Biology subjects

Mahmoudi, M.

Publications and source records attributed to Mahmoudi, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Salience network expansion as a transdiagnostic neural marker for psychopathology risk in adolescence

Increased cortical surface area of the brain's salience network (SAL) has been observed in depression and appears to emerge during early adolescence. However, similar expansion has also been reported in bipolar disorder (BD), obsessive compulsive disorder (OCD), and other atypicalities of salience network function have been broadly implicated across multiple psychiatric conditions. Whether increased SAL surface area is specific to depression or related more generally with psychopathology remains unclear. Using data collected as part of the Adolescent Brain Cognitive Development (ABCD) Study (baseline: N = 7942; ages 9-10; Year 2: N = 5901; ages 11-12), we quantified individual SAL size and examined associations with dimensional symptoms from the Child Behavior Checklist. SAL surface area showed substantial inter-individual variability, with expansion occurring primarily through encroachment into the default mode (DMN), action-mode (AMN), and frontoparietal (FP) networks. Larger SAL size showed a modest positive association with depressive symptoms in the baseline sample, consistent with prior reports; however, this association did not replicate in the year 2 internal replication sample. Instead, associations with total problems were stronger and replicated across both timepoints, suggesting a subtle, dimensional relationship between SAL organization and general psychopathology burden. These findings suggest that individual differences in SAL organization may represent a broader transdiagnostic neural correlate of dimensional psychopathology rather than a disorder-specific neural signature.

neuroscience↗

bioRxiv2026

An age-preserving neuronal iSpheroid platform for modeling human aging and Alzheimer disease

Aging is the strongest risk factor for Alzheimer disease (AD), yet existing human neuronal models either erase age-associated features during reprogramming or fail to recapitulate three-dimensional organization of human neuronal tissue. Here, we establish directly induced neuronal spheroids (iSpheroids), a scalable three-dimensional platform generated by direct conversion of primary fibroblasts without pluripotency. iSpheroids generate long-lived, electrophysiologically active neurons from young, unimpaired aged, and sporadic AD donors while preserving donor-specific epigenetic age. Single-nucleus RNA sequencing revealed approximately 96% of cells acquired a neuronal identity and were distributed across multiple neuronal states, including a diversity of neurons. The platform supports incorporation of astrocytes and microglia and generation from non-human primate fibroblasts. AD iSpheroids spontaneously recapitulated neuronal degeneration, amyloid-beta; accumulation, progressive Tau pathology, and metabolic dysfunction. Integrated proteomic, metabolomic, and lipidomic profiling distinguished physiological aging from AD and revealed disease-associated metabolic remodeling. Oxaliplatin shifted AD iSpheroids toward oxidative metabolism, whereas a multi-compound screen identified trametinib as a modulator of inflammatory and age-associated programs.

neuroscience↗

bioRxiv2026

Deep nanoparticle protein corona plasma proteomics resolves a stage-specific peripheral signature of Alzheimer's disease

Structured AbstractO_ST_ABSINTRODUCTIONC_ST_ABSAlzheimers disease (AD) progresses over decades, yet plasma biomarkers that resolve disease stage rather than simply detect disease remain scarce. This distinction is clinically consequential because effective AD intervention depends on identifying patients before disease biology has progressed beyond a therapeutically responsive stage. METHODSWe used small-molecule-modulated protein corona proteomics to profile plasma from 90 individuals in the Australian Imaging, Biomarker and Lifestyle cohort, stratified by Centiloid (CL) A{beta}-amyloid burden (30 amyloid- negative, CL < 15; 30 moderate-to-high, CL 26 to 100; 30 very high, CL > 100). We quantified 3,176 proteins and applied differential abundance and actual causality analyses to identify stage-specific and candidate causal proteins. RESULTSDifferential protein abundance was exclusively captured during the moderate-to-high AD transition, revealing a discrete proteomic "switch." The switch was marked by accumulation of the autophagy receptor CALCOCO1, together with coordinated depletion of the S100A8/S100A9 calprotectin complex and core erythroid-cytoskeletal network structural markers (e.g., SPTA1, SPTB, ANK1). Adhesion G protein-coupled receptor G6 (ADGRG6) showed a significant moderate positive monotonic association with absolute CL burden, providing a proportional molecular anchor for cumulative disease burden. Actual causality analysis identified COL6A2, FOXRED2, P3H1, PRR4, and GOLGA5 as candidate upstream drivers linking matrix remodeling, Golgi trafficking, and collagen processing to AD progression. DISCUSSIONThese findings suggest a candidate blood-accessible framework for staging AD by active disease biology, which, if replicated in independent cohorts, may have implications for therapeutic selection and mechanism-guided clinical trials. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/740710v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1ead718org.highwire.dtl.DTLVardef@cfa523org.highwire.dtl.DTLVardef@62a367org.highwire.dtl.DTLVardef@1d5c9a5_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

Contingency degradation overwrites initial learning and depends on lateral orbitofrontal cortex

Relapse after treatment for various mental health disorders has been linked to tendency for reductions in responding to increase over time or following re-exposure to motivating stimuli. Here we show that, in rats, responding reduced through non-contingent outcome delivery does not recover in these ways, and that this learning depends on an intact lateral orbitofrontal cortex. These findings suggest that contingency degradation overwrites original learning which may support the development of relapse-resistant behavioural interventions.

animal behavior and cognition↗

bioRxiv2026

cGAS activation during human cytomegalovirus infection is driven by exogenous DNA

Type I interferon (IFN) induction is a central component of the innate immune response to viral infection, and the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) has been identified as a key mediator of IFN production during human cytomegalovirus (HCMV) infection. However, how cGAS detects HCMV remains unresolved, as the viral genome is encapsidated and trafficked directly to the nucleus, limiting cytoplasmic exposure. Here, we show that IFN induction during HCMV infection of primary fibroblast cells is predominantly driven by cGAS recognition of exogenous DNA present in standard laboratory virus preparations rather than the encapsidated viral genome. DNase treatment of AD169 and low-passage TB40/E-GFP viral stocks substantially reduced total DNA content without affecting infectivity, yet markedly abrogated IFN induction, IFN-stimulated gene expression and IRF3 nuclear translocation. Immunofluorescence analysis further revealed cytoplasmic accumulation of DNA in cells infected with untreated virus stocks, which was absent following DNase treatment. Together, these findings demonstrate that contaminating DNA in viral preparations is sufficient to activate cGAS and drive IFN responses during HCMV infection in vitro, highlighting a critical confounding factor in studies of innate immune sensing. Author SummaryHuman cytomegalovirus (HCMV) is a common herpesvirus that establishes lifelong infection and can cause serious disease in immunocompromised individuals and newborns. When cells detect viral infection, they produce type I interferons (IFNs), antiviral molecules that help limit virus spread. Previous studies have suggested that HCMV is sensed by a cellular DNA sensor called cGAS, which detects viral DNA in the cytoplasm and triggers IFN production. However, how cGAS gains access to the HCMV genome has remained unclear, because the viral DNA is enclosed within a protective capsid and transported directly to the nucleus during infection. In this study, we show that most IFN production observed during HCMV infection of fibroblast cells in vitro is driven not by sensing of the viral genome itself, but by contaminating DNA present in standard laboratory virus preparations. Treating virus stocks with DNase to remove this exogenous DNA abolished IFN induction without affecting viral infectivity. These findings highlight the importance of controlling for exogenous nucleic acids when interpreting how host cells detect viral infection.

microbiology↗

bioRxiv2026

Cooperative siderophore use stabilizes a protective leaf microbiome

Plant-associated microbial communities provide crucial protection against pathogens. Specialized metabolites play key roles in plant-microbe and microbe-microbe interactions and, ultimately, in plant health; however, the molecular mechanisms underlying their plant-protecting properties remain largely unknown. Nutrient deficiency (e.g., iron) on leaf surfaces creates intense competition among microbes, driving both antagonism and cooperation. Using a gnotobiotic Arabidopsis thaliana model and a synthetic leaf microbial community, we show that community stability and plant protection depend on cooperative siderophore exchange between the basidiomycete yeast Rhodotorula kratochvilovae and commensal Pseudomonas species. Removal of Pseudomonas caused a strong shift in the community metabolome and accumulation of the yeast siderophore rhodotorulic acid (RA). RA selectively promoted the growth of commensal Pseudomonas via TonB-dependent transporters, which are absent in pathogenic Pseudomonas strains. Inactivation of these transporter genes abolished RA uptake, destabilized the synthetic community, and eliminated protection against Pseudomonas syringae infection. RA and Rhodotorula also induced host iron-deficiency and jasmonate-related defense metabolites, linking microbial cooperation to plant stress responses. These findings reveal that microbial siderophore exchange acts as a key mechanism that maintains stability in the phyllosphere microbiome. Rather than solely promoting competition, iron-binding compounds can serve as cooperative currencies that align microbial fitness with host protection.

microbiology↗

bioRxiv2026

Recalibrating Nanoparticle Protein Corona Analysis for Accurate Biological Identity and Soluble Plasma Proteome Profiling

The nanoparticle (NP) protein corona is considered the biological identity that determines NP fate, safety, targeting, and therapeutic effectiveness in biofluids. Nonetheless, standard corona isolation workflows assume the recovered protein signature originates primarily from plasma proteins adsorbed directly onto the NP surface, while largely overlooking co-isolation of endogenous nanoscale biological structures such as extracellular vesicles (EVs). This oversight can distort the apparent "biological identity" of the NP. Here, we show that EVs are a major hidden contributor to the perceived protein corona composition in human plasma. Using highly monodispersed polystyrene NPs (50-1000 nm) and superparamagnetic beads, we compared corona formation in standard human plasma and plasma depleted of an EV- enriched sedimentable fraction by ultracentrifugation at 100,000 x g for 2 h, with the recovered vesicles subsequently characterized by MACSPlex immunoaffinity analysis. Mass spectrometry revealed that EV depletion reduced the number of proteins identified on polystyrene NPs by 60-75% and on magnetic beads by 45-50%, demonstrating a substantial fraction of the conventionally assigned corona proteome arises from EV- associated carryover. EV depletion also restructured the apparent abundance hierarchy, increasing the relative prominence of soluble plasma proteins such as albumin and shifting dominant signals away from intracellular cytoskeletal component proteins that are characteristic of EV carryover towards genuine soluble plasma proteins and complement factors. These results highlight that standard corona workflows can inadvertently co-isolate a vast array of EV-associated material and thereby yield inaccurate assignments of protein origin. Distinguishing proteins adsorbed from the soluble phase from EV-surface and intravesicular material is essential for accurate interpretation of NP-biofluid interactions, biomarker discovery, and therapeutic targeting because molecular compartment determines both analytical meaning and drug accessibility. Significance StatementThe nanoparticle (NP) "protein corona" defines how engineered nanomaterials interact with living systems, influencing therapeutic safety, efficacy, and diagnostic utility. Conventionally, corona isolation workflows assume that recovered proteins were adsorbed directly from the fluid phase. This study reveals a major, previously overlooked source of analytical distortion: standard separation techniques routinely co-isolate endogenous extracellular vesicles (EVs), drastically distorting the perceived biological identity of NPs. Depletion of an EV-enriched sedimentable fraction by ultracentrifugation reduced identified corona proteins by up to 75% and restructures the apparent proteomic hierarchy. Distinguishing true soluble adsorbates from vesicular carryover is essential for accurately predicting NP behavior in vivo and prevents false positives in nano- diagnostics, establishing a critical new standard for high-fidelity biomarker discovery and nanomedicine.

bioengineering↗

bioRxiv2026

Cortical Thickness and Curvature in Autism and ADHD: A Mega-Analysis

BackgroundExisting evidence suggests cortical morphometric alterations occur in people with autism and ADHD. However, these findings remain tentative due to small sample sizes, heterogeneous imaging pipelines, varied statistical approaches, and limited harmonization across acquisition sites. Few studies have applied standardized processing to large, clinically enriched datasets or addressed site-related batch effects. MethodsWe leveraged six large-scale brain imaging datasets (n = 9,647; male=5,835; female=3,812; ages 5-64 years), including 1,533 individuals with ADHD, 1,080 with autism spectrum disorder, and 7,034 matched controls. All imaging data were processed using the validated ABCD-HCP pipeline, with cortical parcellation into 360 regions based on the Human Connectome Project (HCP) atlas, and ComBat harmonization was applied to account for variability across 67 acquisition sites. Group-level differences in cortical thickness and sulcal curvature were examined with ANCOVAs, controlling for covariates and using Bonferroni correction for multiple comparisons. ResultsOur analyses revealed distinct neuroanatomical signatures for both autism and ADHD. Individuals with autism exhibited regionally thinner cortex and curvature alterations particularly in the Cingulo-Opercular network. In contrast, individuals with ADHD displayed regionally thicker cortex, particularly in the default mode and somatomotor networks, alongside curvature differences. Control participants showed intermediate patterns, suggesting that autism and ADHD may represent diverging extremes of cortical maturation. ConclusionsCortical thickness and curvature emerge as potential biomarkers that can advance understanding of neurodevelopmental conditions and disentangle heterogeneity across diagnostic groups. These findings highlight the value of harmonized, large-scale, standardized analyses for resolving inconsistencies in the literature.

neuroscience↗

bioRxiv2025

Lipid nanoparticle protein coronas form via lipoprotein fusion rather than shell-like adsorption

The protein corona influences the in vivo biodistribution of ionizable lipid nanoparticles (LNPs) in nucleic acid delivery, yet its structural architecture remains poorly defined. Using cryo-transmission electron microscopy, we visualized LNP-protein interactions in their native state. We show that, unlike the discrete "fuzzy" shells observed on hard nanoparticles, LNPs displayed no peripheral protein shell. Instead, controlled incubation and competitive "dual-particle" assays, supported by molecular dynamics simulations, indicate that LNP membranes undergo localized thickening and electron-dense remodeling consistent with lipoprotein integration rather than surface adsorption. Similar features were observed in extracellular vesicles, suggesting this behavior is shared among lipid-based carriers, and proteomic analysis identified apolipoproteins as the dominant associated proteins. Together, these findings support a model in which the biological identity of LNPs arises through membrane remodeling rather than shell-like adsorption, and provide a framework for the rational design of targeted nanomedicines. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/695162v2_ufig1.gif" ALT="Figure 1"> View larger version (79K): org.highwire.dtl.DTLVardef@a6f2b2org.highwire.dtl.DTLVardef@879d12org.highwire.dtl.DTLVardef@159196dorg.highwire.dtl.DTLVardef@945749_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Spatially precise neuron formation via hydrogel mediated modulation of the host astrocyte response

The regenerative capacity of the central nervous system after injury or disease is limited. Advancements in genetic and epigenetic reprogramming of non-neuronal cells into induced neurons presents a promising strategy for neuronal replacement and circuit reconstruction yet is hindered by suboptimal reprogramming efficacy. Here, we have achieved high astrocyte-to-neuron reprogramming efficacy through the ectopic expression of a SOX2 transcription factor using adeno-associated viral vectors. We subsequently designed a hybrid composite biomaterial to act as an implantable reprogramming workshop that perform sequential operations. Once injected, this bespoke system forms a tissue mimetic hydrogel encouraging the ingress of astrocytes to act as our raw material. We demonstrate that the system localized and enhanced the spatially confined delivery of reprogramming factors, entrapping astrocytes to then pass through an intermediate neuroblast state to robustly yield mature neurons. Sustained delivery of valproic acid within the system further promoted neuronal maturation. Overall, using design rules informed by requirements of the reprogramming strategy, we have designed a smart delivery system optimized for both the target tissue and reprogramming factors in a minimally invasive manner to enhance neural repair. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=163 HEIGHT=200 SRC="FIGDIR/small/695501v1_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@397e41org.highwire.dtl.DTLVardef@90047forg.highwire.dtl.DTLVardef@1175831org.highwire.dtl.DTLVardef@19f30eb_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Development of Dendritic Cell Membrane-Coated Nanoparticles for Antigen-Specific T Cell Engagement

Dendritic cell (DC) membrane-coated nanoparticles (DCmPs) hold significant potential for antigen-specific therapies. DCmPs carry key DC membrane proteins that facilitate DC-T cell interaction, such as major histocompatibility complex (MHC), costimulatory CD80/86, and adhesive molecules ICAM-1. However, our current understanding of the impact of the coating processes and the composition of the final products is very limited, significantly hindering the development of DCmP-based therapy. Here, using DC2.4 cell membrane proteins and poly (lactic-co-glycolic acid) (PLGA) nanoparticles, we comprehensively characterized and compared the compositions and functions of DCmPs produced using sonication, extrusion, and a newly developed combined coating approach (sonication coating following by extrusion process). The combined coating approach achieved relatively high level of protein coating and exerted superior control over the diameter and uniformity of DCmPs relative to sonication and extrusion. We also developed a characterization strategy by leveraging the homotypic interactions between DCmPs and DC2.4 cells and determined that about 80% of PLGA particles are coated with membrane proteins and both unbound proteins and uncoated particles similarly present in the final products after the three coating processes. Because DC2.4 cells exclusively express MHC class I molecules, DCmPs showed preferentially bind to cognate B3Z CD8+ T cells over DOBW CD4+ T cells, confirming that DCmPs bind to T cells in an antigen-specific fashion. Furthermore, we demonstrated that DCmPs can activate B3Z CD8+ T cells in vitro, similar to DC2.4 cells. These findings demonstrate a new coating approach that potentially improves size control over membrane-coated particles and a characterization strategy for detailed analysis of coated particle composition, having important and broad implications for the therapeutic development of DCmPs and other membrane-coated particle technology.

bioengineering↗

bioRxiv2025

Organ-specific microbiomes in natural Lotus corniculatus populations: Metacommunity dynamics in the plant endosphere

The structure of plant microbial communities vary due to a broad range of factors such as host and environmental factors, abiotic and biotic perturbations, and various assembly processes occurring at multiple tempo-spatial scales. In natural environments plant microbial communities are constantly exposed to such perturbations and processes. Thus, to attain a systemic understanding of the ecology of plant microbiomes, it is essential to study assembly processes that influence patterns of microbial community structures in natural environments. In this study we examined bacterial, fungal, and eukaryotic communities in plant organs of Lotus corniculatus in natural populations at seven grassland sites for four years. We used the framework of metacommunity theory of ecology to understand assembly processes that shape community structures and variations by defining microbial communities associated with the roots, shoots, flowers, and seeds as distinct communities linked by dispersal. In this study we show the organ-specificity of plant endophytic communities. Our findings suggest that selective filtering by plant organs, microbial interactions, as well as abiotic and biotic factors at tempo-spatial scales result in distinct core microbiomes of plant organs. In addition, transmission of microorganisms from within and outside the plant hosts accounts for the distinct yet overlapping organ microbiomes. We could provide a comprehensive knowledge of the stochastic and deterministic assembly processes that shape plant microbial communities in natural conditions. Understanding these ecological processes is essential for harnessing beneficial effects of plant-associated microbial communities on plant productivity, resilience, and pathogen defense.

microbiology↗

bioRxiv2024

Biotic interactions shape infection outcomes in Arabidopsis

The plant microbiome protects plants from stresses, including pathogen attacks. However, identifying microbes that provide plant protection remains challenging in complex microbial communities. In this study, we analysed samples from natural A. thaliana populations, including both plants infected with the pathogenic oomycete Albugo laibachii and uninfected plants, over six years. Using machine learning classification models, we achieved high accuracy in distinguishing infected and uninfected plants based on microbiome abundance. We identified 80 key taxa associated with health and disease. Among the health-associated microbes (HCom), we selected bacteria, fungi, and cercozoa that effectively reduced pathogen presence in co-inoculation assays. In comparison, disease-associated microbes (DCom) were less effective in conferring protection. Our findings highlight the complexity of plant-microbe interactions and advance our understanding of microbial roles in plant disease ecology. By integrating ecological insights with machine learning, we take a significant step towards designing robust microbial consortia that enhance plant resilience against pathogens.

microbiology↗

bioRxiv2024

Causality Analysis of Protein Corona Composition: Phosphatidylcholine-Enhances Plasma Proteome Profiling by Proteomics

The study of the protein corona, the immediate and evolving biomolecular coating that forms on the surface of nanoparticles when exposed to a biological environment, is a crucial area in nanomedicine. This phenomenon significantly influences the behavior, functionality, and biological interactions of nanoparticles with biosystems. Until now, conclusions regarding the role of the protein corona in specific biological applications have been based on establishing correlation rather than causation. By understanding causality, researchers can predict how changes in nanoparticle properties or biological conditions will affect protein corona composition, in turn affecting the nanoparticle interactions with the biosystems and their applications. This predictive capability is essential for designing nanoparticles with specific characteristics tailored for therapeutic and diagnostic nanomedicine applications. Here, we explore the concept of "actual causality" (by Halpern and Pearl) to mathematically prove how various small molecules, including metabolites, lipids, vitamins, and nutrients, spiked into plasma can induce diverse protein corona patterns on identical nanoparticles. This approach significantly enhances the depth of plasma proteome profiling. Our findings reveal that among the various spiked small molecules, phosphatidylcholine was the actual cause of the observed increase in the proteomic depth of the plasma sample. By considering the concept of causality in the field of protein corona, the nanomedicine community can substantially improve their ability to design safer and more efficient nanoparticles for both diagnostic and therapeutic purposes.

bioengineering↗

bioRxiv2024

Strong pairwise Interactions do not Drive Interactions in a Plant Leaf Associated Microbial Community

Microbial communities that promote plant growth show promise in reducing the impacts of climate change on plant health and productivity. Understanding microbe-microbe interactions in a community context is paramount for designing effective microbial consortia that enhance plant resilience. In this study, we investigated the dynamics of a synthetic microbial community (SynCom) assembled from Arabidopsis thaliana leaves to elucidate factors shaping community composition and stability. We found notable disparities between in vitro pairwise interactions and those inferred from correlation networks in planta. Our findings suggested that secondary metabolites, particularly antimicrobials, might mediate interactions in vitro, but fade into the background in the community context. Through co-cultivation experiments, we identified the siderophore pseudobactin as a potent antimicrobial agent against several SynCom members, but its impact on community composition in planta was negligible. Notably, dominant SynCom members, such as Pseudomonas koreensis, Flavobacterium pectinovorum, and Sporobolomyces roseus, exhibited only positive correlations, suggesting synergism based on for example exopolysaccharides and biotransformation might drive community dynamics rather than competition. Two correlations between SynCom members in the co-abundance network corresponded with their pairwise in vitro interactions, highlighting the potential for further research, and demonstrating the usefulness of correlation networks in identifying key microbe-microbe interactions. Our findings highlight the importance of considering microbiome-wide interaction studies and synthetic communities in understanding and manipulating plant microbiomes.

microbiology↗

bioRxiv2024

Hippocampal neuroinflammation causes sex-specific disruptions in instrumental conditioning, Pavlovian approach, and neuronal excitation

Hippocampal neuroinflammation is present in multiple diseases and disorders that impact motivated behaviour in a sex-specific manner, but whether neuroinflammation alone is sufficient to disrupt such behaviour is unknown. We investigated this question here using mice. First, the application of an endotoxin to primary cultures containing only hippocampal neurons did not affect their activation. However, when the same endotoxin was applied to mixed neuronal/glial cultures it did increase neuronal activation, providing initial indications of how it might be able to effect behavioural change. We next demonstrated neuroinflammatory effects on behaviour directly, demonstrating that intra-hippocampal administration of the same endotoxin increased locomotor activity and accelerated goal-directed learning in both male and female mice. In contrast, hippocampal neuroinflammation caused sex-specific disruptions to the acquisition of instrumental actions and to Pavlovian food-approach memories. Finally, we showed that hippocampal neuroinflammation had a sexually dimorphic effect on neuronal activation: increasing it in females and decreasing it in males.

animal behavior and cognition↗

bioRxiv2024

Standardizing protein corona characterization in nanomedicine: a multi-center study to enhance reproducibility and data homogeneity

Our recent findings reveal substantial variability in the characterization of identical protein corona across different proteomics facilities, demonstrating that protein corona datasets are not easily comparable between independent studies. We have shown that heterogeneity in the final composition of the identical protein corona mainly originates from variations in sample preparation protocols, liquid chromatography mass spectrometry (LC-MS) workflows, and raw data processing. Here, to address this issue, we developed standardized protocols and unified sample preparation workflows, and distributed identical protein corona digests to several proteomics centers that performed better in our previous study. Additionally, we examined the influence of using similar mass spectrometry instruments on data homogeneity. Furthermore, we evaluated whether standardizing database search parameters and data processing workflows could enhance data uniformity. More specifically, our new findings reveal a remarkable, stepwise improvement in protein corona data consistency across various proteomics facilities. Streamlining the whole workflow results in a dramatic increase in protein ID overlaps from 11% for good centers to 40% across core facilities that utilized similar instruments and were subjected to a uniform database search. This comprehensive analysis identifies key factors contributing to data heterogeneity in mass spectrometry-based proteomics of protein corona and plasma-related samples. By streamlining these processes, our findings significantly advance the potential for consistent and reliable nanomedicine-based diagnostics and therapeutics across different studies.

bioengineering↗

bioRxiv2024

Discovery of shared epigenetic pathways across human phenotypes

Omics-based association studies typically consider the marginal effects of a feature, such as CpG DNA methylation, on a trait (e.g, independent models for each feature). Although some methods can assess all features together in joint and conditional estimation, this is currently done on a trait-by-trait basis. Here, we introduce MAJA, a method to learn shared and outcome-specific effects for multiple traits in multi-omics data. MAJA determines the unique contribution of individual loci, genes, or molecular pathways, to variation in one or more traits, conditional on all other measured "omics" data genome-wide. Simulations show MAJA accurately finds shared and distinct associations between omics-data and multiple traits and estimates omics-specific (co)variances, allowing for sparsity and correlations within the data. Applying MAJA to 12 outcome traits in Generation Scotland methylation data (n=18,264), we find novel shared epigenetic pathways among cholesterol metabolism, osteoarthritis, blood pressure and asthma. In contrast to marginal testing, we find only 10 CpG probes with significant effects above the genome-wide background. This highlights the need for joint association testing in highly correlated methylation data from whole blood and for studies of increased sample size in order to refine epigenomic associations in observational data.

genetics↗