Biology subjects

Parker, B.

Publications and source records attributed to Parker, B..

At least 19 recordsLinked to original sources

bioRxiv2026

GenomeProt: User friendly proteogenomics for canonical and non-canonical proteoform characterisation

Quantifying the diversity of RNAs and proteins produced by cells is fundamental to the biological and clinical sciences. However, many RNAs and proteins remain uncharacterised, especially proteins translated from alternate RNA isoforms; untranslated regions of mRNAs and non-coding RNAs, as well as the effects of DNA variation on protein sequences. Proteogenomics aims to characterise the complete proteome by integrating genomics and/or transcriptomics with proteomics, but current tools have limitations in useability, analysis features and visualisation of resulting data. To address these gaps, we developed GenomeProt, a user-friendly GUI-based tool for integrative proteogenomic analysis. We demonstrate its utility by integrating long-read RNA sequencing with mass-spectrometry-based proteomics to pinpoint proteoform expression generated by alternative splicing; discover novel, unannotated proteins in human brain samples; and quantify variant-containing peptides associated with treatment resistance in a melanoma xenograft model. GenomeProt brings the discovery power of proteogenomics to biologists, illuminating the hidden proteome.

bioinformatics↗

bioRxiv2026

Targeting DNA Methylation Reactivates Type I Interferon Signalling in Bone-Metastatic Breast Cancer

Bone metastasis remains a major clinical challenge in advanced breast cancer. Downregulation of type I interferon signalling, a critical immunomodulatory pathway in anti-cancer immunity and disease progression, is a defining feature of this process. Here, we utilised an IFN-reporter system to perform unbiased epigenetic compound screens to identify agents that could restore type I IFN signalling. This screen identified Decitabine, a DNA hypomethylating agent, that enhanced tumor immunogenicity across a broad range of mouse and human breast cancer cell lines, including bone-derived lines. Mechanistically, suppression of interferon-stimulated genes is highly correlated with elevated DNMT1 expression in bone metastasis compared with primary tumor, in both mouse models and matched human samples. Decitabine treatment was sufficient to reactivate interferon stimulated genes in bone-derived 4T1.2 cell lines via hypomethylation of type I interferon pathway gene promoter regions. Correspondingly, in the syngeneic 4T1.2 metastasis mouse model, Decitabine treatment conferred a survival benefit and reduced metastatic potential, particularly in bone. Our findings reveal DNA methylation as a key regulator of the transcriptional programs underlying bone metastasis, providing mechanistic insight into how Decitabine reactivates type I interferon signalling and reduces metastatic potential, highlighting epigenetic reprogramming as a promising approach for targeting metastatic breast cancer. STATEMENT OF SIGNIFICANCEBone metastasis remains a major clinical challenge and a key mechanism of progression to bone is the suppression of tumor-inherent type I interferon signalling. We identified Decitabine, a DNA hypomethylating agent, as a promising therapeutic agent to enhance tumor immunogenicity across a broad range of breast cancer cell lines, including bone metastasis-derived lines. Our findings support DNA methylation as a key regulator of transcriptional programs associated with bone metastatic progression, and provide mechanistic insight into how Decitabine reactivates type I interferon signalling and reduces metastatic potential in vivo. These results highlight epigenetic reprogramming as a promising approach for targeting metastatic breast cancer.

Cancer Biology↗

bioRxiv2026

Rac1 deficiency reduces mitochondrial respiratory capacity, impairs fatty acid metabolism and causes muscle wasting

BackgroundThe age-related progressive decline in skeletal muscle function is characterised by declining mitochondrial quality control and perturbed fatty acid metabolism, contributing to frailty and increased mortality. The actin cytoskeleton, a key structural component of skeletal muscle, has recently been implicated in mitochondrial anchoring and dynamics. However, the role of actin-regulating proteins, including the Rho GTPase Rac1, in mitochondrial function and age-associated metabolic and functional muscle deterioration remains undefined. MethodsSkeletal muscle from mice with inducible muscle-specific deletion of Rac1 (Rac1 imKO) underwent unbiased mass spectrometry-based proteomic profiling. Mitochondrial morphology was assessed by transmission electron microscopy, and physiological parameters, including muscle mass and contraction-stimulated palmitate oxidation in isolated soleus muscle, were evaluated. Mitochondrial respiratory function was determined by high-resolution respirometry in permeabilised gastrocnemius skeletal muscle fibre bundles. Biochemically, muscular triacylglycerol (TG) content, mRNA (qPCR) and protein (immunoblotting) content were determined. In vastus lateralis muscle biopsies from healthy, untrained young (20-30 years) and old, sarcopenic (83-94 years) men, Rac1 and mitochondrial respiratory protein abundances were measured. A complementary human genetic association analysis was performed using the FinnGen dataset. ResultsRac1 deficiency triggered muscle wasting in middle-aged mice (Gastrocnemius: -10%; Quadriceps: -7%). Preceding muscle wasting, gene set enrichment analysis identified enrichment in fatty acid metabolism and oxidative phosphorylation pathways, consistent with increased mitochondrial volume density in Rac1 imKO muscle (subsarcolemmal: +467%; intermyofibrillar: +166%). Despite mitochondrial expansion at this stage, Rac1 deficiency attenuated the increase in palmitate oxidation in response to muscle contraction (-62%). At the muscle-wasting stage, Rac1 imKO muscle exhibited reduced mitochondrial respiratory capacity (-25-32%). Additionally, the mitochondrial dysfunction was associated with an accumulation of muscle TG (+78%, p = 0.096) and upregulation of fatty acid transporter, CD36 protein content (+25%), indicative of altered fatty acid handling. In humans, Rac1 muscle protein content was increased in old, sarcopenic subjects compared to young (+41%), and negatively correlated with quadriceps cross-sectional area (CSA) (r = -0.475) and type II fibre CSA (r = -0.466). In old, sarcopenic muscle, Rac1 protein content correlated negatively with protein content of multiple mitochondrial respiratory complexes (CI: r = -0.690, CIV: r = -0.938, CV: r = -0.704). GWAS further identified associations between Rac1 SNP variants and lipid metabolic and muscle-wasting diseases. ConclusionsMuscle Rac1 deficiency reduces mitochondrial respiratory capacity and metabolic flexibility through impaired fatty acid metabolism, leading to muscle wasting and highlighting a potential therapeutic target in age-related functional decline.

Molecular Biology↗

bioRxiv2026

RNAElectra: An ELECTRA-Style RNA Foundation Model for RNA Regulatory Inference

BackgroundRNA regulation programs gene expression through sequence-encoded mechanisms--including RNA structure formation, protein binding, chemical modification, and RNA-RNA targeting--whose rules span nucleotide-scale motifs and longer-range context. RNA foundation models aim to learn transferable representations from large RNA corpora, but most rely on masked language modeling (MLM), where the model loss is computed on a small subset of positions and training relies on artificially corrupted inputs that are absent at downstream inference, introducing a pretraining-downstream discrepancy. ResultsWe introduce RNAElectra, a single-nucleotide-resolution RNA foundation model pretrained on diverse non-coding RNAs from RNAcentral using ELECTRA-style replaced-token detection (RTD). RTD trains a discriminator with a loss defined over all input positions on realistically corrupted sequences, providing dense supervision that better aligns pretraining with sequence-to-function fine-tuning. RNAElectra combines nucleotide-resolution tokenization with an efficient attention design to capture local regulatory motifs and longer-range dependencies within a single reusable backbone. Using a unified, sequence-only fine-tuning pipeline without task-specific architectures or auxiliary inputs, RNAElectra demonstrates strong cross-task generalization across benchmarks and downstream evaluations spanning RNA structure and function, RNA-protein and RNA-RNA interactions, RNA modification landscapes, and quantitative regulatory readouts such as translation efficiency and mRNA stability, outperforming widely used RNA foundation model baselines on the majority of evaluated tasks. In addition to predictive performance, RNAElectra supports interpretability by enabling analysis of learned representations and sequence determinants underlying model predictions. ConclusionRNAElectra establishes RTD pretraining as a practical alternative to MLM for RNA foundation modeling, coupling dense position-wise supervision with an efficient architecture to deliver broadly transferable RNA representations. This framework provides a reusable backbone for RNA regulatory prediction and supports sequence-level RNA engineering and design.

bioinformatics↗

bioRxiv2026

Alternative promoters used during myeloid differentiation and upon activation change the gene products available for innate immune programs.

Macrophages are innate immune cells present in most tissues of the body, whose molecular programs are determined by their ontogeny and environment. From the earliest stages of embryonic development, macrophages are recruited into developing tissues where they support organogenesis with trophic factors such as WNT, VEGF and PDGF. While macrophage subsets have been described in different tissues at single cell resolution, little is known about transcript isoforms and proteoforms that underpin their differentiation and function. Here we assessed enhancer, promoter, transcript and proteomic variation as pluripotent stem cells differentiate to macrophages, identifying over 200 previously uncharacterised genes and over 20,000 new mRNA isoforms, updating our current understanding of the human genome, its regulation and potential output. Newly discovered myeloid-expressed transcripts and proteins were enriched for motifs associated with secreted proteins, and these included previously uncharacterised isoforms of growth factors, in which we predict N-terminal changes impact on their location and function. Activation of primary adult monocytes and monocyte-derived macrophages was also characterised by the expression of diverse transcript isoforms, largely arising from alternate transcription initiation sites and predicted to impact on the acute response to bacterial or fungal stimuli. Understanding the full spectrum of gene products expressed by these cells further extends our understanding of the phenotypic plasticity and trophic potential of macrophages in human development and may lead to the discovery of new clinical targets for tissue engineering or immune-related studies. Graphical AbstractIn this manuscript, Berrocal-Rubio and colleagues examined the differentiation of human macrophages using an iPSC model of tissue macrophage biology. Combining long-read sequencing technology with promoter profiling identified over 17, 700 genes implicated in pluripotency-myeloid specification. 7% of transcripts profiled from previously characterised genes were predicted to encode new proteins, and a further 3% of transcripts were derived from genes newly discovered in this project. They confirmed that a high proportion of these alternate transcripts were detectable in primary monocytes but also discovered that activation of primary monocytes led to further alternate promoter usage, with the potential to further diversify the innate immune responses to a broad set of pathogens. The newly described macrophage genes and transcripts encoded proteins enriched for motifs associated with secreted peptides. These data suggest that alternate transcription of macrophage genes leads to new effectors of innate immune function, that include a substantially expanded number of growth factors or secreted proteins. Created in BioRender. Berrocal, M. (2025) https://BioRender.com/d0n47le O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/703142v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@454cf0org.highwire.dtl.DTLVardef@1be28e8org.highwire.dtl.DTLVardef@16fb2e8org.highwire.dtl.DTLVardef@4aca30_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2025

NucEL: Single-Nucleotide ELECTRA-Style Genomic Pre-training for Efficient and Interpretable Representations

Pre-training large language models on genomic sequences has become a powerful approach for learning biologically meaningful representations. While masked language modeling (MLM)-based approaches, such as DNABERT and Nucleotide Transformer (NT), achieve strong performance, they are hindered by inefficiencies due to partial token supervision, pre-training/fine-tuning mismatches, and high computational costs. We introduce NucEL, the first ELECTRA-style pre-training framework for genomic foundation models, which overcomes these challenges. Through a discriminator network identifying tokens modified by a generator, Nu-cEL achieves comprehensive token-level supervision across all sequence positions, thereby markedly improving training efficiency relative to the partial supervision of masked positions inherent in MLM frameworks. By integrating ModernBERTs architectural advancements, including hybrid local-global attention and flash attention mechanisms, NucEL establishes an optimized BERT architecture for genomic sequence modeling. Unlike traditional methods that tokenize genomic sequences into 6-mers, NucEL implements single-nucleotide tokenization, enabling fine-grained resolution and improving both efficiency and interpretability. Pre-trained on the human genome only, NucEL achieves state-of-the-art performance on benchmark datasets across diverse downstream tasks in both human and non-human species, including regulatory element identification (e.g., promoters, enhancers), transcription factor binding prediction in human and mouse, open chromatin region classification, and histone modification profiles, surpassing MLM-based models of similar size and rivaling models 25 times larger, such as NT. Ablation studies provide critical insights into tokenization and masking strategies, optimizing ELECTRA-style pretraining for DNA sequences. Attention analyses reveal NucELs superior ability to capture biologically relevant sequence motifs compared to NT, offering valuable insights into its hierarchical learning process and regulatory element modeling capabilities. This work highlights the potential of ELECTRA-style pretraining as an efficient and effective strategy for advancing genomic representation learning with broad implications for future genomic research.

genomics↗

bioRxiv2025

Embryonic stem cell factors DPPA2/4 facilitate a unique chromatin state in non-small cell lung cancer

Embryonic regulators are often re-expressed in cancers, however the functional and molecular significance of this is not always understood. The epigenetic priming factors Developmental Pluripotency Associated 2 and 4 (DPPA2/4) have crucial roles in early development and are implicated in cancer pathogenesis. We reveal in non-small cell lung cancer (NSCLC), DPPA2/4 co-expression is associated with poorly differentiated tumours, impaired patient outcomes and accelerated in vivo xenograft tumour growth. Proteomic analyses reveal DPPA2/4 dimerise to enhance their protein stability and binding efficiency to nucleosomes. Our multiomic epigenomic analysis uncovered novel functions for DPPA2/4 in facilitating a unique chromatin landscape in NSCLC cells at active promoters and enhancers. These domains are simultaneously marked by active H3K4me3, PRC1 deposited H2AK119Ub but devoid of PRC2 deposited H3K27me3. This paradoxical uncoupling between the activity of the Polycomb Repressive Complexes is likely driven by H3K27ac at these regions that prevents PRC2 catalytic activity but not recruitment. Our results demonstrate how in NSCLC cells, DPPA2/4 promote a "poised for repression" chromatin state, uncoupling complex recruitment from catalytic activity. Our study highlights how aberrant re-activation of embryonic factors in cancers may take on new functions, promoting tumourigenesis.

molecular biology↗

bioRxiv2025

Heritable viral symbionts in the family Iflaviridae are widespread among aphids

AO_SCPLOWBSTRACTC_SCPLOWHeritable microbes shape host phenotypes and are important drivers of evolution. While interactions between insects and bacterial symbionts have been extensively studied, the prevalence and consequences of insect-viral symbiosis are an open question. We show that viral symbionts in the family Iflaviridae are widespread among aphids, an important model for research on bacterial symbiosis. We discovered multiple new species of iflaviruses that are maintained in asexual lines without apparent fitness costs and are transmitted vertically from mothers to offspring. Using field data and phylogenetic evidence, we further show that aphid iflaviruses likely move horizontally across species, but through laboratory experiments, we demonstrated that horizontal transfer among species infesting the same host plants does not persist throughout clonal lineages. Using quantitative PCR and immunohistochemistry, we discovered that viral infections localize in the host fat bodies and developing embryos. Surprisingly, we also found viral infections inside bacteria-housing cells called bacteriocytes, with a positive correlation between viral and bacterial symbiont density, indicating a mechanism for vertical transmission. Together, our work suggests that iflaviruses are an important but previously unrecognized piece of aphid symbiosis and sets the stage to use this model to answer new questions about host-microbe associations. IO_SCPLOWMPORTANCEC_SCPLOWIn recent years, the rise of metatranscriptome sequencing has led to the rapid discovery of novel viral sequences in insects. However, few studies have carefully investigated the dynamics of insect-virus interactions to produce a general understanding of viral symbiosis. Aphids are a significant agricultural pest but also an important model for understanding the evolution of host-microbe interactions and the molecular basis of bacterial symbiosis. We show that heritable iflaviruses are an important but previously unrecognized part of the aphid heritable microbiome, with viral symbionts transmitted alongside bacteria from mothers to offspring, potentially via specialized bacteriocytes that house symbiotic microbes. Our findings have important implications for furthering the understanding of insect-microbe symbiosis and the potential for biocontrol of agriculturally relevant pest species.

evolutionary biology↗

bioRxiv2025

Revisiting the Central Dogma: the distinct roles of genome, methylation, transcription, and translation on protein expression in Arabidopsis thaliana

BackgroundWe investigated the flow of information from genome sequence to protein expression implied by the Central Dogma, to determine the impact of intermediate genomic levels in plants. ResultsWe performed genomic profiling of rosettes in two Arabidopsis accessions, Col-0 and Can-0, and assembled their genomes using long reads and chromatin interaction data. We measured gene and protein expression in biological replicates grown in a controlled environment, also measuring CpG methylation, ribosome-associated transcript levels and tRNA abundance. Each omic level is highly reproducible between biological replicates and between accessions despite their 0.5% sequence divergence; the single best predictor of any level in one accession is the corresponding level in the other. Within each accession, gene codon frequencies accurately model both mRNA and protein expression. The effects of a codon on mRNA and protein expression are highly correlated but are unrelated to genome-wide codon frequencies or to tRNA levels which instead match genome-wide amino acid frequencies. Ribosome-associated transcripts closely track mRNA levels. ConclusionsIn the absence of environmental perturbation, neither methylation, tRNA nor ribosome-associated transcript levels add appreciable information about constitutive protein abundance beyond that in DNA codon frequencies and mRNA expression levels. The impact of constitutive gbM is mostly explained by gene codon composition. tRNA abundance tracks overall amino acid demand. However, genetic differences between accessions associate with differential gbM by inflating differential expression variation. Our data show that the Central Dogma holds only if both sequence and abundance information in mRNA are considered.

plant biology↗

bioRxiv2024

ThunderBolt: An interactive data sharing and analysis platform for large-omics experiments

SummaryMass-spectrometry (MS) datasets present a unique set of challenges that make in-depth bioinformatics analysis non-trivial, with analysis requiring both expertise and time. Often these datasets have unique structures that need to be dealt with on an individual basis. Currently, tools providing a fast, interactive and guided way of exploring and analysing these data sets are not readily available. To this end, we have developed ThunderBolt: a highly interactive, point-and-click web-based application providing both bioinformaticians and biologists with a platform for i) searching and comparing multiple omics datasets, ii) fast data exploration and quality control, iii) interactive visualization, iv) pre-processing, v) statistical analysis and vi) functional and network enrichment analysis of large proteomics datasets using the Shiny framework. AvailabilityThunderBolt is a shiny-application accessible at https://thunderbolt.sydney.edu.au/ Contactjames.burchfield@sydney.edu.au Supplementary information

systems biology↗

bioRxiv2024

Torque Teno Sus Virus 1: A Potential Surrogate Pathogen to Study Pig-Transmitted Transboundary Animal Diseases

Understanding the epidemiology and transmission dynamics of transboundary animal diseases (TADs) among wild pigs (Sus scrofa) will aid in preventing the introduction or containment of TADs among wild populations. Given challenges associated with studying TADs in free-ranging populations, a surrogate pathogen system for in situ studies of pathogen dynamics would be ideal to elucidate how pathogens may circulate and be maintained within populations, how they may spillover into domestic populations, and how disease spread may be mitigated. We assessed the suitability of Torque teno sus virus 1 (TTSuV1) to serve as a surrogate pathogen for molecular epidemiological studies in wild pigs by investigating the prevalence, persistence, correlation with host health status and genetic variability at two study areas: Archbolds Buck Island Ranch in Florida and Savannah River Site in South Carolina. We then conducted a molecular epidemiological case study within the Archbolds Buck Island Ranch site to determine how analysis of this pathogen could inform transmission studies. Prevalence was high at both study areas (40%, n = 190). Phylogenetic analyses revealed high levels of genetic variability within and between study sites. Our case study showed that pairwise host relatedness and geographic distance were highly correlated to pairwise viral genetic similarity. Molecular epidemiological analyses revealed a distinct pattern of direct transmission from pig to pig occurring within and between family groups. Our results suggest TTSuV1 is highly suitable for molecular epidemiological analyses and will be useful for future in situ studies of transmission dynamics in wild pigs.

ecology↗

bioRxiv2024

Prenylation controls proliferation in human pluripotent stem cell-derived cardiomyocytes

Induction of cardiomyocyte proliferation to replace damaged heart tissue is a promising therapeutic approach. A recent drug screen revealed that cardiomyocytes require the mevalonate pathway for proliferation, although the specific mechanisms are unknown. In this study, we use human pluripotent stem cell-derived cardiomyocytes and cardiac organoids to further interrogate the role of the mevalonate pathway in cardiomyocyte proliferation. Chemical and genetic perturbations of the mevalonate pathway indicated that the post-translational modification, prenylation, regulates cardiomyocyte proliferation. We use prenyl probes and mass spectrometry to identify a catalogue of 40 prenylated proteins in human cardiac cells, including proteins where prenylated function had not yet been investigated. We show that multiple prenylated proteins control cardiomyocyte proliferation including RRAS2 and NAP1L4. We demonstrate that prenylation has differential effects on distinct proteins, with RRAS2 prenylation controlling membrane localization and NAP1L4 prenylation regulating cardiomyocyte mitosis and centrosome homeostasis. Together, these data show that protein prenylation is required for cardiomyocyte proliferation through multiple targets and these processes may need to be re-activated for cardiac regeneration.

cell biology↗

bioRxiv2024

LiF-MS+, a revised technique for mapping peptide-protein interactions

Short linear motifs are sequences of amino acids present in unstructured polypeptide regions that function as ligands for specific sites on folded protein domains. These interactions, which often occur with low to modest affinity, modulate dynamic biological processes such as signal transduction and membrane trafficking. We recently described Ligand Footprinting-Mass Spectrometry (LiF-MS), a technique that rapidly and precisely maps sites at which short peptide ligands bind their biologically relevant recognition sites on folded protein domains. This approach marks the binding location of a peptide ligand on a structured protein using a cleavable crosslinker appended to the ligand that leaves behind a stable chemical modification following cleavage. This modification serves as a mass tag detectable by mass spectrometry, pinpointing sites of peptide ligand binding. Here we present LiF-MS+, an improved version of the footprinting technique that replaces the butanol mass tag with 1-butylpyrrolidine, which is positively charged at neutral pH and thus aids in ionization of the crosslinked peptide for analysis by mass spectrometry. We show ligand-mediated butylpyrrolidine footprinting effectively maps the well characterized binding interaction of the p38 mitogen-activated protein kinase (MAPK) with a MKK6 D-motif short linear motif peptide ligand, uncovering additional binding site information not observed in our original experiment. LiF-MS+ is thus a straightforward improvement of our previously published methodology for mapping the binding of short linear motifs to folded protein domains.

biochemistry↗

bioRxiv2024

Facile detection of peptide-protein interactions using an electrophoretic crosslinking shift assay

Protein-protein interactions with high specificity and low affinity are functionally important but are not comprehensively understood because they are difficult to identify. Particularly intriguing are the dynamic and specific interactions between folded protein domains and short unstructured peptides known as short linear motifs (SLiMs). Such domain-motif interactions (DMIs) are often difficult to identify and study because affinities are modest to weak. Here we describe "electrophoretic crosslinking shift assay" (ECSA), a simple in vitro approach that detects transient, low affinity interactions by covalently crosslinking a prey protein and a fluorescently labeled bait. We demonstrate this technique on the well characterized DMI between MAP kinases and unstructured D-motif peptide ligands. We show that ECSA detects sequence-specific micromolar interactions using less than a microgram of input prey protein per reaction, making it ideal for verifying candidate low-affinity DMIs of components that purify with low yield. We propose ECSA as an intermediate step in SLiM characterization that bridges the gap between high throughput techniques such as phage display and more resource-intensive biophysical and structural analysis.

biochemistry↗

bioRxiv2023

eNODAL: an experimentally guided nutriomics data clustering method to unravel complex drug-diet interactions

Unraveling the complex interplay between nutrients and drugs via their effects on omics features could revolutionize our fundamental understanding of nutritional physiology, personalized nutrition and ultimately human health-span. Experimental studies in nutrition are starting to use large-scale omics experiments to pick apart the effects of such interacting factors. However, the high dimensionality of the omics features, coupled with complex fully-factorial experimental designs together pose a challenge to the analysis. Current strategies for analyzing such types of data are based on between-feature correlations. However, these techniques risk overlooking important signals that arise from the experimental design and produce clusters that are hard to interpret. We present a novel approach for analyzing high-dimensional outcomes in nutriomics experiments, termed experiment-guided NutriOmics DatA cLustering (eNODAL). This three-step hybrid framework takes advantage of both ANOVA-type analyses and unsupervised learning methods to extract maximum information from experimental nutriomics studies. First, eNODAL categorizes the omics features into interpretable groups based on the significance of response to the different experimental variables using an ANOVA-like test. Such groups may include the main effects of a nutritional intervention, and drug exposure, or their interaction. Second, consensus clustering is performed within each interpretable group to further identify subclusters of features with similar response profiles to these experimental factors. Third, eNODAL annotates these subclusters based on their experimental responses and biological pathways enriched within the subcluster. We validate eNODAL using data from a mouse experiment to test for the interaction effects of macronutrient intake and drugs that target aging mechanisms in mice.

bioinformatics↗

bioRxiv2022

Ventral temporal and posteromedial sulcal morphology in autism spectrum disorder

Two recent parallel research tracks link tertiary sulcal morphology--sulci that emerge last in gestation and continue to develop after birth--with functional features of the cerebral cortex and cognition, respectively. The first track identified a relationship between the mid-fusiform sulcus (MFS) in ventral temporal cortex (VTC) and cognition in individuals with Autism Spectrum Disorder (ASD). The second track identified a new tertiary sulcus, the inframarginal sulcus (IFRMS), that serves as a tripartite landmark within the posteromedial cortex (PMC). As VTC and PMC are structurally and functionally different in individuals with ASD compared to neurotypical controls (NTs), here, we integrated these two tracks with a twofold approach. First, we tested if there are morphological differences in VTC and PMC sulci between 50 NTs and 50 individuals with ASD. Second, we tested if tertiary sulcal morphology was linked to cognition in ASD individuals. Our twofold approach replicates and extends recent findings in five ways. First, in terms of replication, the standard deviation (STD) of MFS cortical thickness (CT) was increased in ASDs compared to NTs. Second, MFS length was shorter in ASDs compared to NTs. Third, the CT STD effect extended to other VTC and PMC sulci. Fourth, a subset of VTC and PMC morphological features were correlated between regions in ASD. Fifth, IFRMS depth was negatively associated with ADOS-GS score. These results empirically support a relationship between later-developing, tertiary sulci and ASD, providing a novel framework to study the relationship between brain structure and cognition in additional neurodevelopmental disorders in future studies. Lay SummaryWe observed that some, but not all, morphological features of later-developing tertiary indentations (sulci) in the cerebral cortex differed significantly between neurotypical controls and individuals with autism spectrum disorder (ASD). In ASD, a subset of sulcal morphological features also correlated between brain areas and one feature reflected differences in cognition. Thus, studying these structures provides insight into how individual variability in structure is related to individual variability in cognition in ASD.

neuroscience↗

bioRxiv2022

Defining tertiary sulci in lateral prefrontal cortex in chimpanzees using human predictions

Similarities and differences in brain structure and function across species is of major interest in systems neuroscience, comparative biology, and brain mapping. Recently, increased emphasis has been placed on tertiary sulci, which are shallow indentations of the cerebral cortex that appear last in gestation, continue to develop after birth, and are largely either human- or hominoid-specific. While tertiary sulcal morphology in lateral prefrontal cortex (LPFC) has been linked to functional representations and cognition in humans, it is presently unknown if LPFC tertiary sulci also exist in non-human hominoids. To fill this gap in knowledge, we leveraged two freely available multimodal datasets to address the following main question: Can LPFC tertiary sulci be defined in chimpanzee cortical surfaces from human predictions? We found that 1-3 components of the posterior middle frontal sulcus (pmfs) in the posterior middle frontal gyrus are identifiable in nearly all chimpanzee hemispheres. In stark contrast to the consistency of the pmfs components, we could only identify components of the paraintermediate frontal sulcus (pimfs) in two chimpanzee hemispheres. LPFC tertiary sulci were relatively smaller and shallower in chimpanzees compared to humans. In both species, two of the pmfs components were deeper in the right compared to the left hemisphere. As these results have direct implications for future studies interested in the functional and cognitive role of LPFC tertiary sulci across species, we share probabilistic predictions of the three pmfs components to guide the definitions of these sulci in future studies.

neuroscience↗

bioRxiv2021

High-throughput screening of aqueous two-phase systems for polyphenol extraction from A. nodosum: a green chemistry approach

Brown macroalgae are an attractive third-generation feedstock of natural products, in order to design green chemistry-compliant processes and reduce the use of organic solvents in bioactive product extraction, aqueous two-phase systems (ATPS) was applied. This research aimed to develop a high-throughput screening (HTS) to recover polyphenols from Ascophyllum nodosum using ATPS. In total, 384 different 2-phase systems were assessed using an automated liquid-handling system to evaluate polyphenol recovery using a model system of phloroglucinol to establish an optimal 2-phase system for polyphenol partitioning. Various ratios of PEG:potassium phosphate solutions were explored to evaluate partitioning of polyphenols via a scale-down approach. Scale-down selected system showed a recovery of phloroglucinol of 62.9{+/-}12.0%, this system was used for scale-up trials. Scale-up studies confirmed that the HTS method was able to recover polyphenols with a 54.8{+/-}14.2% in the phloroglucinol model system. When the optimised ATPS system was tested with a polyphenol extract, 93.62{+/-}8.24% recovery was observed. When ATPS was applied to a fucoidan and alginate biorefinery residue, 88.40{+/-}4.59% polyphenol was recovered. These findings confirm that ATPS is a valuable addition to the bioprocess toolkit for sustainable extraction of natural products from macroalgae in a multiproduct biorefinery approach. Practical applicationSelection of the best concentrations of phase-forming components and recovery conditions for the application of aqueous two-phase systems in an industrial setup has been proved to be laborious and cumbersome. This paper presents an automated platform to rapidly assess several ATPS to recover polyphenols from brown macroalgae and a subsequent confirmation with the scale-up of the potential candidates and contrasted with two case studies. This methodology allows a quick screening for the best aqueous two-phase system and can be expanded to recover high-value products from other types of macroalgae or microalgae.

bioengineering↗