Biology subjects

Johnson, W. E.

Publications and source records attributed to Johnson, W. E..

At least 19 recordsLinked to original sources

bioRxiv2026

Serum nutritional-metabolic recovery during tuberculosis treatment across BMI-defined undernutrition strata: A longitudinal proteomic reanalysis

Background Tuberculosis remains the leading cause of death from a single infectious agent, and undernutrition is a major modifiable risk factor. Serum proteomics can capture systemic host recovery during therapy, but whether baseline BMI-defined undernutrition alters this trajectory is unclear. Methods We reanalysed processed longitudinal tandem-mass-tag serum proteomics from 30 adults with pulmonary tuberculosis and durable cure sampled at baseline and weeks 8, 17, 26 and 52. Thirteen participants had baseline BMI <18.5 kg/m2 and 17 had BMI >=18.5 kg/m2. Protein-level analyses evaluated baseline differences and week-specific within-participant change; module and recovery-axis models evaluated BMI-by-time interactions, with random-intercept mixed models added as a repeated-measures sensitivity analysis. Three complementary treatment-responsive modules were integrated into an exploratory, nonredundant 36-protein nutritional-metabolic summary axis. Results The reconstructed dataset contained 1,923 quantified features across 150 participant-visits. Inflammatory/acute-phase and metal-handling/nutritional-immunity module scores declined during follow-up, whereas lipid/apolipoprotein-transport, nutritional-carrier and endocrine-immunometabolic scores increased. In the primary week-specific paired-change analyses, no protein-level between-BMI difference in longitudinal change survived false-discovery-rate correction; no curated-module BMI-by-time interaction survived correction. The 36-protein summary axis increased in both BMI strata from week 17 onward. In a random-intercept model without interaction, the BMI <18.5 kg/m2 stratum had a lower average axis score across visits than the BMI >=18.5 kg/m2 comparison stratum, although the confidence interval included zero (difference -1.34, 95% CI -2.76 to 0.08; p = .064). Categorical and continuous BMI-by-time interaction tests did not detect differential axis trajectories. Conclusions Tuberculosis treatment was accompanied by broad longitudinal remodelling of circulating inflammatory and nutritional-metabolic protein systems. An exploratory 36-protein summary axis increased in both baseline BMI strata, while formal interaction tests did not detect BMI-dependent trajectories and remained too imprecise to establish equivalence. BMI should be regarded as an anthropometric proxy rather than a comprehensive measure of nutritional state. The defined axis provides a framework for prospective validation alongside direct measures of body composition, micronutrients, treatment exposure and clinical outcomes.

bioinformatics↗

bioRxiv2026

Distinct transcriptional remodeling of immune and metabolic pathways in severe undernutrition during latent tuberculosis infection does not consistently predict tuberculosis progression across independent cohorts

Background: Undernutrition increases tuberculosis (TB) risk, but whether severe undernutrition during latent TB infection (LTBI) produces blood transcriptional changes that resemble active disease or identify future TB remains unclear. Methods: We reanalyzed whole-blood RNA sequencing from adults with LTBI in GSE152218, comparing severe undernutrition (BMI <16 kg/m2; n=16) with adequate nutrition (BMI >=18.5 kg/m2; n=11). Genes and Reactome pathways were evaluated. A seven-module summary was compared with active TB among severely undernourished adults and tested prospectively in GSE79362 and GC6-74/GSE94438 after pathway-representation assessment. Results: No genes reached FDR <0.05 in the primary model; two did only in sensitivity analysis. In contrast, 241 Reactome pathways were significant and directionally concordant in both models (NES rho=0.954), including complement/Fc-receptor, B-cell, phospholipid/phagocytosis, neutrophil, vascular, autophagy, and cytokine-signaling pathways. Most changed opposite to the active-TB comparison (178/241; pathway rho=-0.390). The seven-module score was unrelated to baseline progression in GSE79362 (adjusted OR per SD=1.090; P=0.6922). In GC6, four modules met the prespecified representation criterion; their baseline score was inversely associated with progression (adjusted OR per SD=0.711; P=0.0218), but secondary and longitudinal analyses were non-confirmatory. Conclusions: Severe undernutrition during LTBI is associated with reproducible immune- and metabolism-related transcriptional remodeling that differs from active-TB biology and does not consistently identify future TB progression.

molecular biology↗

bioRxiv2026

ComBatFamQC: Streamlining Interactive Batch-Effect Diagnostics and Harmonization for Neuroimaging Data in R

As multisite and multi-study data aggregation becomes increasingly common for improving statistical power and sample diversity, robust harmonization methods are needed to address biases introduced by batch variation, particularly in neuroimaging research. Although a variety of harmonization approaches are available, the lack of systematic guidance for diagnosing batch effects and selecting appropriate methods remains a major challenge. To address this gap, we introduce ComBatFamQC, a comprehensive R package designed to streamline batch-effect diagnosis, harmonization, and post-harmonization analysis. ComBatFamQC integrates a user-friendly Shiny app for interactive batch-effect diagnostics, state-of-the-art harmonization methods from the ComBat family, including ComBat, longitudinal ComBat, ComBat-GAM, and CovBat, and tools for downstream analysis after harmonization. The package provides qualitative visualizations, statistical tests for batch-effect assessment, and a consistent interface that supports both in-sample and out-of-sample harmonization through the Shiny app, the R console, or the command line. In addition, it includes functions for post-harmonization analyses to facilitate downstream modeling. Its modular design also supports the systematic incorporation of future harmonization methods and expanded downstream analysis capabilities.

bioinformatics↗

bioRxiv2026

Impacts of batch effects on the performance of machine learning classifiers across multiple studies

Precision medicine relies on accurate and generalizable predictions for patients across the spectrum of human diversity. Because capturing biological heterogeneity requires large sample sizes, researchers must often aggregate data from several experimental batches or independent studies. This integration allows for greater statistical power and diversity than a single study could provide, while avoiding the costs of generating massive new -omics datasets. Predictive models trained on these aggregated data are theoretically better equipped to detect subtle patterns that generalize to new data. However, this potential is frequently undermined by "batch effects"--systematic technical artifacts that can bias model training to predict experimental batches and shadow meaningful biological conditions. Models trained on data with batch effects can exhibit substantially degraded performance when applied to data from new batches. Statistical adjustment methods can mitigate these artifacts while preserving biological signals. To ensure these adjustments actually facilitate generalization, we emphasize the use of external, independent cohorts for rigorous validation. This chapter examines how batch effects impact predictions and compares various adjustment methods.

bioinformatics↗

bioRxiv2026

Erythrocyte Count and the Human Natural Lifespan Limit: Evidence from the Long Life Family Study

Erythropoiesis is the most replication-intensive process in the body. Its lifelong replicative demands may erode hematopoietic cells replicative capacity, leading to a decline in erythrocyte count (EC) in older adults and limiting their lifespan. We examined the relationship between EC and mortality among 1,620 participants aged [≥]70 years in the Long Life Family Study and found that lower EC further augmented the exponential, age-dependent rise in mortality. We identified an EC threshold (ECT) (3.8x1012/L) below which mortality was amplified (p=9.3x10-6). As EC declined with age (p=8.2x10-18), it fell below this threshold in many participants, sharply increasing their mortality risk. This mortality-based ECT emerged from modeling, independent of the World Health Organization anemia definition, which is based on statistical thresholds (5th centiles) of hemoglobin distribution in populations [≤] 65 years. Thus, declining EC may be one of the biological factors imposing a natural lifespan limit on many older adults.

physiology↗

bioRxiv2026

Reproducible Tools and Enhanced Computational Workflows for Batch Effect Evaluation of High-Throughput Data Using BatchQC

Batch effect correction is a common and often necessary step in data analysis to reduce bias due to technical and experimental factors when combining multiple batches of data. The severity of the batch effects dictates the correction strategy; therefore, a careful assessment of each datasets batch effects is necessary. BatchQC is an R package that provides reproducible tools and visualizations for quantitatively and qualitatively addressing batch effects across a broad range of data types. BatchQC integrates with standardized Bioconductor data structures and features an object-oriented design, enabling the application of workflows that can freely evaluate and process data within and outside the package tools. Common batch evaluation methods, along with novel quantitative metrics, help determine the benefits of batch correction for each dataset and enable direct comparisons between methods. Here, we present BatchQC as the first comprehensive batch-correction R package, with independent tools, reproducible workflows, visualization, and novel statistics.

bioinformatics↗

bioRxiv2026

Assessing climate adaptation among Canada lynx (Lynx canadensis) populations at the trailing edge

Species must acclimate, shift their distributions, or adapt in place in response to anthropogenic climate change. Populations at low-latitude trailing edges of species distributions typically experience thermal conditions closest to the upper limit of their thermoregulatory capacity. Landscape and functional genomic approaches provide quantitative measures of risk and adaptive capacity which can inform and prioritize conservation actions. Using low-coverage whole genomes from Canada lynx (Lynx canadensis), we characterized population genomic structure and identified putatively adaptive loci using genotype-environment association analyses across the eastern extent of their distribution. We detected genetic breaks across two previously identified biogeographical barriers, the St. Lawrence River and the Strait of Belle Isle, and found relatively high genome-wide diversity in the Maine population at the southern trailing edge, suggesting a reservoir of warm-adapted variation. We identified 759 loci from 329 genes as putatively adaptive, many associated with temperature during warm and dry periods, and functionally enriched in photoreception, circadian entrainment, and temperature regulation. We identified ten putatively adaptive genes linked to epilepsy, presenting candidate genes underlying reports of idiopathic epilepsy in captive populations of closely related lynx species (L. lynx and L. pardinus). Genetic offset showed lynx in Western Newfoundland, and the Gaspe Peninsula in Quebec are at the greatest risk of maladaptation under future conditions. If gene flow allows, introgression of climate-adapted loci from the trailing-edge may benefit regional populations under future climates. Together, these findings demonstrate the conservation value of locally adapted range-edge populations.

genomics↗

bioRxiv2025

Defining the Mycobacterium tuberculosis Pangenome and Suggestions for a New Composite Reference Sequence

Mycobacterium tuberculosis (Mtb) causes tuberculosis (TB), a global disease with diverse clinical and microbiological manifestations. Studies into the biological causes of this phenotypic diversity have been largely limited to a few reference strains. A pangenome approach is likely to provide new insights. Pangenomic tuberculosis studies have been limited the availability of only fragmented genome sequences and error-prone reference genomes. We used a de novo assembly pipeline that generates extremely complete and accurate whole genome sequences to generate 50 closed Mtb genomes across all seven major lineages. We identified 3,377 core gene clusters and 379 accessory clusters. Analysis showed multi-copy core clusters were largely due to gene fragmentation (76%), paralogs (12%), nearly identical gene duplications (4%), or combinations (8%). Sixteen hypervariable regions (HVRs) were identified, including novel paralogs and variable PE/PPE genes. We consolidated these findings into a Pangenome Gene Reference Resource (PGRR) for precision alignment. Our study demonstrates the closed nature of the Mtb pangenome, with most variation in accessory genes and HVRs. The PGRR provides a foundation for improved drug/vaccine target discovery and highlights the need to move beyond the commonly used H37Rv strain to study Mtb genetic and phenotypic diversity. IMPORTANCETuberculosis (TB), caused by Mycobacterium tuberculosis, affects millions globally. Genetic differences among Mtb strains have been difficult to resolve due to incomplete genome references. We sequenced and analyzed complete genomes of 50 Mtb strains from all lineages, identifying 16 hypervariable regions and 3,498 core gene clusters whose diversity mostly stemmed from gene fragmentation, paralog duplication and deletion events and differences in the PE/PPE gene family representation. These differences may explain many of the varied clinical manifestations of TB. We created Pangenome Gene Reference Resource to unify genetic data for precise comparison studies to aid in developing new drugs vaccines and other interventions against this disease.

microbiology↗

bioRxiv2025

MetaScope: A High-Resolution Framework for Species-Level 16S Metataxonomic Classification

Accurate species-level classification of microbial communities remains a major challenge in microbiome analysis, particularly when using traditional 16S rRNA amplicon sequencing pipelines such as QIIME2 and DADA2. These methods often fail to resolve taxonomy beyond the genus level due to limitations in clustering algorithms and ambiguous marker genes. To address this, we present MetaScope, a modular, R-based software package that reimplements and extends the PathoScope 2.0 framework for high-resolution microbial classification. MetaScope introduces two key innovations: (1) the integration of user-defined or empirical prior weights into the Bayesian read reassignment algorithm to improve abundance estimation, and (2) MetaBlast, a secondary BLAST-based validation module for refining species-level assignments. Benchmarking against mock and clinical datasets demonstrates that MetaScope significantly outperforms QIIME2 and DADA2, achieving up to 93.6% species-level classification accuracy. This translates to offering enhanced resolution for downstream analyses such as ecological diversity metrics. These results highlight MetaScope as a powerful tool for advancing microbial community profiling in both research and clinical settings.

bioinformatics↗

bioRxiv2025

Sex specific correction of maternal inflammation-induced behavioral abnormalities by the inhibition of colony-stimulating factor 1 receptor

We have previously reported the therapeutic effect of depletion and regeneration of endogenous microglia on autism spectrum disorder-like behaviors in offspring from the dams under maternal immune activation (MIA) by dampening their neuritogenic activation. Here we show a long-lasting pathological effect by MIA, leading to abnormal behaviors in offspring mice in a sex-specific manner at 3 months of age. MIA was induced by injecting Polyinosinic:polycytidylic acid [Poly(I:C)] at 10mg/kg at E9.5 with preselected dams based on the immunoreactivity to low-dose Poly(I:C) injection. MIA offspring show impairments in sociability, repetitive behavior, and spatial working and associative memories in both sexes, whereas only male offspring show social novelty deficit. MIA has no effect on anxiety-like behavior nor sensori-motor or locomotor activity. Administering colony stimulating factor receptor (CSF1R) inhibitor in young adult MIA offspring regenerates microglia and ameliorates sociability deficits in males and spatial working and associative memory impairments in both sexes without effect on social novelty impairments. Transcriptomic analysis of prefrontal cortex and hippocampal tissues reveals MIA and sex-specific pathways and highlights potential key genes involved in the corrective effect of microglial regeneration in MIA offspring. Our results underscore the potential of the sex-specific therapeutic applications of CSF1R inhibitor for MIA-related social and cognitive disorders.

animal behavior and cognition↗

bioRxiv2025

Helminth infection favors reprogramming and proliferation of lung neutrophils

Neutrophils are a granulocytic population of myeloid cells that have critical effector functions during infectious disease but are generally thought to be short-lived and nonproliferative with markedly limited activation states. In these studies, we directly compared lung neutrophil activation following infection with different groups of pathogens including bacteria, fungi, and helminths. Our results demonstrate considerable heterogeneity depending on the type of infectious agent. In contrast to bacterial and fungal infection, after helminth infection neutrophils expressed markers associated with characteristic type 2 responses and unexpectedly upregulated genes associated with cell cycling and protein synthesis. Further studies showed reduced neutrophil cell death following helminth infection and increased proliferation, which was dependent on IL-4R signaling. This distinct subset of proliferating neutrophils expanded following helminth infection and was released from the endothelial niche to colocalize with invading parasites in the airways. These studies demonstrate a novel long-lived cycling phenotype for neutrophils following helminth infection.

immunology↗

bioRxiv2024

Bulk Transcriptomic Analysis with InMoose, the Integrated Multi-Omic Open-Source Environment in Python

We introduce InMoose, an open-source Python environment aimed at omic data analysis. We illustrate its capabilities for bulk transcriptomic data analysis. Due to its wide adoption, Python has grown as a de facto standard in fields increasingly important for bioinformatic pipelines, such as data science, machine learning, or artificial intelligence (AI). As a general-purpose language, Python is also recognized for its versatility and scalability. InMoose aims at bringing state-of-the-art tools, historically written in R, to the Python ecosystem. Our intent is to provide a drop-in replacement for R tools, so our approach focuses on the faithfulness to the original tools outcomes. The first development phase has focused on bulk transcriptomic data, with current capabilities encompassing data simulation, batch effect correction, and differential analysis and meta-analysis.

bioinformatics↗

bioRxiv2024

EPITHELIAL REMODELING AND MICROBIAL DYSBIOSIS IN THE LOWER RESPIRATORY TRACT OF VITAMIN A-DEFICIENT MOUSE LUNGS

The World Health Organization identified vitamin A deficiency (VAD) as a major public health issue in low-income communities and developing countries, while additional studies have shown dietary VAD leads to various lung pathologies. Once believed to be sterile, research now shows that transient microbial communities exist within healthy lungs and are often dysregulated in patients suffering from malnourishment, respiratory infections, and disease. The inability to parse vitamin A-mediated mechanisms from other metabolic mechanisms in humans with pathogenic endotypes, as well as the lack of data investigating how VAD affects the lung microbiome, remains a significant gap in the field. To address this unmet need, we compared molecular, metatranscriptomic, and morphometric data to identify how dietary VAD affects the lung as well as the lung microbiome. Our research shows structural and functional alterations in host-microbe-diet interactions in VAD lungs compared to vitamin A-sufficient (VAS) lungs; these changes are associated with epithelial remodeling, a breakdown in mucociliary clearance, microbial imbalance, and altered microbial colonization patterns after 8 weeks of vitamin A deficient diet. These findings confirm vitamin A is critical for lung homeostasis and provide mechanistic insights that could be valuable for the prevention of respiratory infections and disease. ONE SENTENCE SUMMARYVitamin A deficiency leads to epithelial remodeling, ciliary dysfunction, a loss of mucociliary clearance, and an increase in biofilm formation and microbial abundance in adult mouse lungs.

molecular biology↗

bioRxiv2024

Conserved residues of the immunosuppressive domain of MLV are essential for regulating the fusion-critical SU-TM disulfide bond

The ENV protein of murine leukemia virus (MLV) is the prototype of a large clade of retroviral fusogens, collectively known as gamma-type Envs. Gamma-type ENVs are found in retroviruses and related endogenous retroviruses (ERV) representing a broad range of vertebrate hosts. All gamma-type Envs contain a highly conserved stretch of 26-residues in the transmembrane subunit (TM) comprising two motifs, a putative immunosuppressive domain (ISD) and a CX6CC motif. The extraordinary conservation of the ISD and its invariant association with the CX6CC suggests a fundamental contribution to Env function. To investigate function of the ISD, we characterized several mutants with single amino acid substitutions at conserved positions in the MLV ISD. A majority abolished infectivity, although we did not observe a corresponding loss in intrinsic ability to mediate membrane fusion. Ratios of the surface subunit (SU) to capsid protein (CA) in virions were diminished for a majority of the mutants, while TM/CA ratios were similar to wild type. Specific loss of SU reflected premature isomerization of the labile disulfide bond that links SU and TM prior to fusion and entry. Indeed, all non-infectious mutants displayed significantly lower disulfide stability than wild type MLV Env. These results reveal a role for residues at MLV ISD positions 2, 3, 4, 7, and 10 in regulating a late step in fusion, and suggest that the ISD is part of a larger domain, encompassing both the ISD and CX6CC motifs, that is critical for formation and regulation of the metastable, intersubunit disulfide bond. IMPORTANCEThe gamma-type Env is an extremely prevalent viral fusogen, extensively found within retroviruses and endogenous loci across vertebrate species and are further found in filoviruses such as Ebola virus. The fusion mechanism of gamma-type Envs is unique from other Class I fusogens such as those of IAV and HIV-1. Gamma-type Envs contain a hallmark feature known as the immunosuppressive domain (ISD) that has been the subject of some controversy in the literature surrounding its putative immunosuppressive effects. Despite the distinctive conservation of the ISD, little has been done to investigate the role of this region for the function of this widespread fusogen. Our work demonstrates the importance of the ISD for the function of gamma-type Envs in infection, particularly in regulating the intermediate steps of fusion with the host membrane. Understanding the fusion mechanism of gamma-type Envs has broad implications for understanding entry of extant viruses and aspects of host biology connected to co-opted endogenous gamma-type Envs.

microbiology↗

bioRxiv2024

Atp1a2 and Kcnj9 are candidate genes underlying oxycodone behavioral sensitivity and withdrawal in C57BL/6 substrains

Opioid use disorder is heritable, yet its genetic etiology is largely unknown. C57BL/6J and C57BL/6NJ mouse substrains exhibit phenotypic diversity in the context of limited genetic diversity which together can facilitate genetic discovery. Here, we found C57BL/6NJ mice were less sensitive to oxycodone (OXY)-induced locomotor activation versus C57BL/6J mice in a conditioned place preference paradigm. Narrow-sense heritability was estimated at 0.22-0.31, implicating suitability for genetic analysis. Quantitative trait locus (QTL) mapping in an F2 cross identified a chromosome 1 QTL explaining 7-12% of the variance in OXY locomotion and anxiety-like withdrawal in the elevated plus maze. A second QTL for EPM withdrawal behavior on chromosome 5 near Gabra2 (alpha-2 subunit of GABA-A receptor) explained 9% of the variance. To narrow the chromosome 1 locus, we generated recombinant lines spanning 163-181 Mb, captured the QTL for OXY locomotor traits and withdrawal, and fine-mapped a 2.45-Mb region (170.16-172.61 Mb). Transcriptome analysis identified five, localized striatal cis-eQTL transcripts and two were confirmed at the protein level (KCNJ9, ATP1A2). Kcnj9 codes for a potassium channel (GIRK3) that is a major effector of mu opioid receptor signaling. Atp1a2 codes for a subunit of a Na+/K+ ATPase enzyme that regulates neuronal excitability and shows functional adaptations following chronic opioid administration. To summarize, we identified two candidate genes underlying the physiological and behavioral properties of opioids, with direct preclinical relevance to investigators employing these widely used substrains and clinical relevance to human genetic studies of opioid use disorder.

genetics↗

bioRxiv2023

Analysis of the Cross-Study Replicability of Tuberculosis Gene Signatures Using 49 Curated Transcriptomic Datasets

BackgroundTuberculosis (TB) is the leading cause of infectious disease mortality worldwide. Numerous blood-based gene expression signatures have been proposed in the literature as alternative tools for diagnosing TB infection. Ongoing efforts are actively focused on developing additional signatures in other TB-related contexts. However, the generalizability of these signatures to different patient contexts is not well-characterized. There is a pressing need for a well-curated database of TB gene expression studies for the systematic assessment of existing and newly developed TB gene signatures. ResultsWe built the curatedTBData, a manually-curated database of 49 TB transcriptomic studies. This data resource is freely available through GitHub and as an R Bioconductor package that allows users to validate new and existing biomarkers without the challenges of harmonizing heterogeneous studies. We also demonstrate the use of this data resource with cross-study comparisons for 72 TB gene signatures. For the comparison of subjects with active TB from healthy controls, 19 gene signatures had weighted mean AUC of 0.90 or greater, with the highest result of 0.94. In active TB disease versus latent TB infection, 7 gene signatures had weighted mean AUC of 0.90 or greater, with a maximum of 0.93. We also explore ensembling methods for averaging predictions from multiple gene signatures to significantly improve diagnostic ability beyond any single signature. ConclusionsThe curatedTBData data package offers a comprehensive resource of curated gene expression and clinically annotated data. It could be used to identify robust new TB gene signatures, to perform comparative analysis of existing TB gene signatures, and to develop alternative gene set scoring or ensembling methods, among other things. This resource will also facilitate the development of new signatures that are generalizable across cohorts or more applicable to specific subsets of patients (e.g. with rare comorbid conditions, etc.). We demonstrated that these blood-based gene signatures could distinguish patients with distinct TB outcomes; moreover, the combination of multiple gene signatures could improve the overall predictive accuracy in differentiating these subtypes, which point out an important aspect for the translation of genomics to clinical implementation.

genomics↗

bioRxiv2023

Analysis of nasopharyngeal microbiome patterns in Zambian infants with fatal acute febrile illness

IntroductionAssociative connections have previously been identified between nasopharyngeal infections and infant mortality. The nasopharyngeal microbiome may potentially influence the severity of these infections. MethodsWe conducted an analysis of a longitudinal prospective cohort study of 1,981 infants who underwent nasopharyngeal sampling from 1 week through 14 weeks of age at 2-3-week intervals. In all, 27 microbiome samples from 9 of the infants in the cohort who developed fatal acute febrile illness (fAFI) were analyzed in pooled comparisons with 69 samples from 10 healthy comparator infants. We completed 16S rRNA amplicon gene sequencing all infant NP samples and characterized the maturation of the infant NP microbiome among the fAFI(+) and fAFI(-) infant cohorts. ResultsBeta diversity measures of fAFI(-) infants were markedly higher than those of fAFI(+) infants. The fAFI(+) infant NP microbiome was marked by higher abundances of Escherichia, Pseudomonas, Leuconostoc, and Weissella, with low relative presence of Alkalibacterium, Dolosigranulum, Moraxella, and Streptococcus. ConclusionsOur results suggest that nasopharyngeal microbiome dysbiosis precedes fAFI in young infants. Early dysbiosis, involving microbes such as Escherichia, may play a role in the causal pathway leading to fAFI or could be a marker of other pathogenic forces that directly lead to fAFI.

microbiology↗

bioRxiv2023

Total RNA sequencing reveals gene expression and microbial alterations shared by oral pre-malignant lesions and cancer.

Head and neck cancers are a complex malignancy comprising multiple anatomical sites, with cancer of the oral cavity ranking among the deadliest and most disfiguring cancers globally. Oral cancer (OC) constitutes a subset of head and neck cancer cases, presenting primarily as tobacco-and alcohol-associated oral squamous cell carcinoma (OSCC), with a 5-year survival rate of [~]65%, partly due to the lack of early detection and effective treatments. OSCC arises from premalignant lesions (PMLs) in the oral cavity through a multi-step series of clinical and histopathological stages, including varying degrees of epithelial dysplasia. To gain insights into the molecular mechanisms associated with the progression of PMLs to OSCC, we profiled the whole transcriptome of 66 human PMLs comprising leukoplakia with dysplasia and hyperkeratosis non-reactive (HkNR) pathologies, alongside healthy controls and OSCC. Our data revealed that PMLs were enriched in gene signatures associated with cellular plasticity, such as partial EMT (p-EMT) phenotypes, and with immune response. Integrated analyses of the host transcriptome and microbiome further highlighted a significant association between differential microbial abundance and PML pathway activity, suggesting a contribution of the oral microbiome towards PML evolution to OSCC. Collectively, this study reveals molecular processes associated with PML progression that may help early diagnosis and disease interception at an early stage. AUTHOR SUMMARYPatients harboring oral premalignant lesions (PMLs) have an increased risk of developing oral squamous cell carcinoma (OSCC), but the underlying mechanisms driving transformation of PMLs to OSCC remain poorly understood. In this study, Khan et al., analyzed a newly generated dataset of gene expression and microbial profiles of oral tissues from patients diagnosed with PMLs from differing histopathological groups, including hyperkeratosis not reactive (HkNR) and dysplasia, comparing these profiles with OSCC and normal oral mucosa. Significant similarities between PMLs and OSCC were observed, with PMLs manifesting several cancer hallmarks, including oncogenic and immune pathways. The study also demonstrates associations between the abundance of multiple microbial species and PML groups, suggesting a potential contribution of the oral microbiome to the early stages of OSCC development. The study offers insights into the nature of the molecular, cellular and microbial heterogeneity of oral PMLs and suggests that molecular and clinical refinement of PMLs may provide opportunities for early disease detection and interception. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/534064v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@86cf7org.highwire.dtl.DTLVardef@129e6d1org.highwire.dtl.DTLVardef@1f0ae31org.highwire.dtl.DTLVardef@3c4d67_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗