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Young, D.

Publications and source records attributed to Young, D..

At least 19 recordsLinked to original sources

A low-annotation-budget PubMedBERT classifier for chondrogenesis regulator discovery via active learning

Motivation: Biomedical natural language processing (Bio-NLP) classification tasks are often limited by the cost of manual annotation, especially for specialised extraction problems where labelled corpora are scarce. Active learning can reduce this cost by prioritising informative samples, while large language models (LLMs) avoid task-specific annotation, but at high computational cost. We ask whether an encoder trained via active learning can match LLM performance at a lower computational cost, using identification of chondrogenesis regulators from PubMed abstracts as a test case applicable to other under-annotated Bio-NLP problems. Results: We built an active learning framework to fine-tune PubMedBERT to classify gene mentions as regulators of chondrocyte differentiation, achieving an AUC-ROC of 0.93 using 1,238 annotated sentences. Against open-weight LLMs (Qwen3, Llama-3.1), PubMedBERT matched the top-performing LLMs on AUC-ROC and achieved the highest precision (0.69) of any model, while classifying the full corpus far faster. Applied to 67,111 gene mentions, it identified 1,128 candidate regulators, recovered 79% of Gene Ontology-annotated genes related to chondrocyte differentiation (94 genes recovered), and proposed 981 new candidates. The pipeline is agnostic to the target process, suggesting it could be adapted to identify regulators of other biological processes. Availability and Implementation: Code is available at https://github.com/ChondroTextomics/ALRegulatorDiscovery. Data are available at Zenodo: https://doi.org/10.5281/zenodo.22746090. Final model is available in HuggingFace Hub amav/pubmedbert-chondrogenesis-classifier Supplementary information: Supplementary data are available in a separate file

bioinformatics↗

Multi omics reveals mesodermal fate bias and enables predictive cell state control in human pluripotent stem cell biomanufacturing

Human induced pluripotent stem cells can retain conventional markers of pluripotency while acquiring environmentally dependent molecular states that may influence their developmental competence. Yet, how biomanufacturing conditions reorganize the interconnected networks governing cell state remains poorly characterized. Here, we first examined compensation of hiPSCs to static aggregation and dynamic agitation by proteomics. We then examined hiPSCs during single-passage culture in stirred-suspension bioprocesses under varying oxygen and agitation conditions. Intracellular metabolomic and transcriptomic profiling revealed distinct responses across culture configuration, hydrodynamic exposure, and oxygenation. Transition into dynamic culture broadly remodeled mitochondrial organization, carbon allocation, mechanotransduction, proteostasis, and developmental regulation. Increasing agitation produced a persistent response involving cellular architecture, growth-factor signaling, genome maintenance, and Epiblast- and lineage-aligned programs, whereas oxygenation elicited a smaller and more transient metabolic and transcriptional response. Through comparison with a human gastrulation reference, we show that these adaptations intersect with natural developmental programs without reproducing coherent epiblast state or lineage commitment. These findings demonstrate that bioprocess conditions can preserve core pluripotent identity while remodeling broader molecular states associated with developmental responsiveness, providing perspective on evaluating and optimizing hiPSC quality in biomanufacturing beyond restricted marker panels.

bioengineering↗

Systematic screening identifies elevated neurovascular BCL-XL in Parkinson's disease.

BackgroundVascular cells are emerging as active players in Parkinsons disease (PD), yet their molecular contribution to -Synuclein (-Syn) pathology remains undefined. Here, we show that human brain pericytes respond in a distinct manner to unique -Syn strains, with systematic validation identifying BCL-XL as a potential regulator of the neurovascular unit in PD. MethodsPrimary human brain-derived pericytes were exposed to five recombinant -Syn strains (Fibrils, Fibrils-65, Fibrils-91, Fibrils-110, and Ribbons). Transcriptomic profiling identified differentially expressed genes (DEGs), which were validated at the protein level using multiplex immunocytochemistry and in situ labelling of post-mortem middle temporal gyrus (MTG) tissue microarrays from PD (n = 24) and neurologically normal (n = 24) cases. Results-Syn strain exposure produced 300 DEGs with limited overlap between strains. BCL-XL and CSNK1D were upregulated in -Syn-treated pericytes. In post-mortem PD tissue BCL-XL showed marked pericyte-specific elevation in the MTG and increased pericytic and microglial expression in the substantia nigra. ConclusionBCL-XL emerges as a potential regulator of pericyte and microglial resilience in PD, linking acute -Syn strain-specific responses in pericytes to broader neurovascular alterations. Its upregulation likely represents a generalised compensatory response to chronic -Syn-associated stress beyond individual strain effects, identifying BCL-XL as a possible therapeutic target within the neurovascular unit.

neuroscience↗

Dysregulated TGFb-ERK Signaling Drives Aberrant Extracellular Matrix Production in Noonan Syndrome-Associated Pulmonary Valve Stenosis

Pulmonary valve stenosis (PVS) is the most common congenital heart defect in Noonan syndrome (NS) and related RASopathies, yet the molecular mechanisms linking pathogenic variants to the valve pathology remain poorly defined. Here, we utilized a human iPSC-based valve differentiation platform to generate the cardiac valve cell lineages--including fibrosa and spongiosa valve interstitial cell (VIC) subtypes. CRISPR-edited iPSCs harboring NS gain-of-function RAS/MAPK and Noonan syndrome with multiple lentigines (NSML) dominant-negative RAS/MAPK variants exhibited early defects in mesodermal and endocardial specification in all genotypes. Additionally, NS-iPSC endocardial cells exhibited defects in endothelial-to-mesenchymal transition (EndMT) specifically towards fibrosa VICs, which was most pronounced in PTPN11N308D (N308D) cells. Single-cell transcriptomics revealed widespread dysregulation of extracellular matrix (ECM) programs in N308D fibrosa VICs, including increased expression of collagens and proteoglycans, as well as dysregulation of multiple genes involved in ECM remodeling. We also detected activation of RAS-MAPK, TGF{beta}, and fibrosis-associated pathways in our transcriptional dataset. Mass spectrometry-based phosphoproteomics confirmed coordinated increases in ERK, PKC, and stress-related kinases, as well as enhanced activity of the TGF{beta} receptor. Functionally, N308D fibrosa VICs exhibited exaggerated upregulation of ECM genes in the presence of TGF{beta}2 ligand, suggesting that these cells are hypersensitive to TGF{beta} stimulation. Furthermore, we demonstrated that this pathological ECM-program occurs independently of BAMBI, a negative regulator of TGF{beta} signaling that was found to be decreased in N308D fibrosa VICs. Lastly, we performed histopathological analyses of stenotic pulmonary valves from two NS infants, which demonstrated marked overproduction and disorganization of ECM, mirroring the findings from our iPSC-based disease model. Together, our data reveal a central mechanism where NS-associated alleles sensitize fibrosa VICs to TGF{beta}, which leads to aberrant downstream signaling and drives the pathological ECM program in NS-associated PVS.

cell biology↗

Therapeutic modulation of the calpastatin/calpain pathway restores calpain-mediated synaptic proteolysis and preserves motor neurons survival and function in C9orf72 ALS

A hexanucleotide repeat expansion (GGGGCC) in the C9orf72 gene is the most prevalent genetic cause of ALS, with early neuromuscular junction (NMJ) dysfunction being a key pathological feature. Current therapies provide only limited symptomatic relief, underscoring the need for targeted, mechanism-based interventions. Using a C9orf72 ALS zebrafish model (C9-miR) and patient-derived induced pluripotent stem cell (iPSC) motor neurons, we identified significant downregulation of calpastatin, the endogenous inhibitor of calpains, a calcium-dependent protease family implicated in neurodegeneration. We demonstrate that restoring calpastatin activity with a cell-permeable calpastatin-derived peptide or the small molecule, calpeptin, ameliorates locomotor deficits and NMJ dysfunction in the C9-miR zebrafish model. These interventions enhance synaptic vesicle turnover and quantal release at the NMJ while improving motor neuron excitability and synaptic integrity in iPSC-derived motor neurons. N-terminomic/TAILS mass spectrometry revealed direct calpain-mediated cleavage of synaptic proteins in motor neurons derived from C9orf72 patients. Proteolysis of novel ALS-relevant synaptic and axonal proteins is prevented by calpeptin and calpastatin peptide treatments. Our findings establish the calpastatin as a pivotal regulator of synaptic function in C9orf72-associated ALS and identify it as a promising therapeutic target, offering a novel strategy to restore synaptic transmission and potentially halt disease progression.

neuroscience↗

Protein kinase F regulates the virulence of Mycobacterium tuberculosis

The serine/threonine protein kinase F (PknF) of Mycobacterium tuberculosis (Mtb) has poorly defined targets and functions but is involved in limiting NLRP3 inflammasome activation in murine macrophages and dendritic cells in vitro. The importance of PknF for the virulence of Mtb in vivo is not known. Here, we demonstrate that the Mtb CDC1551 deletion mutant of pknF ({Delta}pknF) expresses significantly increased levels of the lipid pthiocerol dimycoserosate (PDIM), a polyketide lipid with pro-virulence properties. The {Delta}pknF mutant strain, when compared to the Mtb and complemented strains, had a 100-fold increase in growth at day 28 and about a 10-fold increase in growth at days 90-98 in the lungs of mice. The increase in pulmonary bacterial loads after infection with {Delta}pknF strain was conserved even in Nlrp3-deficient mice, arguing that PknF modulates Mtb virulence independently of NLRP3-inflammasome activation in mice. Staining of lung sections revealed increased inflammation in the lungs of {Delta}pknF strain-infected mice when compared to Mtb and the complemented mutant strain. Highly susceptible B6.Sst1S mice displayed decreased host resistance with significantly decreased survival when infected with the {Delta}pknF strain compared to the complemented strain or Mtb. In conclusion, our data suggest that expression of PknF, as a modulator of multiple downstream effector proteins, restricts the virulence of Mtb in the lungs of mice through an NLRP3 inflammasome-independent mechanism but potentially via suppressing expression of the virulence lipid, PDIM. Author summaryThe human pathogen Mycobacterium tuberculosis (Mtb) encodes 11 serine/threonine protein kinases (Pkn A-I,K and L). In vitro, PknF inhibits activation of innate immune responses in macrophages and dendritic cells. The importance of that protein for the virulence of the bacteria in the context of a live animal infection is unknown. We used a hypersusceptible mouse strain to analyze the impact of deleting the pknF gene on the virulence of the bacteria by monitoring the survival of the mice. We show that the {Delta}pknF deletion mutant kills mice faster than wild-type bacteria or {Delta}pknF mutant bacteria expressing a wild-type copy of the pknF gene ({Delta}pknF-C). Next, we analyzed the growth of the different bacterial strains in the infected mice and demonstrated that at day 28 and day 90-98 timepoints the {Delta}pknF mutant bacterial strains showed a significant increase in bacterial burden in the lungs, bronchoalveolar lavage fluid and the spleen. An analysis of the total lipids of the bacterial stocks showed that the {Delta}pknF Mtb bacteria increased expression of the virulence lipid, pthiocerol dimycoserosate (PDIM), suggesting a negative regulation of this lipid by PknF likely affecting bacterial virulence in the lungs of mice.

microbiology↗

Integrated proteogenomics uncovers ancestry-specific and shared molecular drivers in localized prostate cancer

Our integrative proteogenomics (genome, proteome and phosphoproteome) of localized prostate cancer (PCa) in an equal-access Military Health System patient cohort (57 Black and 55 White) revealed significant ancestry-associated differences. Somatic and germline regulatory differences converged on androgen, metabolic, PI3K/AKT/mTOR, and DNA damage response (DDR) pathways, with ancestry-specific immune- and stromal-associated signals. Black patients displayed greater genomic variability, enhanced androgen response, fatty-acid metabolism, and epithelial-mesenchymal transition, while White patients showed prevalent DDRG alterations, activated oncogenic signaling (MYC, E2F, mTORC1), and cell cycle regulation. Phosphoproteomics highlighted distinct kinase activities and candidate druggable dependencies. Multiomics integration revealed three exploratory tumor subtypes whose distinct biological programs were reproducibly validated. Ancestry-associated eQTLs supported inherited regulation of the proteome independent of CNAs. Ancestry-specific CNA and protein panels improved progression risk prediction beyond PSA and pathology models. These findings provide a framework for ancestry-informed prognostic models and generate testable hypotheses for precision therapies to reduce outcome disparities.

cancer biology↗

The role of aging on endothelial cell-cell junctions and pulmonary microvascular permeability

Lung injury leads to pulmonary microvascular endothelial cell (PMVEC) damage, disruption of cell-cell junctions, and increased permeability. Previously, we demonstrated in a mechanical ventilation-induced model of lung injury that aging exacerbated pulmonary microvascular permeability. Based on this, we hypothesized that aging was associated with increased PMVEC barrier dysfunction due to impaired cell-cell junction integrity. PMVEC were isolated from young and aged mice and cultured to confluence in vitro. Barrier function and cell-cell junction integrity were assessed through electric cell-substrate impedance sensing, XPerT permeability assay, immunofluorescence, and western blot analysis. Further studies were conducted to examine alterations in the proteome, markers of inflammation, and actin cytoskeleton organization. To model injurious conditions, PMVEC were stimulated with inflammatory cytokines; permeability and actin cytoskeletal alterations were subsequently assessed. We observed increased basal permeability in PMVEC from aged mice, which was associated with disrupted cell-surface localization of the adherens junction protein, vascular endothelial (VE)-cadherin. Protein abundance of VE-cadherin was significantly increased with age; however, levels of the adapter protein,{gamma} -catenin, and the tight junction protein, claudin-5, were decreased. Measures of inflammation, including cytokine expression and cell surface abundance of adhesion molecules, did not differ with age. Alterations in actin cytoskeleton organization, characterized by augmented presence of actin stress fibers, were observed in aged PMVEC. Under inflammatory conditions, permeability and actin stress fiber formation were exacerbated with age. It is concluded that aging predisposes PMVEC to elevated injury, due to inherent deficiencies in cell-cell junctions and barrier function, potentially mediated through altered actin cytoskeleton organization. New and NoteworthyCompared with pulmonary microvascular endothelial cells (PMVEC) from young mice, PMVEC isolated from aged mice had higher permeability, which was directly associated with impairments in cell-cell junctions. The higher permeability in aged PMVEC was not associated with augmented inflammatory signaling but was associated with actin cytoskeletal alterations. Following an inflammatory insult, PMVEC from aged mice had further exacerbated permeability. These findings may begin to highlight why older patients exhibit higher mortality during lung injury.

cell biology↗

Fecal proteomics of wild capuchins reveals impacts of season, diet, age, and, sex on gut physiology

Understanding how the physiology of free-ranging mammals is impacted by environmental stressors is a major focus of ecological research. However, the constraints of non-invasive sampling pose serious challenges to the acquisition of physiological data from most species of primates. As a result, little is known about how the gut responds to ecological stimuli at the cellular level in wild populations. Recent research has demonstrated that proteomics could fill this knowledge gap by sequencing and quantifying proteins directly from primate feces. In order to ascertain how the gut of free-ranging white-faced capuchin monkeys (C. imitator) is influenced by environmental heterogeneity, diet, age, and sex, we sequenced 45 fecal proteomes from 24 individuals from the Sector Santa Rosa population in Costa Rica, using liquid chromatography-tandem mass spectrometry with label-free quantification. Fecal proteins assigned to C. imitator were strongly localized to gut tissues and functionally enriched for digestive and immune functions. We identified 41 capuchin candidate proteins linked to seasonality, age, sex, and diet. We also quantified abundances of dietary fruit, dietary insects, helminth gut parasites, and gut microbes. Our results demonstrate the viability of using quantitative fecal proteomics in free-ranging populations of mammals to integrate host physiology, diet, and microbial ecology through non-invasive means.

ecology↗

Loss of CARM1 alters the developmental programming of Glioma stem-like cells and creates a druggable NGFR/NTRK dependency

A key driver of Glioblastoma (GBM) heterogeneity and therapy resistance is the capacity of glioma stem-like cells (GSCs) to hijack developmental signaling programs. However, it remains unclear how GSCs regulate these adapted developmental signaling pathways and how these pathways might be therapeutically exploited. The arginine methyltransferase, CARM1, has been shown to play critical roles in maintaining stem cell pluripotency, preventing differentiation, and recently was discovered to be upregulated in Glioblastoma. To date, there is little to no understanding of the role that CARM1 plays in regulating developmental processes in Glioblastoma. To address this gap in knowledge, we applied a multi-omics approach to characterize developmental processes that are specifically regulated by CARM1 in GSCs. We found that loss of CARM1 results in dysregulation of several developmental markers: ARX, GFAP, NGFR, PDGFRA and results in both a proteomic and transcriptomic shift towards the radial glia cell lineage. Moreover, CARM1 depleted cells reprogram their signaling to develop an increased survival dependency on NGFR/NTRK signaling and are hypersensitive to the FDA approved brain penetrant NTRK inhibitor--Entrectinib. Mechanistically, we find that NFIA is a CARM1 substrate and can repress NGFR signaling just as CARM1 does, and thus the CARM1/NFIA relationship is likely a key regulator of NGFR/NTRK signaling in GSCs. Altogether, we demonstrate that CARM1 regulates the cell lineage of GSCs at the transcriptomic and proteomic level, and naturally represses NGFR/NTRK signaling--likely through CARM1 dependent methylation of NFIA. Further, CARM1 depletion leads GSCs to develop a survival dependency on NGFR/NTRK signaling and creates a therapeutic vulnerability to NTRK inhibition.

cancer biology↗

Identification of a sub-population of synovial mesenchymal stem cells with enhanced treatment efficacy in a rat model of Osteoarthritis

Osteoarthritis (OA) is a painful and debilitating disease which has no cure and there are no treatments which can predictably stop/reverse its progression. Treating this disease is particularly difficult since the articular cartilage lacks intrinsic repair capacity even though mesenchymal stem cells (MSCs) are present in the joint environment and have robust chondrogenic potential. We have previously shown that there is heterogeneity of MSC sub-types within the human synovium, yet it remains unclear if any of these MSC types can regenerate cartilage and/or impact OA disease progression. Therefore, we have undertaken this study focusing on clonally derived MSC populations derived from the synovium of normal and OA patients to characterize if any MSC populations can positively impact OA disease trajectory in a rat model of OA. MSCs were clonally isolated by indexed flow cytometry, expanded in culture and then characterized for differentiation capacity and by quantitative proteomics. MSC clones were then transplanted into a xenograft rat OA model and treatment effect was determined by histology and immunofluorescence outcomes. We identified heterogeneity in putative MSCs derived from within and between patient groups (normal vs. OA) and the ability of these cells to effect repair in a rat OA model. However, these different sub-types of MSCs could not be distinguished by traditional cell surface markers showing the need for a better understanding of these populations at the single cell level. Using an unbiased proteomics approach, CD47 was identified a novel marker of human MSCs. Using the same rat model of OA, CD47Hi expressing cells were found to have robust treatment efficacy and directly contributed to the formation of new articular cartilage tissue. Characterizing MSCs is essential to understand which sub-types are appropriate for further clinical investigation. If OA patients still have functional MSCs in their synovium, then it is possible these cells can be exploited for cartilage regeneration / OA treatment strategies.

cell biology↗

A first-in-kind MAPK13 inhibitor that can correct stem cell reprogramming and post-injury disease

The stress kinase MAPK13 (aka p38delta-MAPK) is an attractive entry point for therapeutic intervention because it regulates the structural remodeling that can develop after epithelial injury in the lung and likely other tissue sites. However, a selective, safe, and effective MAPK13 inhibitor is not yet available for experimental or clinical application. Here we identify a first-in-kind MAPK13 inhibitor using structure-based drug design combined with a screening funnel for cell safety and molecular specificity. In a mouse model of severe respiratory viral infection, treatment with this inhibitor (formulated as NuP-4A for intravenous use or Nu4-B for inhaled delivery) did not influence recovery from acute infectious illness, but still down-regulated basal-epithelial stem cell (basal-ESC) hyperplasia/metaplasia and in turn airway inflammation, mucus production, and pathophysiology biomarkers of chronic lung disease. Treatment prevented and reversed disease readouts equivalently to Mapk13 gene-knockout, and this benefit persisted after stopping treatment as a sign of disease modification. Further, NuP-4 treatment even at pM levels directly blocked basal-ESC reprogramming endpoints in organoid and cell-culture models derived from non-disease control and asthma subjects. The results thereby provide a new tool compound and drug candidate for basal-ESC reprogramming towards muco-obstructive lung diseases like asthma and any overlap with COPD and related diseases that depend on overactivity of MAPK13.

immunology↗

MAPK13 controls structural remodeling and disease after epithelial injury

All living organisms are charged with repair after injury particularly at epithelial barrier sites, but in some cases this response leads instead to structural remodeling and long-term disease. Identifying the molecular and cellular control of this divergence is key to disease modification. In that regard, stress kinase control of epithelial stem cells is a rational entry point for study. Here we examine the potential for mitogen-activated protein kinase 13 (MAPK13) regulation of epithelial stem cells using models of respiratory viral injury and post-viral lung disease that resembles asthma. We show that Mapk13 gene-knockout mice handle acute infectious illness as expected but are protected against basal-epithelial stem cell (basal-ESC) hyperplasia and mucous metaplasia. In corresponding organoid models, Mapk13-deficiency directly controls the basal-ESC program for stemness endpoints of hyperplasia and mucous metaplasia. Extension to human studies shows induction/activation of MAPK13 in basal-epithelial cells in lung tissue samples from asthma and COPD patients. Further, in human organoid models, MAPK13 mRNA knockdown regulates basal-ESC stemness similarly to mouse models. Together, the data identify MAPK13 as a control point for structural remodeling after epithelial injury and a suitable target for down-regulation as a disease-modifying strategy.

immunology↗

Endogenous hydrogen peroxide positively regulates secretion of a gut-derived peptide in neuroendocrine potentiation of the oxidative stress response in C. elegans

The gut-brain axis mediates bidirectional signaling between the intestine and the nervous system and is critical for organism-wide homeostasis. Here we report the identification of a peptidergic endocrine circuit in which bidirectional signaling between neurons and the intestine potentiates the activation of the antioxidant response in C. elegans in the intestine. We identify a FMRF-amide-like peptide, FLP-2, whose release from the intestine is necessary and sufficient to activate the intestinal oxidative stress response by promoting the release of the antioxidant FLP-1 neuropeptide from neurons. FLP-2 secretion from the intestine is positively regulated by endogenous hydrogen peroxide (H2O2) produced in the mitochondrial matrix by sod-3/superoxide dismutase, and is negatively regulated by prdx-2/peroxiredoxin, which depletes H2O2 in both the mitochondria and cytosol. H2O2 promotes FLP-2 secretion through the DAG and calcium-dependent protein kinase C family member pkc-2 and by the SNAP25 family member aex-4 in the intestine. Together, our data demonstrate a role for intestinal H2O2 in promoting inter-tissue antioxidant signaling through regulated neuropeptide-like protein exocytosis in a gut-brain axis to activate the oxidative stress response.

neuroscience↗

Chewing Through Challenges: Exploring the Evolutionary Pathways to Wood-Feeding in Insects

Decaying wood, while an abundant and stable resource, presents considerable nutritional challenges due to its structural rigidity, chemical recalcitrance, and low nitrogen content. Despite these challenges, certain insect lineages have successfully evolved saproxylophagy (consuming and deriving sustenance from decaying wood), impacting nutrient recycling in ecosystems and carbon sequestration dynamics. This study explores the uneven phylogenetic distribution of saproxylophagy across insects and delves into the evolutionary origins of this trait in disparate insect orders. Employing a comprehensive analysis of gut microbiome data, encompassing both previously published datasets and newly generated data, from both saproxylophagous insects and their non-saproxylophagous relatives, this Hypothesis paper discusses the broader phylogenetic context and potential morphological, physiological, and symbiotic adaptations necessary for this dietary specialization. The study proposes the "Detritivore-First Hypothesis," suggesting an evolutionary pathway to saproxylophagy through detritivory, and highlights the critical role of symbiotic gut microbiomes in the digestion of decaying wood. The article aims to provide a deeper understanding of the macroevolutionary landscape and mechanisms underpinning the multiple origins and distribution of saproxylophagy in insects.

evolutionary biology↗

Network-driven cancer cell avatars for combination discovery and biomarker identification for DNA Damage Response inhibitors

Combination therapy is well established as a key intervention strategy for cancer treatment, with the potential to overcome monotherapy resistance and deliver a more durable efficacy. However, given the scale of unexplored potential target space and the resulting combinatorial explosion, identifying efficacious drug combinations is a critical unmet need that is still evolving. In this paper, we demonstrate a network biology-driven, simulation-based solution, the Simulated Cell. Integration of omics data with a curated signaling network enables the accurate and interpretable prediction of 66,348 combination-cell line pairs obtained from a large-scale combinatorial drug sensitivity screen of 684 combinations across 97 cancer cell lines (BAC= 0.62, AUC=0.7). We highlight drug combination pairs that interact with DNA Damage Response pathways and are predicted to be synergistic, and deep network insight to identify biomarkers driving combination synergy. We demonstrate that the cancer cell avatars capture the biological complexity of their in vitro counterparts, enabling the identification of pathway-level mechanisms of combination benefit to guide clinical translatability.

cancer biology↗

Systems analysis of miR-199a/b-5p and multiple miR-199a/b-5p targets during chondrogenesis

Changes in chondrocyte gene expression can contribute to the development of osteoarthritis (OA), and so recognition of the regulative processes during chondrogenesis can lead to a better understanding of OA. microRNAs (miRNAs) are key regulators of gene expression in chondrocytes/OA and we have used a combined experimental, bioinformatic, and systems biology approach to explore the multiple miRNA-mRNA interactions that regulate chondrogenesis. A longitudinal chondrogenesis bioinformatic analysis identified paralogues miR-199a-5p and miR-199b-5p as pro-chondrogenic regulators. Experimental work demonstrated alteration of miR-199a-5p or miR-199b-5p expression led to significant inverse modulation of key chondrogenic genes and extracellular matrix production. miR-199a/b-5p targets FZD6, ITGA3 and CAV1 were identified by inhibition experiments and verified as direct targets by luciferase assay. The experimental work was used to generate and parameterize a multi-miRNA 14-day chondrogenesis kinetic model to be used as a repository for the experimental work and as a resource for further investigation of this system. This is the first multi-miRNA model of a chondrogenesis-based system, and highlights the complex relationships between regulatory miRNAs, and their target mRNAs.

systems biology↗

Patterns and determinants of the global herbivorous mycobiome

In spite of their indispensable role in host nutrition, the anaerobic gut fungal (AGF) component of the herbivorous gut microbiome remains poorly characterized. To examine global patterns and determinants of AGF diversity, we generated and analyzed an amplicon dataset from 661 fecal samples from 34 animal species, 9 families, and 6 continents. We identified 56 novel genera, greatly expanding AGF diversity beyond current estimates. Both stochastic (homogenizing dispersal and drift) and deterministic (homogenizing selection) processes played an integral role in shaping AGF communities, with a higher level of stochasticity observed in foregut fermenters. Community structure analysis revealed a distinct pattern of phylosymbiosis, where host-associated (animal species, family, and gut type), rather than ecological (domestication status and biogeography) factors predominantly shaped the community. Hindgut fermenters exhibited stronger and more specific fungal-host associations, compared to broader mostly non-host specific associations in foregut fermenters. Transcriptomics-enabled phylogenomic and molecular clock analyses of 52 strains from 14 genera indicated that most genera with preferences for hindgut hosts evolved earlier (44-58 Mya), while those with preferences for foregut hosts evolved more recently (22-32 Mya). This pattern is in agreement with the sole dependence of herbivores on hindgut fermentation past the Cretaceous-Paleogene (K-Pg) extinction event through the Paleocene and Eocene, and the later rapid evolution of animals employing foregut fermentation strategy during the early Miocene. Only a few AGF genera deviated from this pattern of co-evolutionary phylosymbiosis, by exhibiting preferences suggestive of post-evolutionary environmental filtering. Our results greatly expand the documented scope of AGF diversity and provide an ecologically and evolutionary-grounded model to explain the observed patterns of AGF diversity in extant animal hosts.

microbiology↗