Biology subjects

Soni, S.

Publications and source records attributed to Soni, S..

18 recordsLinked to original sources

bioRxiv2026

Mercury bioaccumulation varies across breeding-site height and life-history traits in Amazonian phytotelm-breeding frogs

Mercury (Hg) concentrations in the environment have significantly increased in the Amazon. Despite the observed deleterious effects on freshwater wildlife, the impacts of Hg contamination in phytotelmata (i.e., waterbodies contained in plant structures) and the species therein remain undocumented. We investigated the effects of Hg contamination on a phytotelm-breeding frog community in an otherwise pristine rainforest in French Guiana. Total Hg concentrations were measured in 28 pools at different heights (i.e. ground to canopy), and in the bodies of 103 tadpoles from five species with contrasting life histories. Tadpoles from ground pools had higher Hg concentrations than those from arboreal pools, revealing a vertical gradient in Hg contamination; tadpoles from species with slow development and parental care (i.e., tadpole transport) exhibited higher Hg concentrations than those of species with fast development without parental care. Finally, although Hg burdens were not associated with oxidative DNA levels, individuals reaching metamorphosis exhibited lower DNA damage than early-stage tadpoles, possibly reflecting reduced oxidative damage resulting from cellular remodelling undergone during metamorphosis, or selective mortality processes. Our findings highlight the joint influence of habitat type and life-history traits on Hg accumulation and that, even in pristine forests, Hg exposure varies strongly across microhabitats and species.

ecology↗

bioRxiv2026

Combinatorial Control of Corticospinal Axon Growth by Retinoic Acid Receptors

Regeneration of central nervous system (CNS) axons depends on Transcription Factors (TFs) that reactivate developmental growth programs, yet most such factors remain unknown. By intersecting developmental chromatin binding with pro-growth gene networks, we identified two retinoic acid receptor transcription factors, RARA and RARG, whose occupancy at growth-associated genes is progressively lost as neurons mature. Restoring both factors together increased neurite outgrowth beyond either alone in two independent systems, the Neuro-2a cell line and primary cortical neurons. In vivo, the same combination drove cross-midline sprouting after pyramidotomy and long-tract regeneration after thoracic spinal cord crush, with concordant recovery of hindlimb gait and grip strength. Interestingly, neither receptor alone was sufficient, hinting at combinatorial regulation. Single-nucleus transcriptomics delineated that only the combination reactivated relevant cytoskeletal and gene-expression programs, while genome-wide binding maps showed that RARA and RARG partition the regulatory landscape, with RARG dominating promoters and RARA occupying distal enhancers, so that neither receptor reconstitutes the developmental growth state alone. Intriguingly, this cooperative requirement was specific to the CNS: in peripheral sensory neurons, RARG alone was sufficient and RARA was dispensable. These data identify RARA and RARG as novel cooperative regulators of regenerative axon growth in mammalian CNS and PNS neurons and potential targets for therapeutic intervention.

neuroscience↗

bioRxiv2026

Cellular protein delivery through membrane potential driven water pores

Providing immediate access for functional proteins inside living cells would unlock unprecedented control over cellular processes; however, commonly used endocytic delivery suffers from endosomal trapping and degradation. One of the most powerful non-endosomal delivery methods uses cell surface anchored cell penetrating peptide (CPP)-additives that allow proteins to enter cells directly. Nevertheless, the underlying molecular mechanism involved in direct entry via crossing the cell membrane (protein translocation through the cell) and the major driving forces remain controversially discussed. Here, we provide a stepwise molecular picture on how CPP-additives enable uptake of protein cargoes through direct membrane translocation. CPP-additives accumulate on the cell surface in nucleation zones, locally hyperpolarizing the membrane, and induce transient water pores that allow selective CPP-protein entry without compromising membrane integrity. These fundamental mechanistic insights provide a firm basis for rationally optimizing delivery strategies using highly cationic CPPs, ultimately resulting in innovative and smart protein delivery strategies to advance therapeutic protein applications. Abstract Figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/707441v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@14c1386org.highwire.dtl.DTLVardef@195f765org.highwire.dtl.DTLVardef@a52258org.highwire.dtl.DTLVardef@171dd7c_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

Privacy-Preserving Pangenome Graphs

The human pangenome reference, often represented as a graph, promises to capture genetic diversity across populations, but open release of individual haplotypes raises significant privacy concerns, including risks of re-identification and inference of sensitive traits. To address these challenges, we introduce PanMixer, a framework for privacy-preserving pangenome graph releases that selectively obfuscates an individuals haplotypes while retaining the utility of the reference graph. PanMixer formulates the privacy-utility trade-off as a knapsack problem, where privacy risk is quantified using information theory and utility is measured using graph properties. Using the recently released draft human pangenome containing 47 individuals, we show that PanMixer robustly reduces re-identification risk under linkage attacks and genome reconstruction attempts. We also show that PanMixer preserves the accuracy of key downstream applications, including allele frequency estimation, linkage disequilibrium analysis, and read mapping. By addressing privacy concerns, PanMixer enables the inclusion of individuals, particularly those from underrepresented populations, who might otherwise be reluctant to contribute but seek representation in future genomic studies. Our results provide both a practical tool and a generalizable framework for balancing privacy and utility in future large-scale pangenome references.

bioinformatics↗

bioRxiv2026

Severity-dependent proteomic alterations in the rat hippocampus following pilocarpine-induced status epilepticus

Status epilepticus (SE) is a prolonged seizure state that can induce lasting hippocampal damage and promote the development of spontaneous seizures and cognitive deficits. The severity and duration of SE strongly influence these long-term outcomes; however, many experimental studies rely on behavioral assessments such as the Racine scale, which may not capture subclinical or non-convulsive seizure activity. Consequently, the molecular consequences of lower-severity seizures that do not meet conventional criteria for severe SE, but may nonetheless contribute to epileptogenesis, remain poorly understood. To address this gap, we investigated whether behavioral seizure severity in the pilocarpine model correlates with distinct proteomic alterations in the hippocampus. Seizures were induced in adult male rats using pilocarpine, and animals were behaviorally classified into three groups: control, mild SE, and severe SE. Hippocampal tissue was collected from control (n = 3), mild SE (n = 5), and severe SE (n = 6) rats and subjected to mass spectrometry-based proteomic analysis. Proteomic profiles were analyzed using partial least squares discriminant analysis (PLS-DA), and differentially expressed proteins (DEPs) were identified using volcano plots. Functional enrichment analyses were performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway databases. Our findings revealed distinct hippocampal proteomic signatures across control, mild SE, and severe SE groups, as revealed by PLS-DA. Severe SE was associated with widespread proteomic alterations, including 129 DEPs linked to synaptic structure, RNA regulation, and metabolic processes. In contrast, mild SE was associated with fewer changes (81 DEPs), primarily involving synaptic organization and endocytosis. A direct comparison of the severe and mild SE groups identified 76 DEPs enriched in pathways related to synaptic plasticity and neurodegeneration. Notably, 23 proteins showed a stepwise expression pattern across groups, suggesting a molecular gradient correlated with seizure severity. Correlation analyses identified and further confirmed glial and inflammatory molecules as candidate molecular markers associated with seizure burden. In conclusion, behavioral seizure severity in the pilocarpine model corresponds to distinct hippocampal proteomic profiles, with severe SE inducing broader and more pronounced molecular alterations than mild SE. Importantly, lower-severity SE is associated with biologically meaningful changes in pathways related to synaptic organization and cellular processing, highlighting mechanistic differences between mild and severe SE that may contribute to epileptogenic progression.

neuroscience↗

bioRxiv2025

Deep Neurite Analysis Tool (DeNAT): A machine-learning framework for precise automated neurite outgrowth measurement

Accurate quantification of neurite sprouting after injury is a critical step in axon regeneration research. Yet it remains a major bottleneck, as the current gold standard relies on manual counting by multiple blinded observers. This process is slow, labor-intensive, and prone to variability. While some software can measure total neurite length, they arent made to specifically measure new growth in complicated images from real-life injury models, like the thoracic crush and pyramidotomy model. Existing software can measure total neurite length in culture, but it is not designed to capture new growth in complex images from injury models, such as thoracic crush or pyramidotomy. Crucially, these tools lack the ability to selectively analyze growth within user-defined regions, a key requirement for injury paradigms. To address this need, we developed the Deep Neurite Analysis Tool (DeNAT), an accessible deep-learning-based platform that automatically measures neurite outgrowth after injury. DeNAT allows users to define regions of interest to specifically quantify sprouting in images from common spinal cord injury paradigms. We benchmarked its performance against manual scoring and conventional automated approaches. DeNAT achieved 87 percent accuracy in detecting neurite sprouts relative to manual counts, while reducing variability and labor. By combining user-guided region selection with automated deep learning analysis, DeNAT offers an accurate, reproducible, and efficient solution for measuring neurite outgrowth in injury models.

bioinformatics↗

bioRxiv2025

Nuclear Receptor Transcription factors promote axon regeneration in the Adult Corticospinal Tract

Transcription factors are potent levers for neural repair, but which factors govern regenerative capacity in the corticospinal tract remains largely unknown. By intersecting developmental RNA-seq with ATAC-seq footprinting, we identified two nuclear-receptor transcription factors, NR2F1 and NR2F6, neither previously linked to CNS axon growth, whose chromatin occupancy at pro-growth enhancers is progressively lost as neurons mature. Forced expression of either factor significantly increased neurite outgrowth in single-neuron tracing assays, and each drove strong cross-midline sprouting after pyramidotomy and long-tract CST regeneration after complete thoracic crush, with concordant recovery of hip-rise kinematics and grip strength. Parallel multi-omic profiling (CUT&RUN, snRNA-seq and Ribo-seq) of both factors together with NR2F6 Hi-C revealed distinct mechanisms: NR2F1 reactivated chromatin-remodeling and cytoskeletal programs, whereas NR2F6, via a conserved corepressor domain, re-occupied developmental enhancers, reorganized three-dimensional chromatin architecture into new topologically associating domains, and imposed a transient translational down-shift in which growth-relevant modules were selectively preserved through translational buffering. Together, these data identify NR2F nuclear receptors as regulators of corticospinal regeneration, acting through enhancer redeployment, translational reprogramming and three-dimensional genome reorganization.

neuroscience↗

bioRxiv2025

Drug tolerant persisters and immunotherapy persister cells exhibit cross-resistance and share common survival mechanisms

Persisters are a rare sub-population of tumor cells that survive anti-cancer therapy and are thought to be a major cause of recurrence. These cells have been identified following both drug- and immune-therapy but are generally considered to be distinct entities. Since both pharmacological agents and immune cells often kill via apoptosis, we tested a hypothesis that both types of cells survive based on reduced mitochondrial apoptotic sensitivity, which in turn would yield a similar and reciprocal multi-agent resistant phenotype. Supporting this hypothesis, we indeed observed that IPCs acquired a reduced sensitivity to multiple drug classes and radiotherapy, suggesting non-immune mechanisms are important in the survival of cancer cells after immunotherapy. Likewise, DTPs developed not only a reduced sensitivity to multiple drug classes and radiotherapy, but also acquired a reduced sensitivity to T cell killing. Both IPCs and DTPs developed a decreased sensitivity to mitochondrial apoptosis. A sub-population of IPCs downregulated antigen and upregulated PD-L1. Intriguingly, in the IPCs that didnt employ these mechanisms of resistance, a greater decrease in sensitivity to mitochondrial apoptosis was observed, suggesting that the presence or absence of a resistance mechanism can exert selective pressures over the emergence of others. Targeting anti-apoptotic dependencies in persisters increased sensitivity to chemotherapy or CAR T therapy. These results suggest that common biological mechanisms underly survival of persisters, whether derived from immune or drug therapy, and offer an explanation for the acquired cross-resistance to these two types of therapies often observed in the clinic. HighlightsO_LIImmunotherapy persister cells (IPCs) are less sensitive to drugs and radiation. C_LIO_LIDrug tolerant persisters (DTPs) are less sensitive to radiation and CAR T cell attack. C_LIO_LIIPCs and DTPs are less sensitive to mitochondrial apoptosis. C_LIO_LITargeting anti-apoptotic dependencies helps eliminate IPCs/DTPs. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/641492v2_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@fe98b4org.highwire.dtl.DTLVardef@db7bfdorg.highwire.dtl.DTLVardef@1a94469org.highwire.dtl.DTLVardef@1ca6b2c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Reduced methane emissions in transgenic rice genotypes are associated with altered rhizosphere microbial hydrogen cycling

Rice paddies contribute substantially to atmospheric methane (CH4) and these emissions are expected to increase as the need to feed the human population grows. Here, we show that two independent rice genotypes overexpressing genes for PLANT PEPTIDES CONTAINING SULFATED TYROSINE (PSY) reduced cumulative CH4 emissions by 38% (PSY1) and 58% (PSY2) over the growth period compared with controls. Genome-resolved metatranscriptomic data from rhizosphere soils reveal lower ratios of gene activities for CH4 production versus consumption, decrease in activity of H2-producing genes, and increase in bacterial H2 oxidation pathways in the PSY genotypes. Metabolic modeling using metagenomic and metabolomic data predicts elevated levels of H2 oxidation and suppressed H2 production in the PSY rhizosphere. The H2-oxidizing bacteria have more genes for utilization of gluconeogenic acids than H2-producing counterparts, and their activities were likely stimulated by the observed enrichment of gluconeogenic acids (mostly amino acids) in PSY root exudates. Together these results suggest that decreased CH4 emission is due to the reduction of H2 available for hydrogenotrophic methanogenesis. The combination of rice phenotypic characterization, microbiome multi-omic analysis, and metabolic modeling described here provides a powerful strategy to discover the mechanisms by which specific plant genotypes can alter biogeochemical cycles to reduce CH4 emissions.

microbiology↗

bioRxiv2024

Potential Benefits of Ketone Therapy as a Novel Immunometabolic Treatment for Schizophrenia

RationaleCurrent treatment options for patients with schizophrenia-spectrum disorders (SSD) remain unsatisfactory, leaving patients with persistent negative and cognitive symptoms and metabolic side effects. Therapeutic ketosis was recently hypothesized to target the bio-energetic pathophysiology of SSD. However, neuro-inflammation plays an important role in the pathobiology of SSD as well. Ideally, novel treatments would target both the bio-energetic, and the inflammatory aspects of SSD. In this study, we aimed to investigate the effects of ketone bodies on neuro-inflammation in an acute inflammation mouse model. Methods8-week-old male C57BL/6 N mice (n=11) were treated with either ketone ester (KE) or vehicle for 3 days. On day 3, a single intraperitoneal injection of lipopolysaccharide (LPS) or phosphate buffered saline (PBS) was administered. Mice were euthanized 24 h after LPS/PBS injection. Whole brain gene expression analysis using RT-PCR was done for Tnf-a, Il-6 and Il-1b. ResultsLPS caused a potent transcriptional upregulation of Tnf-a, Il-6 and Il-1b in the vehicle-treated mouse brain compared to PBS-injected controls. KE strongly and significantly attenuated the increased transcription of pro-inflammatory cytokines (Tnf-a, Il-6 and Il-1b) in the brain upon LPS injection compared to vehicle. ConclusionsKE potently dampened neuro-inflammation in this acute inflammation mouse model. Ketone therapy holds great promise as a treatment for SSD patients by simultaneously targeting two main pathophysiological disease pathways. We encourage more research into the immunometabolic potential of therapeutic ketosis in SSD. HighlightsO_LIA brain bio-energetic deficit and neuro-inflammation are involved in schizophrenia C_LIO_LIKetone therapy is being investigated as a bio-energetic treatment of schizophrenia C_LIO_LIKetone ester inhibits neuro-inflammation in an acute inflammation mouse mode C_LIO_LITherapeutic ketosis could target both pathophysiological pathways in SSD C_LIO_LIThe Immunometabolic potential of ketone therapy for SSD warrants further attention C_LI

neuroscience↗

bioRxiv2024

Targeting circadian transcriptional programs in triple negative breast cancer through a cis-regulatory mechanism

Circadian clock genes are emerging targets in many types of cancer, but their mechanistic contributions to tumor progression are still largely unknown. This makes it challenging to stratify patient populations and develop corresponding treatments. In this work, we show that in breast cancer, the disrupted expression of circadian genes has the potential to serve as biomarkers. We also show that the master circadian transcription factors (TFs) BMAL1 and CLOCK are required for the proliferation of metastatic mesenchymal stem-like (mMSL) triple-negative breast cancer (TNBC) cells. Using currently available small molecule modulators, we found that a stabilizer of cryptochrome 2 (CRY2), the direct repressor of BMAL1 and CLOCK transcriptional activity, synergizes with inhibitors of proteasome, which is required for BMAL1 and CLOCK function, to repress a transcriptional program comprising circadian cycling genes in mMSL TNBC cells. Omics analyses on drug-treated cells implied that this repression of transcription is mediated by the transcription factor binding sites (TFBSs) features in the cis-regulatory elements (CRE) of clock-controlled genes. Through a massive parallel reporter assay, we defined a set of CRE features that are potentially repressed by the specific drug combination. The identification of cis-element enrichment might serve as a new concept of defining and targeting tumor types through the modulation of cis-regulatory programs, and ultimately provide a new paradigm of therapy design for cancer types with unclear drivers like TNBC.

cancer biology↗

bioRxiv2023

Neuronal connectivity, behavioral, and transcriptional alterations associated with the loss of MARK2

Neuronal connectivity is essential for adaptive brain responses and can be modulated by dendritic spine plasticity and the intrinsic excitability of individual neurons. Dysregulation of these processes can lead to aberrant neuronal activity, which has been associated with numerous neurological disorders including autism, epilepsy, and Alzheimers disease. Nonetheless, the molecular mechanisms underlying aberrant neuronal connectivity remains unclear. We previously found that the serine/threonine kinase Microtubule Affinity Regulating Kinase 2 (MARK2), also known as Partitioning Defective 1b (Par1b), is important for the formation of dendritic spines in vitro. However, despite its genetic association with several neurological disorders, the in vivo impact of MARK2 on neuronal connectivity and cognitive functions remains unclear. Here, we demonstrate that loss of MARK2 in vivo results in changes to dendritic spine morphology, which in turn leads to a decrease in excitatory synaptic transmission. Additionally, loss of MARK2 produces substantial impairments in learning and memory, anxiety, and social behavior. Notably, MARK2 deficiency results in heightened seizure susceptibility. Consistent with this observation, RNAseq analysis reveals transcriptional changes in genes regulating synaptic transmission and ion homeostasis. These findings underscore the in vivo role of MARK2 in governing synaptic connectivity, cognitive functions, and seizure susceptibility.

neuroscience↗

bioRxiv2023

Prolonged exposure to lung-derived cytokines is associated with inflammatory activation of microglia in patients with COVID-19

Neurological impairment is the most common finding in patients with post-acute sequelae of COVID-19. Furthermore, survivors of pneumonia from any cause have an elevated risk of dementia1-4. Dysfunction in microglia, the primary immune cell in the brain, has been linked to cognitive impairment in murine models of dementia and in humans5. Here, we report a transcriptional response in human microglia collected from patients who died following COVID-19 suggestive of their activation by TNF-[a] and other circulating pro-inflammatory cytokines. Consistent with these findings, the levels of 55 alveolar and plasma cytokines were elevated in a cohort of 341 patients with respiratory failure, including 93 unvaccinated patients with COVID-19 and 203 patients with other causes of pneumonia. While peak levels of pro-inflammatory cytokines were similar in patients with pneumonia irrespective of etiology, cumulative cytokine exposure was higher in patients with COVID-19. Corticosteroid treatment, which has been shown to be beneficial in patients with COVID-196, was associated with lower levels of CXCL10, CCL8, and CCL2--molecules that sustain inflammatory circuits between alveolar macrophages harboring SARS-CoV-2 and activated T cells7. These findings suggest that corticosteroids may break this cycle and decrease systemic exposure to lung-derived cytokines and inflammatory activation of microglia in patients with COVID-19.

immunology↗

bioRxiv2021

ZRC3308 monoclonal antibody cocktail shows protective efficacy in Syrian hamsters against SARS-CoV-2 infection

We have developed a monoclonal antibody (mAb) cocktail (ZRC-3308) comprising of ZRC3308-A7 and ZRC3308-B10 in the ratio 1:1 for COVID-19 treatment. The mAbs were designed to have reduced immune effector functions and increased circulation half-life. mAbs showed good binding affinities to non-competing epitopes on RBD of SARS-CoV-2 spike protein and were found neutralizing SARS-CoV-2 variants B.1, B.1.1.7, B.1.351, B.1.617.2 and B.1.617.2 AY.1 in vitro. The mAb cocktail demonstrated effective prophylactic and therapeutic activity against SARS-CoV-2 infection in Syrian hamsters. The antibody cocktail appears to be a promising candidate for the prophylactic use and for therapy in early COVID-19 cases which have not progressed to severe disease.

microbiology↗

bioRxiv2021

Evaluation of efficacy of carfentrazone + metsulfuron, sulfosulfuron + metsulfuron and halauxifen against Rumex spp. in wheat (Triticum aestivum) in Western Haryana

Rumex spp. is most dominating broad-leaf weed of wheat crop. Complaints of poor efficacy of different herbicides against Rumex spp. have reported recently from different locations of Haryana state. Therefore, the present study was carried out under completely randomised design, replicated thrice, using three different herbicides namely carfentrazone + metsulfuron, sulfosulfuron + metsulfuron and halauxifen as treatments applied with three doses against four populations of Rumex spp. Plant height, chlorophyll fluorescence, electrical conductivity, mortality percentage and dry weight were recorded as observations. Results indicated that most of the Rumex biotypes were found resistant against sulfosulfuron + metsulfuron application. Majority of biotypes were moderately controlled by the application of halauxifen. Carfentrazone + metsulfuron effectively controlled the Rumex spp. and provided 70-90 % control to all biotypes at double of the recommended dose. As per results of this study, carfentrazone + metsulfuron can be recommended for control of Rumex spp. in wheat.

plant biology↗

bioRxiv2021

REPROGRAMMING CBX8-PRC1 FUNCTION WITH A POSITIVE ALLOSTERIC MODULATOR

ABSTRACTCanonical targeting of Polycomb Repressive Complex 1 (PRC1) to repress developmental genes is mediated by cell type-specific, paralogous chromobox (CBX) proteins (CBX2, 4, 6, 7 and 8). Based on their central role in silencing and their misregulation associated with human disease including cancer, CBX proteins are attractive targets for small molecule chemical probe development. Here, we have used a quantitative and target-specific cellular assay to discover a potent positive allosteric modulator (PAM) of CBX8. The PAM activity of UNC7040 antagonizes H3K27me3 binding by CBX8 while increasing interactions with nucleic acids and participation in variant PRC1. We show that treatment with UNC7040 leads to efficient PRC1 chromatin eviction, loss of silencing and reduced proliferation across different cancer cell lines. Our discovery and characterization of UNC7040 not only revealed the most cellularly potent CBX8-specific chemical probe to date, but also corroborates a mechanism of polycomb regulation by non-histone lysine methylated interaction partners.

synthetic biology↗

bioRxiv2020

Transcriptome profiling-based evidences reiterate the intrinsic role of MAPKAPK2 in facilitating molecular crosstalk during HNSCC pathogenesis

BackgroundTranscriptome profiling has been pivotal in better comprehending the convoluted biology of tumors including head and neck squamous cell carcinoma (HNSCC). Recently, growing evidence has implicated the role of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK2 or MK2) in many human diseases including tumors. MK2 has been recently reported as a critical regulator of HNSCC that functions via modulating the transcript turnover of crucial genes involved in its pathogenesis. Comprehensive MK2-centric transcriptomic analyses could help the scientific community to delve deeper into MK2-pathway driven mechanisms of tumor progression, but such studies have not yet been reported. Consequently, to delineate the biological relevance of MK2 and its intricate crosstalk in the tumor milieu, an extensive transcriptome analysis of HNSCC was conceptualized and effectuated with MK2 at the nexus. MethodsIn the current study, comprehensive next-generation sequencing-based transcriptome profiling was accomplished to ascertain global patterns of mRNA expression profiles in both in vitro and in vivo models of the HNSCC microenvironment. The findings of the RNA-sequencing analysis were cross-validated via robust validation using nCounter gene expression assays, immunohistochemistry, and real-time quantitative polymerase chain reaction (RT-qPCR). ResultsTranscriptomic characterization followed by annotation and differential gene expression analyses identified certain MK2-regulated candidate genes constitutively involved in regulating HNSCC pathogenesis, and the biological significance of these genes was established by pathway enrichment analysis. Additionally, advanced gene expression assays through the nCounter system in conjunction with immunohistochemical analysis validated the transcriptome profiling outcomes quite robustly. Furthermore, the results obtained from immunohistochemistry and transcript stability analysis indicated the crucial role of MK2 in the modulation of the expression pattern of these genes in HNSCC tumors and cells. ConclusionsConclusively, the findings have paved the way toward the identification of new effective tumor markers and potential molecular targets for HNSCC management. The results have accentuated the importance of certain differentially expressed MK2-regulated genes that are constitutively involved in HNSCC pathogenesis to potentially serve as putative candidates for future endeavors pertaining to diagnosis and therapeutic interventions for HNSCC.

cancer biology↗

bioRxiv2018

Anti-V2 Antibody Deficiency in Individuals Infected With HIV-1

The positive correlation of high levels of plasma anti-V2 antibodies (Abs) with protective immunity in the Phase III anti-HIV RV144 vaccine trial generated interest in the induction of these Abs for HIV vaccine development. We analyzed plasma samples from 79 chronically infected Cameroonian individuals for Ab reactivity against three V1V2 fusion proteins and five cyclic V2 peptides and found that HIV-1 infection induces different levels of anti-V2 Abs. While the majority of plasma samples reacted strongly with one or more V2 antigens, 10% (8) of the samples were nonreactive. Deficiency of anti-V2 Abs was consistently found in longitudinal plasma samples tested over 8 to 54 months of HIV infection. There was a strong correlation between binding activities of plasma anti-V2 Abs and anti-gp120 and anti-gp41 Abs, suggesting that deficiency of V2 Abs could be related, in part, to a limited ability to elicit strong Ab responses. Analysis of gp120 sequences revealed that the V2 region of viruses from donors with V2-deficient versus V2-reactive Abs displayed a tendency toward longer length, more glycans, and lower isoelectric point and charge. No differences between these two patient groups were noted in the same parameters measured in the V1 region. These data suggest that immunogens containing a shorter V2 region with fewer glycosylation sites and higher electrostatic charges would be beneficial for induction of anti-V2 Abs, but the ability to mount a strong general Ab response to HIV-1 appears to be a dominant factor.\n\nIMPORTANCEThe results of the RV144 vaccine clinical trial showed a correlation between plasma Abs against a V1V2 fusion protein and a decreased risk of acquiring HIV-1 infection. This turned the focus of some HIV vaccine design to the induction of elevated levels of anti-V2 Abs to increase vaccine efficacy. In plasma samples from Cameroonian individuals infected with HIV-1, we observed broad variations in levels of anti-V2 Abs, and 8 of the 79 plasma samples tested displayed substantial deficiency of V2 Abs. Sequence analysis of the V2 region from plasma viruses and multivariate analyses of V2 characteristics showed a significant difference in several features between V2-deficient and V2-reactive plasma Abs. These results suggest that HIV vaccine immunogens containing a V2 region with shorter length, fewer glycosylation sites, and higher electrostatic charges may be beneficial for induction of a higher level of anti-V2 Abs and thus contribute to HIV vaccine efficacy.

immunology↗