Multi-omics Analysis Research Articles

Combined multi-omics analysis revealed the aroma characteristics and the formation mechanism in different grape varieties

Combined multi-omics analysis revealed the aroma characteristics and the formation mechanism in different grape varieties

Impact of inoculants on alfalfa silage: a multi-omics analysis reveals microbial community and metabolic shifts despite undesirable fermentation quality

Impact of inoculants on alfalfa silage: a multi-omics analysis reveals microbial community and metabolic shifts despite undesirable fermentation quality

Multiomic evaluation of TEV-56278, a PD-1-targeted attenuated IL-2 molecule, in a human ex vivo tumor model and association with immune activation with enhanced effector CD8 T cell selectivity.

e14506 Background: Interleukin-2 (IL-2) is critical for cancer immunity, but its therapeutic use is limited by systemic toxicity and a narrow therapeutic window. To address this, we developed TEV-56278, an antibody-cytokine fusion protein currently under investigation in a Ph1 dose escalation clinical study. TEV-56278 is designed to deliver an attenuated form of IL-2 (AttIL2) to PD-1-expressing T cells. Unlike similar compounds, TEV-56278 binds to a distinct epitope of PD-1, allowing for combined use with PD-1 blocking antibodies. In mice models, it induced elevation of T cell percentages within tumors and mediated tumor regression without systemic toxicity. To characterize TEV-56278’s mechanism of action and identify potential response/resistance signatures in human samples, we conducted a multiomic analysis on patient-derived tumor fragments (PDTF). Methods: PDTF from 15 renal cell carcinoma patients were treated ex vivo with TEV-56278 [100 µg/ml], aldesleukin [100 ng/ml, as positive control], or a control PD-1 non-targeted-AttIL-2 [100 µg/ml]. Baseline and treated PDTFs were dissociated and sorted for live immune cells and single-cell multiomic profiling was performed. The multiomic dataset includes measurements of cell abundance, cell type-specific RNA and protein expression and clonality of T cell subsets. Cytokine production was measured by multiplex ELISA. All measurements were input into Immunai’s ImmunoDynamics Engine, a proprietary machine learning framework to determine the mechanism of action of TEV-56278. Results: TEV-56278 induces pSTAT5 in PDTF model, supporting highly localized activity of AttIL-2 moiety. TEV-56278 selectively triggers IL-2 signaling in PD1 high T cells and promotes reinvigoration of exhausted CD8+ T cells. In contrast, aldesleukin induces broader transcriptional changes in both PD1 low and PD1 high cell types. TEV-56278 elicits varying degrees of immune activation and a secreted profile associated with immune cell infiltration and PD-1 responsiveness (e.g. CXCL10, CCL20, IL12 p40). The features associated with stronger response are being evaluated to inform indication and patient selection on future trials. Conclusions: We performed in-depth characterization of TEV-56278 in a human tumor ex vivo system that incorporates features of the tumor microenvironment and models the dynamic response of TEV-56278. This study confirms that TEV-56278 targets IL-2 activity to PD-1 expressing T cells within the tumor microenvironment and induces strong immune response, thereby promoting anti-tumor activity. Understanding the mechanisms that drive variable responses in PDTF may improve precision immuno-oncology efforts and help optimize our clinical development strategy.

Mendelian randomization and multi-omics analysis identify C4A as a critical protective biomolecule in head and neck squamous cell carcinoma

Mendelian randomization and multi-omics analysis identify C4A as a critical protective biomolecule in head and neck squamous cell carcinoma

Multi-omics analysis reveals dynamic changes in gut microbiota and metabolites associated with cholecystectomy and post-cholecystectomy diarrhea

Multi-omics analysis reveals dynamic changes in gut microbiota and metabolites associated with cholecystectomy and post-cholecystectomy diarrhea

Integrative multi-omics analysis reveals liver-gut axis adaptation in high-altitude goats.

Integrative multi-omics analysis reveals liver-gut axis adaptation in high-altitude goats.

Species-specific sensitivity to intracerebroventricular streptozotocin in rats and mice highlights pathways and proteins relevant to Alzheimer’s disease

Abstract For over three decades, intracerebroventricular streptozotocin (STZ-icv) has been a key non-transgenic rodent model of sporadic Alzheimer’s disease. Traditionally used in rats, its use in mice is growing due to practical advantages. While factors like strain, sex, vehicle, age, and dosage are well studied in STZ-induced diabetes models, their impact on STZ-icv-related cognitive deficits remains poorly understood. To address this gap, we examine species-specific sensitivity to STZ-icv in two widely used rodent strains (Wistar Han rats and C57BL/6 mice) motivated by the finding that, despite reliably inducing cognitive deficits in rats for over 30 years in our lab, the same STZ-icv procedure yields inconsistent results in C57BL/6 mice. To explore this phenomenon, we first constructed a series of allometric models to assess how different STZ-icv concentrations affect predicted exposure in rats and mice. Next, we provide behavioral and immunohistochemical evidence that C57BL/6 mice exhibit resistance to STZ doses that should achieve sufficient neuronal exposure. Finally, we perform an exploratory multiomic analysis, examining differentially expressed proteins in the hippocampus and prefrontal cortex of STZ-icv-treated rats that also show differential expression between Wistar Han rats and C57BL/6 mice, followed by an investigation of these proteins across independent Alzheimer’s disease cohorts. Through this analysis, we identify three understudied proteins—Tagln2, Slc25a3, and Pafah1b3—that may contribute to the differential sensitivity of Wistar Han rats and C57BL/6 mice to STZ-icv and may play a role in the development and progression of Alzheimer’s disease.

Multi-omics analysis identified and confirmed TNF-α as a key initiator of the inflammatory response following spinal cord injury.

Multi-omics analysis identified and confirmed TNF-α as a key initiator of the inflammatory response following spinal cord injury.

Multiomics informed mathematical model for meropenem and tobramycin against hypermutable Pseudomonas aeruginosa.

Hypermutable P. aeruginosa isolates frequently display resistance emergence during treatment. Mechanisms of such resistance emergence have not been explored using dynamic hollow-fiber studies and multiomics informed mathematical modeling. Two hypermutable and heteroresistant P. aeruginosa isolates, CW8 (MICmeropenem=8 mg/L, MICtobramycin=8 mg/L) and CW44 (MICmeropenem=4 mg/L, MICtobramycin=2 mg/L), were studied. Both isolates had genotypes resembling those of carbapenem- and aminoglycoside-resistant strains. Achievable lung fluid concentration-time profiles following meropenem at 1 or 2 g every 8 h (3-h infusion) and tobramycin at 5 or 10 mg/kg body weight every 24 h (0.5-h infusion), in monotherapy and combinations, were simulated over 8 days. Total and resistant bacterial counts were determined. Resistant colonies and whole population samples at 191 h were whole-genome sequenced, and population transcriptomics performed at 1 and 191 h. The multiomics analyses informed mechanism-based modeling of total and resistant populations. While both isolates eventually displayed resistance emergence against all regimens, the high-dose combination synergistically suppressed resistant regrowth of only CW8 up to ∼96 h. Mutations that emerged during treatment were in pmrB, ampR, and multiple efflux pump regulators for CW8, and in pmrB and PBP2 for CW44. At 1 h, mexB, oprM and ftsZ were differentially downregulated in CW8 by the combination. These transcriptomics results informed inclusion of mechanistic synergy in the mechanism-based model for only CW8. At 191 h, norspermidine genes were upregulated (without a pmrB mutation) in CW8 by the combination, and informed the adaptive loss of synergy in the model. Multiomics information enabled mechanism-based modeling to describe the bacterial response of both isolates simultaneously. Pseudomonas aeruginosa causes serious bacterial infections in people with cystic fibrosis (pwCF), and has numerous resistance mechanisms. Current empirical approaches to informing antibiotic regimen selection have important limitations. This study exposed two P. aeruginosa clinical isolates to concentration-time profiles of meropenem and tobramycin as would be observed in lung fluid of pwCF. The combination elicited different bacterial count profiles between the isolates, despite similar bacterial baseline characteristics. We found differences between the isolates in the expression of a key resistance mechanism against meropenem at 1 h, and expression that implied a loss of cell membrane permeability for tobramycin without the expected DNA mutation. This information enabled mathematical modeling to accurately describe all bacterial profiles over time. For the first time, this multiomics informed modeling approach using DNA and RNA data was applied to a hollow-fiber infection study. Using bacterial molecular insights with mechanism-based mathematical modeling has high potential for ultimately informing personalised antibiotic therapy.

Multi-omics analysis reveals potential mechanisms of diarrhetic shellfish toxin and fatty acid synthesis in marine harmful Prorocentrum.

Multi-omics analysis reveals potential mechanisms of diarrhetic shellfish toxin and fatty acid synthesis in marine harmful Prorocentrum.

Dorsomorphin (DM) inhibits the ovarian development of Portunus trituberculatus by acting on the BMP signaling pathway.

Dorsomorphin (DM) inhibits the ovarian development of Portunus trituberculatus by acting on the BMP signaling pathway.

Multiomics Reveals Biological Mechanisms Linking Macroscale Structural Covariance Network Dysfunction With Neuropsychiatric Symptoms Across the Alzheimer’s Disease Continuum

Multiomics Reveals Biological Mechanisms Linking Macroscale Structural Covariance Network Dysfunction With Neuropsychiatric Symptoms Across the Alzheimer’s Disease Continuum

Integration of comparative cytology, ionome, transcriptome and metabolome provide a basic framework for the response of foxtail millet to Cd stress.

Integration of comparative cytology, ionome, transcriptome and metabolome provide a basic framework for the response of foxtail millet to Cd stress.

Integrated gut microbiota and multi-omics analysis revealed the growth differences of female giant freshwater prawn (Macrobrachium rosenbergii).

Integrated gut microbiota and multi-omics analysis revealed the growth differences of female giant freshwater prawn (Macrobrachium rosenbergii).

Physiological responses to different temperature in the liver of Takifugu rubripes larvae revealed by integrated transcriptomic and metabolomic analyses

Physiological responses to different temperature in the liver of Takifugu rubripes larvae revealed by integrated transcriptomic and metabolomic analyses

Excessive exercise elicits poly (ADP-ribose) Polymerase-1 activation and global protein PARylation driving muscle dysfunction and performance impairment.

Excessive exercise elicits poly (ADP-ribose) Polymerase-1 activation and global protein PARylation driving muscle dysfunction and performance impairment.

Multiomics analysis demonstrated a strong correlation between lipid-mediated chronic kidney disease and stroke: Potential benefits of affected patient cohorts.

Multiomics analysis demonstrated a strong correlation between lipid-mediated chronic kidney disease and stroke: Potential benefits of affected patient cohorts.

Metabolic engineering of Glarea lozoyensis for high-level production of pneumocandin B0.

Metabolic engineering of Glarea lozoyensis for high-level production of pneumocandin B0.

Exploring lipid remodeling and antioxidant responses in Chlorella pyrenoidosa exposed to streptomycin sulfate stress.

Exploring lipid remodeling and antioxidant responses in Chlorella pyrenoidosa exposed to streptomycin sulfate stress.

Dysbiotic Microbiome–Metabolome Axis in Childhood Obesity and Metabolic Syndrome

The prevalence of childhood metabolic syndrome (MetS) and obesity is rising, with emerging evidence suggesting these conditions negatively affect oral health. However, the underlying molecular determinants are unclear. This study investigated the oral microbiome, inflammatory markers, and metabolites in children with obesity and MetS to explore the interrelationships between systemic disease and oral health. We recruited 76 periodontally healthy, caries-free individuals aged 10 to 17 y into 3 groups: MetS (29), metabolically healthy obesity (MHO) (30), and normal-weight healthy (NWH) controls (17). Unstimulated saliva was collected. Bacterial DNA was isolated, V3–V4 regions amplified, and 16S sequencing performed on the Illumina MiSeq platform. Sequences were annotated against the HOMD database. Multiplex assays quantified adipokines and cytokines, with significance determined by Tukey honestly significant difference. Gas chromatography/mass spectrometry identified metabolite peaks that were annotated against the Small Molecule Pathway Database, with enrichment analysis determining significance. Integrated multiomics analysis was performed using multiblock sparse partial least squares regression discriminant analysis. The MHO and MetS groups demonstrated lower abundances of Streptococcus , Actinomyces , and Schaalia and higher levels of Aggregatibacter , Campylobacter , Alloprevotella , Prevotella , Leptotrichia , and Porphyromonas compared with NWH, despite similar clinical oral status in all cohorts. MetS and MHO also had increased leptin, tumor necrosis factor–α, interleukin (IL)–1β, and IL-15 and decreased adiponectin levels versus NWH. Disease-associated metabolites, including glutamate, cholesterol, isoleucine, tyrosine, phenylalanine, serine, and indoleacetic acid, were significantly enriched in the MetS and MHO groups. Integrated multiomic analysis identified key correlations in the saliva of subjects with metabolic health or disease. Decreases in health-associated species and increases in proinflammatory cytokines and disease-associated metabolites in the saliva of MetS and obese adolescents with clinical oral health indicate an “at-risk” environment, potentially explaining their elevated risk for oral diseases. Increased salivary leptin and decreased adiponectin levels highlight the potential of saliva as a noninvasive biomarker source for childhood MetS.