Biology subjects

Sinha, A.

Publications and source records attributed to Sinha, A..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Prophage induction contributes to alterations in the gut phageome during intestinal inflammation

Bacteriophages (phages) are abundant members of the gut microbiota and regulators of bacterial communities. During homeostasis, gut phage communities are longitudinally stable and lysogenic replication is dominant. In chronic gut inflammatory disorders, such as inflammatory bowel diseases (IBDs), there are alterations in phage diversity, which may result from changes in phage replication cycle dynamics. Here, we used a combination of in vitro, simplified community, and whole-community bioinformatics approaches to investigate whether prophage induction contributes to these alterations. We identified several compounds associated with gut inflammation that induced prophages in commensal gut bacterial isolates. Analysing data from two mouse models of colitis, we observed that shifts in the composition of temperate phages occur over the course of inflammation, supporting a switch from lysogenic to lytic replication. Collectively, our observations support the idea that prophage induction contributes to alterations in the phageome associated with inflammation.

microbiology↗

bioRxiv2024

The hyaluronan-binding activity of aggrecan is important, but not essential, for its specific insertion into perineuronal nets

Aggrecan (ACAN) is a large, secreted chondroitin sulfate proteoglycan that includes three globular regions named G1, G2, G3, and is decorated with multiple glycosaminoglycan attachments between its G2 and G3 domains. The N-terminal G1 region interacts with the glycosaminoglycan hyaluronan (HA), which is an essential component of the vertebrate extracellular matrix. In the central nervous system, ACAN is found in perineuronal nets (PNNs), honeycomb-like structures that are enriched on parvalbumin-positive neurons in specific neural circuits. PNNs regulate the plasticity of the central nervous system, and it is believed that association between ACAN and HA is a foundational event in the assembly of these reticular structures. Here, we report the co-crystal structure of the G1 region of ACAN in the absence and presence of an HA decasaccharide and analyze the importance of the HA-binding activity of ACAN for its integration into PNNs. We demonstrate that the single immunoglobulin domain and the two Link modules that comprise the G1 region form a single structural unit, and that HA is clamped inside a groove that spans the length of the tandem Link domains. Introduction of point mutations in the glycosaminoglycan-binding site eliminates HA-binding activity in ACAN, but, surprisingly, only decreases the integration of ACAN into PNNs. Thus, these results suggest that the HA-binding activity of ACAN is important for its recruitment to PNNs, but it does not appear to be essential.

biochemistry↗

bioRxiv2024

AZIN2-dependent polyamine metabolism determines adipocyte progenitor fate and protects against obesity and dysmetabolism

Adipose tissue homeostasis plays a critical role in metabolic disease but the metabolic circuitry regulating adipose tissue dynamics remains unclear. In this study, polyamine metabolism emerges as an important regulator of adipose tissue pathophysiology. We identify AZIN2 (Antizyme inhibitor 2), a protein promoting polyamine synthesis and acetylation, as a major regulator of total acetyl-CoA in adipocyte progenitors (APs). AZIN2 deficient APs demonstrate increased H3K27 acetylation marks in genes related to lipid metabolism, cell cycle arrest and cellular senescence, and enhanced adipogenesis compared to wild-type counterparts. Upon high-fat diet (HFD)-induced obesity, global AZIN2 deficiency in mice provokes adipose tissue hypertrophy, AP senescence, lipid storage perturbations, inflammation and insulin resistance. IL4 promotes Azin2 expression in APs but not mature adipocytes due to diminished IL4 receptor expression in the latter. In human visceral and subcutaneous adipose tissue, AZIN2 expression positively correlates with expression of early progenitor markers and genes associated with protection against insulin resistance, while it negatively correlates with markers of lipogenesis. In sum, AZIN2-driven polyamine metabolism preserves adipose tissue health, a finding that could be therapeutically harnessed for the management of obesity-associated metabolic disease.

cell biology↗

bioRxiv2024

Contactin-1 is a critical neuronal cell surface receptor for perineuronal net structure

Perineuronal nets (PNNs), are neuron-specific substructures within the neural extracellular matrix (ECM). These reticular structures form on a very small subset of neurons in the central nervous system (CNS) and yet have a profound impact in regulating neuronal development and physiology. PNNs are well-established as key regulators of plasticity in the CNS. Their appearance coincides with the developmental transition of the brain more to less plastic state. And, importantly, numerous studies have demonstrated that indeed PNNs play a primary role in regulating this transition. There is, however, a growing literature implicating PNNs in numerous roles in neural physiology beyond their role in regulating developmental plasticity. Accordingly, numerous studies have shown PNNs are altered in a variety of neurological and neuropsychiatric diseases, linking them to these conditions. Despite the growing interest in PNNs, the mechanisms by which they modulate neural functions are poorly understood. We believe the limited mechanistic understanding of PNNs is derived from the fact that there are limited models, tools or techniques that specifically target PNNs in a cell-autonomous manner and without also disrupting the surrounding neural ECM. These limitations are primarily due to our incomplete understanding of PNN composition and structure. In particular, there is little understanding of the neuronal cell surface receptors that nucleate these structures on subset of neurons on which they form in the CNS. Therefore, the main focus our work is to identify the neuronal cell surface proteins critical for PNN formation and structure. In our previous studies we demonstrated PNN components are immobilized on the neuronal surface by two distinct mechanisms, one dependent on the hyaluronan backbone of PNNs and the other mediated by a complex formed by receptor protein tyrosine phosphatase zeta (RPTP{zeta}) and tenascin-R (Tnr). Here we first demonstrate that the Tnr-RPTP{zeta} complex in PNNs is bound to the cell surface by a glycosylphosphatidylinositol (GPI)-linked receptor protein. Using a biochemical and structural approach we demonstrate the GPI-linked protein critical for binding the Tnr-RPTP{zeta} complex in PNNs is contactin-1 (Cntn1). We further show the binding of this complex in PNNs by Cntn1 is critical for PNN structure. We believe identification of CNTN1 as a key cell-surface protein for PNN structure is a very significant step forward in our understanding of PNN formation and structure and will offer new strategies and targets to manipulate PNNs and better understand their function.

neuroscience↗

bioRxiv2024

Cryo-electron microscopy reveals a single domain antibody with a unique binding epitope on fibroblast activation protein alpha

Fibroblast activation protein alpha (FAP) is a serine protease that is expressed at basal levels in benign tissues but is overexpressed in a variety of pathologies, including cancer. Despite this unique expression profile, designing effective diagnostic and therapeutic agents that effectively target this biomarker remain elusive. Here we report the structural characterization of the interaction between a novel single domain antibody (sdAbs), I3, and FAP using cryo-electron microscopy. The reconstructions were determined to a resolution of 2.7 [A] and contained two distinct populations; one I3 bound and two I3 molecules bound to the FAP dimer. In both cases, the sdAbs bound a unique epitope that was distinct from the active site of the enzyme. Furthermore, this report describes the rational mutation of specific residues within the complementarity determining region 3 (CDR3) loop to enhance affinity and selectivity of the I3 molecule for FAP. This report represents the first sdAb-FAP structure to be described in the literature.

biochemistry↗

bioRxiv2024

Improving gut virome comparisons using predicted phage host information

The human gut virome is predominantly made up of bacteriophages (phages), viruses that infect bacteria. Metagenomic studies have revealed that phages in the gut are highly individual specific and dynamic. These features make it challenging to perform meaningful cross-study comparisons. While several taxonomy frameworks exist to group phages and improve these comparisons, these strategies provide little insight into the potential effects phages have on their bacterial hosts. Here, we propose the use of predicted phage host families (PHFs) as a functionally relevant, higher rank unit of phage taxonomy to improve these cross-study analyses. We first show that bioinformatic predictions of phage hosts are accurate at the host family level by measuring their concordance to Hi-C sequencing-based predictions in human and mouse fecal samples. Next, using phage host family predictions, we determined that PHFs reduce intra- and interindividual ecological distances compared to viral contigs in a previously published cohort of 10 healthy individuals, while simultaneously improving longitudinal virome stability. Lastly, by reanalyzing a previously published metagenomics dataset with > 1,000 samples, we determined that PHFs are prevalent across individuals and can aid in the detection of inflammatory bowel disease-specific virome signatures. Overall, our analyses support the use of predicted phage hosts in reducing between-sample distances and providing a biologically relevant framework for making between-sample virome comparisons.

bioinformatics↗

bioRxiv2024

Cappable-Seq reveals the transcriptional landscape of stress responses in the bacterial endosymbiont Wolbachia

Bacterial endosymbionts are highly prevalent among invertebrate animals, in which they can confer fitness benefits such as pathogen defence and/or act as reproductive manipulators, inducing phenotypes including cytoplasmic incompatibility (CI). For the alpha-proteobacterium Wolbachia, its wide distribution among macroparasites and disease-transmitting arthropods coupled with mutualistic roles, reduction of vector competence, and CI have found recent applications in the control of several vector-borne tropical diseases. However, in common with other bacterial endosymbionts, which often lose regulatory elements during genomic erosion, the degree to which Wolbachia can respond to environmental or pharmacological stressors is poorly understood. Here, we apply Cappable-Seq methodology to achieve unprecedented depth and resolution of transcriptional start sites (TSS) in two Wolbachia strains (wMelPop-CLA and wAlbB) that have been used to transinfect mosquitoes for arbovirus control. We exposed Wolbachia in mosquito cell lines to temperature stress (both strains) or antibiotics (wAlbB only) and observed that all classes of TSS (including antisense) exhibited differential regulation, some of which were associated with mobile elements and may control ncRNA expression. Cappable-Seq also resolved the organisation of the bicistronic cifA/cifB operon that is responsible for inducing CI in Wolbachia hosts and shows great promise for revealing regulation of symbiont functions in whole invertebrates.

microbiology↗

bioRxiv2024

Endoglin regulates the integrity of the bone marrow vasculature

Endoglin (Eng) is an accessory receptor for transforming growth factor-{beta} (TGF-{beta}) that is critical for maintaining vascular integrity. Mutations in Eng cause hereditary hemorrhagic telangiectasia (HHT), resulting in arteriovenous malformations (AVMs) and blood abnormalities. Despite the known association between Eng deficiency and AVMs, the underlying mechanisms are unclear. In addition, the role of the bone marrow (BM), a major source of immune and blood cells, in endothelial Eng (EC-Eng) deficiency is unexplored. We show that BM blood vessels conditionally deficient in Eng (cKO) undergo a structured remodeling process over four weeks, with distinct proliferative and resolution phases. These phases involve angiogenic set points, the involvement of integrins, and the modulation of vascular integrity. In addition, we observe changes in hematopoietic stem and progenitor cells (HSPC) and circulating granulocytes, along with reduced red blood cells and platelets due to splenic sequestration. Using a conditional heterozygous EC-Eng deficient mouse model, reflecting the genetics of HHT patients, we identify vascular changes similar to those in the cKO model. Taken together, using multiple in vivo approaches, we suggest that reduced Eng expression in the endothelium drives significant BM vascular remodeling, sharing mechanisms with early vascular processes associated with AVM formation. Explanation of NoveltyOur findings reveal that BM blood vessels deficient in endoglin undergo an orchestrated remodeling process with distinct proliferative and resolution phases over several weeks. We identify specific angiogenic set points and profound alterations in vascular integrity, along with hematopoietic changes starting at the level of hematopoietic stem and progenitor cells. These findings advance our understanding of the role of Eng in vascular remodeling and may provide novel therapeutic targets for HHT. Key PointsO_LIConditional EC-Eng deficiency leads to vascular remodeling in the BM of mice in a temporally orchestrated manner. C_LIO_LIEC-Eng facilitates vascular integrity, hematopoietic homeostasis, and immune cell mobilization. C_LI

molecular biology↗

bioRxiv2024

Stretching the structural envelope of isomeric imatinib analogs that reduce β-amyloid production by modulating both β- and γ-secretase cleavages of APP

We previously showed that the anticancer drug imatinib mesylate (IMT, trade name: Gleevec) and a chemically distinct compound, DV2-103 (a kinase-inactive derivative of the potent Abl and Src kinase inhibitor, PD173955) lower A{beta} levels at low micromolar concentrations primarily through a lysosome-dependent mechanism that renders APP less susceptible to proteolysis by BACE1 without directly inhibiting BACE1 enzymatic activity, or broadly inhibiting the processing of other BACE1 substrates. Additionally, IMT indirectly inhibits {gamma}-secretase and stimulates autophagy, and thus may decrease A{beta} levels through multiple pathways. In two recent studies we demonstrated similar effects on APP metabolism caused by derivatives of IMT and DV2-103. In the present study we investigated how so many structurally diverse compounds affect APP metabolism in the same way, with similar potencies and production of APP metabolites. To this end, we synthesized and tested radically altered IMT regioisomers that possess medium structural similarity to IMT. Independent of structural similarity, these isomers manifest widely differing potencies in altering APP metabolism. These will enable us to choose the most potent isomers for further derivatization.

pharmacology and toxicology↗

bioRxiv2024

Loss of TDP-43 induces synaptic dysfunction that is rescued by UNC13A splice-switching ASOs

TDP-43 loss of function induces multiple splicing changes, including a cryptic exon in the amyotrophic lateral sclerosis and fronto-temporal lobar degeneration risk gene UNC13A, leading to nonsense-mediated decay of UNC13A transcripts and loss of protein. UNC13A is an active zone protein with an integral role in coordinating pre-synaptic function. Here, we show TDP-43 depletion induces a severe reduction in synaptic transmission, leading to an asynchronous pattern of network activity. We demonstrate that these deficits are largely driven by a single cryptic exon in UNC13A. Antisense oligonucleotides targeting the UNC13A cryptic exon robustly rescue UNC13A protein levels and restore normal synaptic function, providing a potential new therapeutic approach for ALS and other TDP-43-related disorders.

neuroscience↗

bioRxiv2024

Redox-driven control of Yuh1/UCHL3 impacts mitochondrial health via NEDD8/Rub1 pathway

The ubiquitin-like protein NEDD8/Rub1 undergoes processing by the enzyme Yuh1/UCHL3 to become functional. While the processed NEDD8/Rub1 modifies Cullin-RING E3 ligases (CRLs) among all studied organisms, its role in facilitating CRL-based substrate degradation is absent in S. cerevisiae. This prompts questions about NEDD8/Rub1 functionality if it does not activate CRLs universally. Previous studies revealed that increased production of reactive oxygen species (ROS) during the glycolysis to mitochondrial respiration transition inhibits cullin NEDDylation in S. cerevisiae, yet the specific affected enzymes remain unidentified. Here, we investigate how redox changes affect Yuh1 activity, revealing a thiol-based redox switch modulating its catalytic function in response to ROS. Temporal inactivation of Yuh1 fine-tunes NEDD8/Rub1 mature and precursor species, both crucial for maintaining mitochondrial integrity and enhancing oxidative stress resilience. These findings unveil a novel role for Rub1/NEDD8 beyond CRL activation, linking redox signaling to NEDD8/Rub1 pathways. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/594945v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1ce0c41org.highwire.dtl.DTLVardef@8690bdorg.highwire.dtl.DTLVardef@8898c6org.highwire.dtl.DTLVardef@1e61a85_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Centromeric localization of KNL2 and CENP-C proteins in plants depends on their centromere-targeting domain and DNA-binding regions

In eukaryotic organisms, proper chromosome segregation during cell division depends on the centromeric histone H3 (CENH3) variant. Our previous studies identified a plant CENH3 assembly factor, Kinetochore Null2 (KNL2), that possesses a centromere-targeting motif, CENPC-k, similar to the CENPC motif in CENP-C. Additionally, we have demonstrated that KNL2 can bind DNA in vitro, independent of its CENPC-k motif. Thus, the mechanism underlying the binding of KNL2 to centromeric DNA remains elusive. Our study shows that the CENPC-k and CENPC motifs alone are not sufficient to target the centromere in N. benthamiana and A. thaliana. In-silico analysis revealed flanking DNA-binding regions near the CENPC-k and CENPC motifs, suggesting their importance in interacting with centromeric DNA. Fusion of protein fragments containing these motifs to EYFP facilitated targeting to the centromere. Deletion of DNA-binding domains reduced the centromeric localization of KNL2-C, whereas fusion of CENPC-k to the H-NS protein from E. coli targeted it to centromeres. We conclude that targeting of KNL2 and CENP-C proteins to centromeres is dependent on the CENPC-k/CENPC motifs, and their sequence-independent DNA-binding promotes anchoring at the centromere. Understanding the targeting mechanisms of KNL2 and CENP-C may help to engineer kinetochore structure by targeting chromatin modifying proteins to centromeres.

plant biology↗

bioRxiv2024

Structure and Functions of Gesture Sequences in Wild Bonnet Macaques (Macaca radiata)

Compositionality, a hallmark of human language, involves generating novel meaning by combining existing units. Nonhuman primates (mostly apes) are known to combine gestural units in non-random ways, but they do not make novel meaning with these combinations. What could, however, be the functional roles of these gesture sequences and whether they bear any significance to language evolution is still unclear. Moreover, studies on gesture-sequences in non-ape primate species is almost non-existent. Here, we investigated for the first time, the structure and functions of gesture sequences in the naturally occurring communication of wild bonnet macaques (Macaca radiata), using analyses akin to ape gesture studies (Genty & Byrne, 2010; Hobaiter & Byrne, 2011). Bonnet macaque gesture sequences exhibit non-random combinations of gestures and non-gesture units - certain gestures are significantly more common in sequences, they associate preferentially with specific other components and certain components are more likely to appear either at the beginning or at the end of a sequence. Interplay of these sequences form distinct gestural clusters, corresponding to affiliative/play and agonistic contexts. Although, the overall functions of bonnet macaque gesture sequences remain obscure, as in apes, we found that gesture sequences were specifically used as a persistence strategy, after the initial single gestures have failed to initiate and sustain social interactions. We discuss our findings in the light of a possibility that primate gesture sequences, coordinating the flow of social interactions, may be evolutionary precursors to pragmatic gestures in human language.

animal behavior and cognition↗

bioRxiv2024

High-throughput nanopore DNA sequencing of large insert fosmid clones directly from bacterial colonies

Fosmids and cosmids are vectors frequently used in functional metagenomic studies. With a large insert capacity (around 30 kb) they can encode dozens of cloned genes or in some cases, entire biochemical pathways. Fosmids with cloned inserts can be transferred to heterologous hosts and propagated to enable screening for new enzymes and metabolites. After screening, fosmids from clones with an activity of interest must be de novo sequenced, a critical step towards identification of the gene(s) of interest. In this work, we present a new approach for rapid and high-throughput fosmid sequencing directly from Escherichia coli colonies without liquid culturing or fosmid purification. Our sample preparation involves fosmid amplification with phi29 polymerase and then direct nanopore sequencing using the Oxford Nanopore Technologies system. We also present a bioinformatics pipeline termed "phiXXer" that facilitates both de novo read assembly and vector trimming to generate a linear sequence of the fosmid insert. Finally, we demonstrate accurate sequencing of 96 fosmids in a single run and validate the method using two fosmid libraries that contain cloned large insert ([~]30-40 kb) genomic or metagenomic DNA. ImportanceLarge-insert clone (fosmids or cosmids) sequencing is challenging and arguably the most limiting step of functional metagenomic screening workflows. Our study establishes a new method for high-throughput nanopore sequencing of fosmid clones directly from lysed E. coli cells. It also describes a companion bioinformatic pipeline that enables de novo assembly of fosmid DNA insert sequences. The devised method widens the potential of functional metagenomic screening by providing a simple, high-throughput approach to fosmid clone sequencing that dramatically speeds the pace of discovery.

molecular biology↗

bioRxiv2024

Niche exclusion of a lung pathogen in mice with designed probiotic communities

For years, the airway microbiota have been theorized to be gatekeepers of respiratory health, as pathogens entering the airway make contact with resident microbes prior to or coincident with their interaction with host cells. Thus, modification of the native airway community may serve as a means of altering the local environment in favor of health. In this work, we hypothesize that synthetic bacterial communities introduced into the airway can serve as prophylactic countermeasures against infection by Burkholderia thailandensis in mice. We demonstrate that understanding of antagonistic interactions between a pathogen and airway microbiota in vitro can guide identification of probiotics with protective capabilities in vivo. Specifically, we show that niche overlap between the probiotic and pathogen is indicative of probiotic performance in vivo. This work serves as a foundation for the rational design of probiotic communities for protection against and treatment of respiratory infections.

microbiology↗

bioRxiv2024

A pipeline for facile cloning of antibody Fv domains and their expression, purification, and characterization as recombinant His-tagged IgGs

We report a functional pipeline for facile conversion of variable Fv domains, typically discovered in antibody discovery programs, into chimeric monoclonal antibodies (mAbs). Often, in initial screenings, a set of candidate mAbs is produced in small volumes and purified from supernatant for testing. Our pipeline also simplifies purification of mAbs by using an extended histidine tag (His-10) fused to the C-terminus of the light chain. Both the length of the His-10 and its location have been shown to affect the efficacy of mAb purification using an inexpensive nickel-based resin at neutral pH. Our antibody cloning and purification pipeline, when followed together with detection and affinity measurements, can be smoothly incorporated into an antibody discovery workflow.

immunology↗

bioRxiv2024

Elephants in a teacup: Ranging and Habitat-use of Asian elephants Elephas maximus in a Plantation Dominated Landscape in Southern Western Ghats, India

Ranging patterns of four focal herds using a plantation-forest matrix of the Valparai plateau was studied by following the individuals on a regular basis, recording all possible sightings, for five years. Although surrounded by a network of protected areas, the focal herds were found to use the plateau extensively. There was minimal spatial overlap observed between the four herds, except between two, PTH and MON, which showed a fairly large overlap of 130 sq.km. The observed ranges of elephants were smaller (119.71 {+/-} 24.11 sq.km) compared to previous studies on the species in India, but were comparable with those from Sri Lanka. Possible risk avoidance strategy is observed in their use of the landscape, as evidenced by the use of high intensity human activity areas mostly during night than day. Compared to previous studies from the same landscape, there is also an observed increase in the use of natural vegetation (in the form of rainforest fragments) than the plantation and monoculture habitats, indicating the importance of forest remnants for elephants on the plateau. The observations indicate importance of anthropogenic areas outside protected areas as potential habitats and, not just as movement pathways or as temporary refugia. Conservation planning should therefore consider such areas while initiating landscape-level management strategies for the species. The study also highlights the importance of longitudinal observation-based studies in ascertaining ranging, in the absence of logistically challenging techniques such as radio telemetry.

ecology↗

bioRxiv2023

Prognostic relevance of correlated co-expression of coding and noncoding RNAs in cervical cancers

Human papillomavirus (HPV) drives cervical cancer (CaCx) pathogenesis and viral oncoproteins jeopardize global gene expression in such cancers. We aimed to identify differentially expressed coding (DEcGs) and long noncoding (sense intronic and Natural Antisense Transcripts) RNA genes (DElncGs) in HPV16-positive CaCx patients (N=44) compared to HPV-negative normal individuals (N=34). Thereby, employing strand-specific RNA-seq, we determined the relationships between DEcGs and DElncGs and their clinical implications. Gene set enrichment and protein-protein interaction analyses of DEcGs revealed enrichment of processes crucial for abortive virus life cycle and cancer progression. The DEcGs formed 16 gene clusters, portraying cancer-related functions. We recorded significantly correlated co-expression of 79 DElncGs with DEcGs at proximal genomic loci, and 24 such pairs portrayed significantly altered correlation coefficients among patients, compared to normal individuals. Of these, 6 DEcGs belonged to 5 gene clusters, one of which was survival-associated. Out of the 24 correlated DEcG: DElncG pairs, 3 pairs were identified, where expression of both members was significantly associated with patient overall survival. Besides being prognostically relevant, disruption of the significant correlative relationships of such gene pairs in CaCx bears immense potential for patient-targeted therapy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/573593v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@19091c8org.highwire.dtl.DTLVardef@52fbeaorg.highwire.dtl.DTLVardef@18ecf3org.highwire.dtl.DTLVardef@6c5e30_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO A schematic representation of the analyses undertaken to draw insights on the biological relevance of joint analysis of co-expressed and significantly correlated DElncGs and DEcGs considering the ncNATs and sense intronic DElncGs, in HPV16-positive CaCx patients compared with HPV-negative normal individuals. C_FIG

cancer biology↗