Biology subjects

Muller, A.

Publications and source records attributed to Muller, A..

At least 19 recordsLinked to original sources

bioRxiv2025

The geometry of cortical sound processing in slow wave sleep

During wake, sound-evoked and spontaneous neural activity of the auditory cortex evolve in distinct subspaces whereas anesthesia disrupts sound responses and merges these spaces. To evaluate if similar modifications of the sound representation geometry explain sensory disconnection during sleep, we followed large neural populations of the mouse auditory cortex across slow wave sleep and wakefulness. We observed that sleep dampens sound responses but preserves the geometry of sound representations which remain separate from spontaneous activity. Moreover, response dampening was strongly coordinated across neurons and varied throughout sleep spanning from fully preserved response patterns to population response failures on a fraction of sound presentations. These failures are more common during high spindle-band activity and more rarely observed in wakefulness. Therefore, in sleep, the auditory system preserves sound feature selectivity up to the cortex for detailed acoustic surveillance, but concurrently implements an intermittent gating mechanism leading to local sensory disconnections.

neuroscience↗

bioRxiv2025

Lysosomal membrane permeabilization enhances the anticancer effects of RNA Polymerase I transcription inhibitors

Lysosomes are known to contribute to the development of drug resistance through a variety of mechanisms that include the sequestration of drugs within their compartments and the activation of adaptive stress pathways. Although targeting POL I (RNA polymerase I) exhibits anticancer effects, little attention has been paid to the contribution of lysosomes to the efficacy and resistance of RNA POL I inhibitors. In this study, we investigated this aspect in the context of two potent POL I inhibitors, CX-3543 (Quarfloxin) and CX-5461 (Pidnarulex). Unexpectedly, CX-3543 was discovered to be sequestered in the lysosomal compartment. This resulted in the permeabilization of lysosomal membranes (LMP) and the subsequent activation of cellular stress adaptation pathways, including the transcription factor (TFEB) and autophagy. Disruption of TFEB or autophagy increased cell sensitivity to CX-3543, highlighting the cytoprotective role of these processes against cell death induced by this compound. Moreover, targeting lysosomal membranes using chloroquine derivatives or blue light excitation induced substantial LMP, resulting in the liberation of CX-3543 from lysosomes. This effect amplified both the inhibition of DNA-to-RNA transcription and cell death induced by CX-3543. Similar effects were observed when chloroquine derivatives were combined with CX-5461. Furthermore, combining CX-3543 with the chloroquine derivative DC661 reduced the growth of fibrosarcoma established in immunocompetent mice more efficiently than either agent alone. Altogether, our results uncover an unanticipated lysosome-related mechanism that contributes to the resistance of cancer cells to POL I transcription inhibitors, as well as a strategy to combat this resistance.

cancer biology↗

bioRxiv2024

Comprehensive multi-omics profiling of a healthy human cohort

Multi-omics approaches can offer powerful insights into personalized biomarker profiles relevant for disease diagnosis, prognosis, and therapeutics. However, separating meaningful biological variability from technical noise remains a major challenge. The EATRIS-Plus consortium analyzed blood samples from 127 healthy adults across six omics layers using twelve platforms, resulting in one of the most comprehensive multi-omics profiling datasets of healthy individuals available to date. We applied reproducible workflows to analyze and integrate these data, revealing several key findings. Sex significantly influenced all omics layers, emphasizing the importance of sex-balanced study designs. Age could be accurately predicted using epigenetic clocks, achieving high performance with our high-resolution enzymatic methylation sequencing data (R2 = 0.90), whereas candidate aging biomarkers were identified across all omics layers. The resulting dataset provides reference ranges in healthy individuals for abundance and variability of omics features, enabling robust power analyses, sample size estimations, and benchmarking of multi-omics integration methods. This resource can guide future biomarker discovery and personalized health research and was made FAIR-compliant and publicly available via the ClinData Portal (https://clindata.imtm.cz) and a Zenodo repository (https://doi.org/10.5281/zenodo.17514796).

bioinformatics↗

bioRxiv2024

Shikimate pathway-Dependent Catabolism:enabling near-to-maximum production yield of aromatics

Catabolism is a complex network of tightly regulated metabolic reactions that provides energy and carbon to fuel anabolism in all living organisms. Rewiring catabolism is essential for harnessing industrial biotechnology but remains a substantial metabolic engineering challenge due to its high genetic stability and tight regulation acquired through evolution. In this study, by combining metabolic modeling, rational engineering, and adaptive laboratory evolution, we fundamentally redesigned bacterial catabolism. We created a new-to-nature shikimate pathway-dependent catabolism (SDC) in Pseudomonas putida by reprogramming the shikimate pathway as the primary catabolic route. SDC supports growth by supplying the glycerol catabolic end-product pyruvate, enabling superior production of shikimate pathway-derived molecules. Through SDC, aromatics production reached over 89% of the pathways maximum theoretical yield, setting a new benchmark for their microbial synthesis. Our study successfully repurposed an anabolic pathway for catabolism, exemplifying the high metabolic plasticity of microbes and providing a bacterial chassis for the efficient production of high-added value compounds.

synthetic biology↗

bioRxiv2024

Flanking Domains Modulate α-Synuclein Monomer Structure: A Molecular Dynamics Domain Deletion Study

Aggregates of misfolded -synuclein proteins (asyn) are key markers of Parkinsons disease. Asyn proteins have three domains: an N-terminal domain, a hydrophobic NAC core implicated in aggregation, and a proline-rich C-terminal domain. Proteins with truncated C-terminal domains are known to be prone to aggregation and suggest that understanding domain-domain interactions in asyn monomers could help elucidate the role of the flanking domains in modulating protein structure. To this end, we used Gaussian accelerated molecular dynamics (GAMD) to simulate wild-type (WT), N-terminal truncated ({Delta}N), C-terminal truncated ({Delta}C), and isolated NAC domain asyn protein variants (isoNAC). Using clustering and contact analysis, we found that removal of the N-terminal domain led to increased contacts between NAC and C-terminal domains and the formation of interdomain {Delta}-sheets. Removal of either flanking domain also resulted in increased compactness of every domain. We also found that the contacts between flanking domains in the WT protein result in an electrostatic potential (ESP) that may lead to favorable interactions with anionic lipid membranes. Removal of the C-terminal domain disrupts the ESP in a way that could result in over-stabilized protein-membrane interactions. These results suggests that cooperation between the flanking domains may modulate the proteins structure in a way that helps maintain elongation and creates an ESP that may aid favorable interactions with the membrane.

biophysics↗

bioRxiv2023

Comprehensive chromatome profiling identifies metabolic enzymes on chromatin in healthy and cancer cells

Metabolic and epigenetic rewiring are widely considered hallmarks of cancer, with emerging evidence of crosstalk between them. Anecdotal evidence of metabolic enzymes moonlighting in the chromatin environment has suggested how this crosstalk might be facilitated, but the extent of nuclear relocalization of metabolic enzymes remains elusive. Here, we provide a comprehensive chromatin proteomics resource across cancer lineages as well as healthy samples and demonstrate that metabolic enzyme moonlighting on chromatin is widespread across tissues and pathways. We show that the abundance of metabolic enzymes on chromatin is tissue-specific, with oxidative phosphorylation proteins depleted in lung cancer samples, perhaps suggesting an interplay between cell identity and nuclear metabolism. Finally, we explore metabolic functions in the chromatin environment and show that one-carbon folate enzymes are associated with DNA damage and repair processes, providing an approach to explore non-canonical functions of metabolic enzymes.

cancer biology↗

bioRxiv2023

Differences in syncytia formation by SARS-CoV-2 variants modify host chromatin accessibility and cellular senescence via TP53

COVID-19 remains a significant public health threat due to the ability of SARS-CoV-2 variants to evade the immune system and cause breakthrough infections. Although pathogenic coronaviruses such as SARS-CoV-2 and MERS-CoV lead to severe respiratory infections, how these viruses affect the chromatin proteomic composition upon infection remains largely uncharacterized. Here we used our recently developed integrative DNA And Protein Tagging (iDAPT) methodology to identify changes in host chromatin accessibility states and chromatin proteomic composition upon infection with pathogenic coronaviruses. SARS-CoV-2 infection induces TP53 stabilization on chromatin, which contributes to its host cytopathic effect. We mapped this TP53 stabilization to the SARS-CoV-2 spike and its propensity to form syncytia, a consequence of cell-cell fusion. Differences in SARS-CoV-2 spike variant-induced syncytia formation modify chromatin accessibility, cellular senescence, and inflammatory cytokine release via TP53. Our findings suggest that differences in syncytia formation alter senescence-associated inflammation, which varies among SARS-CoV-2 variants.

microbiology↗

bioRxiv2023

High-efficiency base editing for Stargardt disease in mice, non-human primates, and human retina tissue

Stargardt disease is a currently untreatable, inherited neurodegenerative disease that leads to macular degeneration and blindness due to loss-of-function mutations in the ABCA4 gene. We have designed a dual adeno-associated viral vector split-intein adenine base-editing strategy to correct the most common mutation in ABCA4 (c.5882G>A, p.G1961E). We optimized ABCA4 base editing in human models, including retinal organoids, iPSC-derived retinal pigment epithelial (RPE) cells, as well as adult human retinal- and RPE/choroid explants in vitro. The resulting gene therapy vectors achieved high levels of gene correction in mutation-carrying mice and in non-human primates, with an average editing of 37% of photoreceptors and 73% of RPE cells in vivo. The high editing rates in primates make way for precise and efficient gene editing in other neurodegenerative ocular diseases.

neuroscience↗

bioRxiv2023

Glioblastoma-instructed microglia transit to heterogeneous phenotypic states with phagocytic and dendritic cell-like features in patient tumors and patient-derived orthotopic xenografts

BackgroundA major contributing factor to glioblastoma (GBM) development and progression is its ability to evade the immune system by creating an immune-suppressive environment, where GBM-associated myeloid cells, including resident microglia and peripheral monocyte-derived macrophages, play critical pro-tumoral roles. However, it is unclear whether recruited myeloid cells are phenotypically and functionally identical in GBM patients and whether this heterogeneity is recapitulated in patient-derived orthotopic xenografts (PDOXs). A thorough understanding of the GBM ecosystem and its recapitulation in preclinical models is currently missing, leading to inaccurate results and failures of clinical trials. MethodsHere, we report systematic characterization of the tumor microenvironment (TME) in GBM PDOXs and patient tumors at the single-cell and spatial levels. We applied single-cell RNA-sequencing, spatial transcriptomics, multicolor flow cytometry, immunohistochemistry and functional studies to examine the heterogeneous TME instructed by GBM cells. GBM PDOXs representing different tumor phenotypes were compared to glioma mouse GL261 syngeneic model and patient tumors. ResultsWe show that GBM tumor cells reciprocally interact with host cells to create a GBM patient-specific TME in PDOXs. We detected the most prominent transcriptomic adaptations in myeloid cells, with brain-resident microglia representing the main population in the cellular tumor, while peripheral-derived myeloid cells infiltrated the brain at sites of blood-brain barrier disruption. More specifically, we show that GBM-educated microglia undergo transition to diverse phenotypic states across distinct GBM landscapes and tumor niches. GBM-educated microglia subsets display phagocytic and dendritic cell-like gene expression programs. Additionally, we found novel microglial states expressing cell cycle programs, astrocytic or endothelial markers. Lastly, we show that temozolomide treatment leads to transcriptomic plasticity and altered crosstalk between GBM tumor cells and adjacent TME components. ConclusionOur data provide novel insights into the phenotypic adaptation of the heterogeneous TME instructed by GBM tumors. We show the key role of microglial phenotypic states in supporting GBM tumor growth and response to treatment. Our data place PDOXs as relevant models to assess the functionality of the TME and changes in the GBM ecosystem upon treatment. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/531162v2_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1549a3corg.highwire.dtl.DTLVardef@159f16aorg.highwire.dtl.DTLVardef@1f89500org.highwire.dtl.DTLVardef@fe6b67_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Maternal diet and gut microbiome composition modulate early life immune responses

In early life, the intestinal mucosa and immune system undergo a critical developmental process to contain the expanding gut microbiome while promoting tolerance towards commensals, yet the influence of maternal diet and gut microbial composition on offspring immune maturation remains poorly understood. We colonized gnotobiotic mice with a defined consortium of 14 strains, fed them a standard fiber-rich chow or a fiber-free diet, and then longitudinally assessed offspring development during the weaning period. Unlike pups born to dams fed the fiber-rich diet, pups of fiber-deprived dams demonstrated delayed colonization with Akkermansia muciniphila, a mucin-foraging bacterium that can also utilize milk oligosaccharides. The pups of fiber-deprived dams exhibited an enrichment of colonic tissue transcripts corresponding to defense response pathways and a peak in Il22 expression at weaning. Removal of A. muciniphila from the community, but maintenance on the fiber-rich diet, was associated with reduced proportions of ROR{gamma}t-positive innate and adaptive immune cell subsets. Our results highlight the potent influence of maternal dietary fiber intake and discrete changes in microbial composition on the postnatal microbiome assemblage and early immune development.

microbiology↗

bioRxiv2023

A multi-omics integrative approach unravels novel genes and pathways associated with senescence escape after targeted therapy in NRAS mutant melanoma

Therapy Induced Senescence (TIS) leads to sustained growth arrest of cancer cells. The associated cytostasis has been shown to be reversible and cells escaping senescence further enhance the aggressiveness of cancers. Together with targeted therapeutics, senolytics, specifically targeting senescent cancer cells, constitute a promising avenue for improved cancer treatments. Understanding how cancer cells evade senescence is needed to optimise the clinical benefits of this therapeutic approach. Here we characterised the response of three different NRAS mutant melanoma cell lines to a combination of CDK4/6 and MEK inhibitors over 33 days. Transcriptomic data show that all cell lines trigger a senescence programme coupled with strong induction of interferons. Kinome profiling revealed the activation of Receptor Tyrosine Kinases (RTKs) and enriched downstream signaling of neurotrophin, ErbB and insulin pathways. Characterisation of the miRNA interactome associates miR-211-5p with resistant phenotypes. Finally, iCELL-based integration of bulk and single-cell RNA-seq data identified biological processes perturbed during senescence, and predicts new genes involved in its escape. Overall, our data associate insulin signaling with persistence of a senescent phenotype and suggest a new role for interferon gamma in senescence escape through the induction of EMT and the activation of ERK5 signaling.

cancer biology↗

bioRxiv2022

Accuracy of a markerless motion capture system for balance related quantities

BackgroundBalance studies usually focus on quantities describing the global body motion, such as the position of the whole-body centre of mass (CoM), its associated extrapolated centre of mass (XCoM) and the whole-body angular momentum (WBAM). Assessing such quantities using classical marker-based approach can be tedious and modify the participants behaviour. The recent development of markerless motion capture methods could bypass the issues related to the use of markers. Research questionCan we use markerless motion capture systems to study quantities that are relevant for balance studies? MethodsSixteen young healthy participants performed four different motor tasks: walking at self-selected speed, balance loss, walking on a narrow beam and countermovement jumps. Their movements were recorded simultaneously by marker-based and markerless motion capture systems. Videos were processed using a commercial markerless pose estimation software, Theia3D. The position of their CoM was computed, and the associated XCoM and WBAM were derived. Bland-Altman analysis was performed and root mean square error and coefficient of determination were computed to compare the results obtained with marker-based and markerless methods across all participants and tasks. ResultsBias remained of the magnitude of a few mm for CoM and XCoM position, and RMSE of CoM and XCoM was around 1 cm. Confidence interval for CoM and XCoM was under 2 cm except for one task in one direction. RMSE of the WBAM was less than 8% of the total amplitude in any direction, and bias was less than 1%. SignificanceResults suggest that the markerless motion capture system can be used in balance studies as the measured errors are in the range of the differences found between different models or populations in the literature. Nevertheless, one should be careful when assessing dynamic movements such as jumping, as they displayed the biggest errors. HighlightsO_LIMarkerless motion capture could bypass issues from classical marker-based approaches C_LIO_LIWe compared balance related quantities computed from both approaches C_LIO_LIMean differences were about 1cm on the position of the whole-body center of mass C_LIO_LIObtained differences are acceptable for most applications C_LI

bioengineering↗

bioRxiv2022

Description, Development and Dissemination of Two Consistent Marker-based and Markerless Multibody Models

In human movement analysis, multibody models are an indispensable part of the process both for marker-based and video-based markerless approaches. Constituents (segments, joint constraints, body segment inertial parameters etc.) of such models and modelers choice play an important role in the accuracy of estimated results (segmental and joint kinematics, segmental and whole-body center of mass positions etc.). For marker-based method, although standard models exist, particularly for the lower extremity (e.g., Conventional Gait Model or models embedded in OpenSim), there seems to be a lack of consolidated explanation on the constituents of the whole-body model. For the markerless approach, multibody kinematic models (e.g., the Theia3D model) have been in use lately. However, there is no clear explanation on the estimated quantities (e.g., joint centers, body surface landmarks etc.) and their relation to the underlying anatomy. This also motivates the need for a description of the markerless multibody model. Moreover, comparing markerless results to those of classical marker-based method is currently the most commonly used approach for evaluation of markerless approaches. This study first aims to develop and describe a whole-body marker-based model ready to be used for human movement analysis. Second, the markerless multibody model embedded in Theia3D is described and inertial parameters are redefined. We also report assessment of the markerless approach compared to marker-based method for a static T-pose performed by 15 subjects. Finally, we disseminate the marker-based and markerless multibody models for their use in Visual3D.

bioengineering↗

bioRxiv2020

Could TDX-1 explain the changes observed in endocrine pancreas due to chronic cola drink consumption in rats? A global point of view

In previous studies, we reported evidence showing that chronic cola consumption in rats impairs pancreatic metabolism of insulin and glucagon and produces some alterations typically observed in the metabolic syndrome (i.e, hyperglycemia, and hypertriglyceridemia) with an increase in oxidative stress. Of note, no apoptosis nor proliferation of islet cells could be demonstrated. In the present study, 36 male Wistar rats were divided in three groups to freely drink regular cola, light cola, or water (controls). We assessed the impact of the three different beverages in glucose tolerance, lipid levels, creatinine levels and immunohistochemical changes addressed for the expression of insulin, glucagon, PDX-1 and NGN3 in islet cells, to evaluate the possible participation of PDX-1 in the changes observed in and {beta} cells after 6 months of treatment. On the other hand, we assessed by stereological methods, the mean volume of islets (Vi) and three important variables, the fractional {beta}-cell area, the cross-sectional area of alpha (A -cell) and beta cells (A {beta}-cell), and the number of {beta} and cell per body weight. Cola drinking caused impaired glucose tolerance as well as fasting hyperglycemia and increase of insulin immunolabeling. Immunohistochemical expression for PDX-1 was significantly high in regular cola consumption group compared to control. In this case, we observed cytoplasmatic and nuclear localization. Likewise, a mild but significant decrease of Vi was detected after 6 months of cola drink consumption compared with control group. Also, we observed a significant decrease of fractional {beta} cell area compared with control rats. Accordingly, a reduced mean value of islet and {beta} cell number per body weight compared to control was detected. Interestingly, consumption of light cola increased the Vi compared to control. In line with this, a decreased cross-sectional area of {beta}-cells was observed after chronic consumption of both, regular and light cola, compared to controls. On the other hand, NGN3 was negative in all three groups. Our results support for the first time, the idea that TDX-1 plays a key role in the dynamics of the pancreatic islets after chronic consumption of sweetened beverages. The loss of islets cells might be attributed to autophagy, favored by the local metabolic conditions.

systems biology↗

bioRxiv2020

Recollection is more than retrieving context or source memory: evidence from ERPs of Recognition and Source Memory combinations

The goal of this study was to investigate a relatively unstudied memory condition for paradoxical combinations of item + source memory confidence responses, which challenged the conventional views of the memory processes supporting item and source memory judgments. We studied instances in which people provided accurate source memory judgments (conventionally ascribed as representing recollection) after having first produced low- confidence item recognition hits for the same items (conventionally thought to reflect familiarity-based processing). This paradoxical combination does not fit traditional accounts of being recollection (because it had low-confidence recognition) nor accounts of familiarity (since it had accurate source memory), and event-related potentials (ERPs) were used to adjudicate which processes support these kinds of memories. ERP results were unlike the conventional ERP effects of memory, lacking both an FN400 and the parietal old-new effect (LPC), and instead exhibited a significant negative-going ERP effect occurring later in time (800-1200ms) in central-parietal sites. Behavioral measures of response times revealed a crossover interaction: low confident recognition hits were slower during recognition but faster during source memory when compared to the opposite pattern seen for instances of high confident hits. Results provide a comprehensive characterization of the individual variability of the FN400 and LPC effects of memory, while adding the behavioral and physiological characterization of a late negative-going ERP effect for accurate source memory without recollection. Conclusions indicated that episodic context could be retrieved independently from recollection, while suggesting a role for a process of context familiarity that is independent from item-familiarity. HighlightsO_LIRecollection is often defined as remembering the source or context of information C_LIO_LIPrior work used ERPs to identify times when source memory did not have recollection C_LIO_LICurrent work replicated ERPs with added response times and measures of variance C_LIO_LIRecollection was not evident in certain source memories, which had a negative ERP C_LIO_LIRecollection is independent of context and is more than just remembering sources C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=182 SRC="FIGDIR/small/339697v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@4926f8org.highwire.dtl.DTLVardef@9d87d4org.highwire.dtl.DTLVardef@40a701org.highwire.dtl.DTLVardef@9460f1_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Primary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine

Patient-derived cancer models are essential tools for studying tumor biology and preclinical interventions. Here, we show that glioma patient-derived orthotopic xenografts (PDOXs) enable long-term propagation of patient tumors and represent clinically relevant patient avatars. We created a large collection of PDOXs from primary and recurrent gliomas with and without mutations in IDH1, which retained histopathological, genetic, epigenetic and transcriptomic features of patient tumors with no mouse-specific clonal evolution. Longitudinal PDOX models recapitulate the limited genetic evolution of gliomas observed in patient tumors following treatment. PDOX-derived standardized tumor organoid cultures enabled assessment of drug responses, which were validated in mice. PDOXs showed clinically relevant responses to Temozolomide and to targeted treatments such as EGFR and CDK4/6 inhibitors in (epi)genetically defined groups, according to MGMT promoter and EGFR/CDK status respectively. Dianhydrogalactitol, a bifunctional alkylating agent, showed promising potential against glioblastoma. Our study underlines the clinical relevance of glioma PDOX models for translational research and personalized treatment studies.

cancer biology↗

bioRxiv2019

Neurophysiological Correlates of the Dunning-Kruger Effect Reveal Contributions of Episodic Memory to Metacognitive Judgments of Illusory Superiority

Abstract.The Dunning-Kruger Effect (DKE) is a metacognitive phenomenon of illusory superiority in which individuals who perform poorly on a task believe they performed better than others, yet individuals who performed very well believe they under-performed compared to others. This phenomenon has yet to be directly explored in episodic memory, nor explored for reaction times or physiological correlates. We designed a novel method to elicit the DKE via a test of item recognition while electroencephalography (EEG) was recorded. Throughout the task, participants were asked to estimate the percentile in which they performed compared to others. Results revealed participants in the bottom 25th percentile overestimated their percentile, while participants in the top 75th percentile underestimated their percentile, exhibiting the classic DKE. Reaction time measures revealed a condition x group interaction whereby over-estimators responded faster than under-estimators when estimating being in the top percentile and responded slower when estimating being in the bottom percentile. Between-group EEG differences were evident between over-estimators and under-estimators during Dunning-Kruger responses, which revealed FN400-like effects of familiarity supporting differences for over-estimators from 400-600 ms, whereas old-new memory ERP effects revealed a late parietal component (LPC) associated with recollection-based processing from 600-900 ms for under-estimators that was not evident for over-estimators. Findings suggest over- and under-estimators use differing cognitive processes when assessing their performance, such that under-estimators rely on recollection during memory and over-estimators draw upon excess familiarity when over-estimating their performance. Episodic memory thus appears to play a contributory role in metacognitive judgments of illusory superiority and inferiority. Graphical AbstractEvent-related potentials (ERPS) were recorded for the Dunning-Kruger Effect as subjects made metacognitive judgments about performance on a memory task. Over- and Under-estimators exhibited a crossover interaction in response times when believing they did best and worst, respectively. A crossover pattern was also observed for ERPs: LPC signals of recollection were found for under-estimators, whereas familiarity-based FN400 effects were evident for over-estimators and correlated with estimates. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/888511v2_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@12d42b2org.highwire.dtl.DTLVardef@75ef31org.highwire.dtl.DTLVardef@aa8a9dorg.highwire.dtl.DTLVardef@725925_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2018

Independent component analysis provides clinically relevant insights into the biology of melanoma patients

The integration of publicly available and new patient-derived transcriptomic datasets is not straightforward and requires specialized approaches to deal with heterogeneity at technical and biological levels. Here we present a methodology that can overcome technical biases, predict clinically relevant outcomes and identify tumour-related biological processes in patients using previously collected large reference datasets. The approach is based on independent component analysis (ICA) - an unsupervised method of signal deconvolution. We developed parallel consensus ICA that robustly decomposes merged new and reference datasets into signals with minimal mutual dependency. By applying the method to a small cohort of primary melanoma and control samples combined with a large public melanoma dataset, we demonstrate that our method distinguishes cell-type specific signals from technical biases and allows to predict clinically relevant patient characteristics. Cancer subtypes, patient survival and activity of key tumour-related processes such as immune response, angiogenesis and cell proliferation were characterized. Additionally, through integration of transcriptomes and miRNomes, the method identified biological functions of miRNAs, which would otherwise not be possible.

genomics↗