mouse models. These results define a mechanism by which VISTA represses NUMB to control malignant epithelial cell growth and signaling. They also define distinct intracellular residues that are critical for VISTA-induced cell-intrinsic signaling that could be exploited to improve immunotherapy.

cancer biology↗

bioRxiv2024

Comparative atlas of genome-wide chromatin-associated protein co-occupancy

Accurate transcriptional regulation and chromatin dynamics requires the coordination and activity of chromatin-associated proteins (CAPs) at distinct loci. While the combinatorial activity of a select set of CAPs has been previously examined, these studies are limited by the underrepresentation of proteins and cell types explored, making it difficult to identify the global associations as well as the conservation of these associations across different cell types. Here, we performed 270 CAP chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) experiments in both K562 and HepG2 cancer cell lines and explored the relationship between cell identity and CAP co-association using three distinct approaches. We employed a machine learning algorithm to organize the genome-wide binding profiles into 56 and 70 interpretable co-association modules for HepG2 and K562 cell lines, respectively. We found CAP co-association modules are mostly cell type-specific, however those present in both cell lines are largely comprised of TFs from a single TF family and anchor to unique loci via lineage-specific factors. While enhancer-associated co-binding modules were largely composed of cell type-specific CAPs, we found regulatory activity at promoter-enhancer module contacts to be enriched for chromatin remodeling proteins. Additionally, we used colocalization information derived from co-association models in conjunction with neural network models of transcription factor (TF) activity to identify high-confidence candidate TF cooperative pairs. Finally, through comparing CAP enrichment in high occupancy target (HOT) regions in K562 and HepG2 cell lines, we found cell type-specific HOT sites, but not common HOT sites, are selectively enriched at high copy number loci. Overall, this study uncovers principles of sequence-level and large-scale CAP genomic organization and demonstrates how this contributes to cell type-specific regulatory mechanisms and cellular functions.

genomics↗

bioRxiv2024

Single-cell spatial mapping reveals alteration of cell type composition and tissue microenvironment during early colorectal cancer formation

Familial adenomatous polyposis (FAP) is a rare, hereditary syndrome that raises the risk of developing colorectal cancer (CRC). This disease model is well suited for studying the early stages of malignant transformation. Our spatial CODEX experiments reveal that, in contrast to normal mucosa, FAP mucosa, pre-cancer polyps and colorectal cancers exhibit substantial alterations in the cell type composition and tissue microenvironment. These early alterations include: an increase in the population of cancer-associated fibroblasts (CAFs), and the inhibition of tumor infiltrated lymphocytes and cell-adhesion protein by CAFs, the transformation of memory T cells into regulatory T cells, nuclear translocation of beta-catenin from the cell membrane, a decrease in the M1:M2 macrophage ratio, a notable increase in angiogenesis events. Our studies define the early stem cell, stromal, and immune steps of colorectal cancer and may benefit early detection, and therapeutic intervention.

cancer biology↗

bioRxiv2024

Scheduled feeding improves sleep in a mouse model of Huntington's disease.

Sleep disturbances are common features of neurodegenerative disorders including Huntingtons disease (HD). The sleep and circadian disruptions are recapitulated in animal models, and these models provide the opportunity to evaluate whether circadian interventions can be effective countermeasures for neurodegenerative disease. Time restricted feeding (TRF) interventions successfully improve activity rhythms, sleep behavior and motor performance in mouse models of HD. Seeking to determine if these benefits of scheduled feeding extend to physiological measures of sleep, electroencephalography (EEG) was used to measure sleep/wake states and polysomnographic patterns in adult mice (six mo-old) under TRF and ad lib feeding (ALF). With each diet, both male and female wild-type (WT) and bacterial artificial chromosome transgenic (BACHD) mice were evaluated. Our findings show that male, but not female, BACHD mice exhibited significant changes in the temporal patterning of wake and non-rapid eye movement (NREM) sleep. The TRF intervention reduced the inappropriate early morning activity by increasing NREM sleep in the male BACHD mice. In addition, the scheduled feeding reduced sleep fragmentation (# bouts) in the male BACHD mice. The phase of the rhythm in rapid-eye movement (REM) sleep was significantly altered by the scheduled feeding. The treatment did impact the power spectral curves during the day in male but not female mice. Sleep homeostasis, as measured by the response to six hours of gentle handling, was not altered by the diet. Thus, TRF improves the temporal patterning and fragmentation of NREM sleep without impacting sleep homeostasis. This work adds critical support to the view that sleep is a modifiable risk factor in neurodegenerative diseases.

neuroscience↗

bioRxiv2023

Diverse and Abundant Viruses Exploit Conjugative Plasmids

Phages exert profound evolutionary pressure on bacteria by interacting with receptors on the cell surface to initiate infection. While the majority of phages use chromosomally-encoded cell surface structures as receptors, plasmid-dependent phages exploit plasmid-encoded conjugation proteins, making their host range dependent on horizontal transfer of the plasmid. Despite their unique biology and biotechnological significance, only a small number of plasmid-dependent phages have been characterized. Here we systematically search for new plasmid-dependent phages targeting IncP and IncF plasmids using a targeted discovery platform, and find that they are common and abundant in wastewater, and largely unexplored in terms of their genetic diversity. Plasmid-dependent phages are enriched in non-canonical types of phages, and all but one of the 64 phages we isolated were non-tailed, and members of the lipid-containing tectiviruses, ssDNA filamentous phages or ssRNA phages. We show that plasmid-dependent tectiviruses exhibit profound differences in their host range which is associated with variation in the phage holin protein. Despite their relatively high abundance in wastewater, plasmid-dependent tectiviruses are missed by metaviromic analyses, underscoring the continued importance of culture-based phage discovery. Finally, we identify a tailed phage dependent on the IncF plasmid, and find related structural genes in phages that use the orthogonal type 4 pilus as a receptor, highlighting the promiscuous use of these distinct contractile structures by multiple groups of phages. Taken together, these results indicate plasmid-dependent phages play an under-appreciated evolutionary role in constraining horizontal gene transfer via conjugative plasmids.

microbiology↗

bioRxiv2023

MPK12 in stomatal CO2 signaling: function beyond its kinase activity

O_LIProtein phosphorylation by kinases is a major molecular switch mechanism involved in the regulation of stomatal opening and closure. Previous research defined interaction between MAP kinase 12 and Raf-like kinase HT1 as a required step for stomatal movements by changes in CO2 concentration. However, whether MPK12 kinase activity is required for regulation of CO2-induced stomatal responses warrants in depth investigation. C_LIO_LIWe apply genetic, biochemical, and structural modeling approaches to examining the non-catalytic role of MPK12 in guard cell CO2 signaling that relies on allosteric inhibition of HT1. C_LIO_LIWe show that CO2/HCO3--enhanced MPK12 interaction with HT1 is independent of its phosphor-transfer activity. By analyzing gas exchange of plant lines expressing various kinase-dead and constitutively active versions of MPK12 in a plant line where MPK12 is deleted, we confirmed that CO2-dependent stomatal responses rely on MPK12s ability to bind to HT1 but not its kinase activity. We also demonstrate that purified MPK12 and HT1 proteins form a heterodimer in the presence of CO2/HCO3- and present structural modeling that explains the MPK12:HT1 interaction interface. C_LIO_LIThese data add to the model that MPK12 kinase-activity-independent interaction with HT1 functions as a molecular switch by which stomatal guard cells sense changes in atmospheric CO2 concentration. C_LI

plant biology↗

bioRxiv2022

Genome-wide detection of positive and balancing selection signatures shared by four domesticated rainbow trout populations (Oncorhynchus mykiss)

Evolutionary processes leave footprints across the genome over time. Highly homozygous regions may correspond to positive selection of favourable alleles, while maintenance of heterozygous regions may be due to balancing selection phenomena. We analyzed 176 genomes coming from 20 sequenced US fish and 156 fish from three different French lines that were genotyped using a HD Axiom Trout Genotyping 665K SNP Array. Using methods based on either Run of Homozygosity or Extended Haplotype Homozygosity, we detected selection signals in four domesticated rainbow trout populations. Nine genomic regions composed of 253 genes, mainly located on chromosome 2 but also on chromosomes 12, 15, 16, and 20, were identified under positive selection in all four populations. In addition, four heterozygous regions containing 29 genes putatively under balancing selection were also shared by the four populations and located on chromosomes 10, 13, and 19. Whatever the homozygous or heterozygous nature of the region, we always found some genes highly conserved among vertebrates due to their critical roles in cellular and nuclear organisation, embryonic development or immunity. We identify new promising candidate genes involved in rainbow trout fitness, as well as genes already detected under positive selection in other fishes (auts2, atp1b3, zp4, znf135, igf-1, brd2, col9a2, mrap2, pbx1, emilin-3). These findings represent a genome-wide map of signatures of selection common over rainbow trout populations, which is the foundation to understand the processes in action and to identify what kind of diversity should be preserved, or conversely avoided in breeding programs, in order to maintain or improve essential biological functions in domesticated rainbow trout populations.

genetics↗

bioRxiv2022

Global loss of fine-scale chromatin architecture and rebalancing of gene expression during early colorectal cancer development

Although 3D genome architecture can be essential for gene regulation, the biological implications of long-range chromatin interactions in disease remain elusive. In this study, we traced the early evolution and malignant transformation of colorectal cancer by generating high-resolution chromatin conformation maps of 33 colon samples spanning different stages of early neoplastic growth from polyps of Familial Adenomatous Polyposis (FAP) patients. Our analysis reveals a substantial progressive loss of genome-wide cis-regulatory connectivity at early stages of malignancy, which correlates with a non-linear effect on gene regulation. Genes with high promoter-enhancer (P-E) connectivity in unaffected mucosa are not correlated with elevated baseline expression, but instead tend to be up-regulated at advanced stages. Inhibition of highly connected promoters preferentially represses gene expression in colorectal cancer cells relative to normal colonic epithelial cells. Our results suggest a two-phase model whereby neoplastic transformation reduces P-E connectivity from a redundant state to a rate-limiting one for transcriptional levels. Overall, our study illuminates the intricate interplay between 3D genome architecture and gene regulation during early colorectal cancer progression, and provides valuable insights for potential therapeutic interventions targeting the connectivity of cis-regulatory elements.

genomics↗

bioRxiv2022

Visuo-motor transformations in the intraparietal sulcus mediate the acquisition of endovascular medical skill

Performing endovascular medical interventions safely and efficiently requires a diverse set of skills that need to be practised in dedicated training sessions. Here, we used multimodal magnetic resonance (MR) imaging to determine the structural and functional plasticity and core skills associated with skill acquisition. A training group learned to perform a simulator-based endovascular procedure, while a control group performed a simplified version of the task; multimodal MR images were acquired before and after training. Using a well-controlled interaction design, we found strong, multimodal evidence for the role of the intraparietal sulcus (IPS) in endovascular skill acquisition that is in line with previous work implicating the structure in simple visuo-motor and mental rotation tasks. Our results provide a unique window into the multimodal nature of rapid structural and functional plasticity of the human brain while learning a multifaceted and complex clinical skill. Further, our results provide a detailed description of the plasticity process associated with endovascular skill acquisition and highlight specific facets of skills that could enhance current medical pedagogy and be useful to explicitly target during clinical resident training.

neuroscience↗

bioRxiv2022

Development of a high-density 665 K SNP array for rainbow trout genome-wide genotyping

Single nucleotide polymorphism (SNP) arrays, also named << SNP chips >>, enable very large numbers of individuals to be genotyped at a targeted set of thousands of genome-wide identified markers. We used preexisting variant datasets from USDA, a French commercial line and 30X-coverage whole genome sequencing of INRAE isogenic lines to develop an Affymetrix 665 K SNP array (HD chip) for rainbow trout. In total, we identified 32,372,492 SNPs that were polymorphic in the USDA or INRAE databases. A subset of identified SNPs were selected for inclusion on the chip, prioritizing SNPs whose flanking sequence uniquely aligned to the Swanson reference genome, with homogenous repartition over the genome and the highest Minimum Allele Frequency in both USDA and French databases. Of the 664,531 SNPs which passed the Affymetrix quality filters and were manufactured on the HD chip, 65.3% and 60.9% passed filtering metrics and were polymorphic in two other distinct French commercial populations in which, respectively, 288 and 175 sampled fish were genotyped. Only 576,118 SNPs mapped uniquely on both Swanson and Arlee reference genomes, and 12,071 SNPs did not map at all on the Arlee reference genome. Among those 576,118 SNPs, 38,948 SNPs were kept from the commercially available medium-density 57K SNP chip. We demonstrate the utility of the HD chip by describing the high rates of linkage disequilibrium at 2 kb to 10 kb in the rainbow trout genome in comparison to the linkage disequilibrium observed at 50 kb to 100 kb which are usual distances between markers of the medium-density chip.

genomics↗

bioRxiv2021

The genome trilogy of Anopheles stephensi, an urban malaria vector, reveals structure of a locus associated with adaptation to environmental heterogeneity

BackgroundAnopheles stephensi is the most menacing malaria vector to watch for in newly urbanizing parts of the world. The fitness is reported to be a direct consequence of the vector adapting to laying eggs in over-head water tanks with street-side water puddles polluted by oil and sewage. Large frequent inversions of malaria vectors are implicated in adaptation. ResultsWe report the assembly of a strain of An. stephensi of the type-form, collected from a construction site from Chennai (IndCh) in 2016. The genome completes the trilogy with respect to a 16 Mbp inversion (2Rb) in An. stephensi associated with adaptation to environmental heterogeneity. Comparative genome analysis revealed breakpoint structure and allowed extraction of 22,650 segregating SNPs for typing this inversion. Using whole genome sequencing of 82 individual mosquitoes, we conclude that one third of both wild and laboratory populations maintain heterozygous genotype of 2Rb. The large number of SNPs are tailored to assign inversion genotype directly from 1740 exonic SNPs 80% of which are expressed in various developmental stages. ConclusionsThe genome trilogy approach accelerates study of fine structure and typing of important inversions in malaria vectors putting the genome resources for the much understudied An. stephensi, on par with the extensively studied malaria vector, Anopheles gambiae. We argue that the IndCh genome is relevant for field translation work compared to those reported earlier by showing that individuals from diverse populations cluster with IndCh pointing to significant commerce between cities, perhaps, allowing for survival of the fittest strain.

genomics↗

bioRxiv2020

Hidden features of the malaria vectormosquito, Anopheles stephensi ,revealed by a high-quality referencegenome

BackgroundThe mosquito Anopheles stephensi is a vector of urban malaria in Asia that recently invaded Africa. Studying the genetic basis of vectorial capacity and engineering genetic interventions are both impeded by limitations of a vectors genome assembly. The existing assemblies of An. stephensi are draft-quality and contain thousands of sequence gaps, potentially missing genetic elements important for its biology and evolution. ResultsTo access previously intractable genomic regions, we generated a reference-grade genome assembly and full transcript annotations that achieve a new standard for reference genomes of disease vectors. Here, we report novel species-specific transposable element families and insertions in functional genetic elements, demonstrating the widespread role of TEs in genome evolution and phenotypic variation. We discovered 29 previously hidden members of insecticide resistance genes, uncovering new candidate genetic elements for the widespread insecticide resistance observed in An. stephensi. We identified 2.4 Mb of the Y-chromosome and seven new male-linked gene candidates, representing the most extensive coverage of the Y-chromosome in any mosquito. By tracking full length mRNA for >15 days following blood feeding, we discover distinct roles of previously uncharacterized genes in blood metabolism and female reproduction. The Y-linked heterochromatin landscape reveals extensive accumulation of long-terminal repeat retrotransposons throughout the evolution and degeneration of this chromosome. Finally, we identify a novel Y-linked putative transcription factor that is expressed constitutively through male development and adulthood, suggesting an important role throughout male development. ConclusionCollectively, these results and resources underscore the significance of previously hidden genomic elements in the biology of malaria mosquitoes and will accelerate development of genetic control strategies of malaria transmission.

genomics↗

bioRxiv2020

A near-chromosome level genome assembly of Anopheles stephensi

Malaria remains a major healthcare risk to growing economies like India and a chromosome-level reference genome of Anopheles stephensi is critical for successful vector management and an understanding of vector evolution. We report a chromosome-level assembly of an Indian strain from draft genomes of two strains using a homology-based iterative approach. The resulting assembly with an L50 of 9 had long enough scaffolds for building 90% of the three chromosomes using physical markers. The sequencing of individuals reveals a genetic diversity ten times higher than what is reported. Based on the developmental transcriptome and orthology of the 54 olfactory receptors (ORs) to those of other Anopheles species, we identify olfactory receptors with the potential for host recognition in the genus Anopheles. A comparative analysis of the genomes suggests limited inter-chromosomal gene flow and chromosomal arm switching with a potential role in adaptive radiation within the genus Anopheles.

genomics↗

bioRxiv2018

Nucl2Vec: Local alignment of DNA sequences using Distributed Vector Representation

The Next Generation Sequencing Technique (NGS) has provided affordable and fast method for generating genetic data. Generation of whole Genome Sequence and extract relevant information from this data is still a computationally expensive process. In this paper we demonstrate a novel approach for local alignment of DNA reads with respect to reference genome. For this process we have used Skip-gram model for creating encoding(Nucl2Vec) and k-nearest neighbor for the alignment. With our new approach we have reduced computation cost for local alignment, while achieving accuracy comparable to existing defacto standard BWA-MEM tool.\n\nIndex TermsGenome, Alignment, Local Alignment, k-nearest Neighbor, Distributed vector representation, Skip-gram

genomics↗