Biology subjects

Aguilar, M.

Publications and source records attributed to Aguilar, M..

15 recordsLinked to original sources

bioRxiv2026

Inflammation is an essential trigger for POLE-driven ultramutated colorectal cancer

Pathogenic variants in the exonuclease (proofreading) domain of DNA polymerase {varepsilon} (POLE) are frequently detected in colorectal cancers (CRC) with high tumor mutational burden (TMB), yet their functional role in intestinal tumorigenesis remains unknown. Here, we investigated the impact of mutation in POLE on intestinal homeostasis using a conditional mouse model expressing the PoleP286R pathogenic driver in intestinal epithelial cells. PoleP286R mutant mice developed invasive adenocarcinomas in the small intestine with incomplete penetrance and extremely long latency but did not spontaneously develop colorectal tumors. However, induction of colitis with dextran sodium sulfate (DSS) resulted in a striking phenotypic shift to colorectal adenocarcinomas at high frequency. Molecular and histological analyses revealed hyperactivation of Wnt/{beta}-catenin, NF-{kappa}B, ERK and STAT3 pathways, accompanied by markedly higher proliferation of intestinal epithelial cells, in DSS-treated PoleP286R mutant mouse colons. Whole genome sequencing of the tumor demonstrated exceptionally high TMB (>100 mutations/megabase) and characteristic trinucleotide signatures, consistent with human POLE tumors. Recurrent mutations in Apc and Ctnnb1 underscored the central role of Wnt signaling in POLE-driven hypermutated CRC. In addition, intestinal organoids derived from PoleP286R mutant mice exhibited accelerated growth and increased expression of pro-proliferative genes. Together, these findings highlight POLE as a gatekeeper of intestinal genomic integrity and identify inflammation as the key driver that unleashes POLE-mutant CRC. Furthermore, this work establishes a mechanistically faithful preclinical platform for studying the molecular pathogenesis of CRC and advancing therapeutic drug discovery.

cancer biology↗

bioRxiv2026

Hypoxia drives asymmetric envelope remodelling to promote membrane adaptation and antibiotic tolerance in mycobacteria

Mycobacterium tuberculosis persists within the host by adapting to stressful microenvironments, with hypoxia representing a key clinically relevant challenge. However, how hypoxia alters mycobacterial membrane organization and function remains poorly understood. Using Mycobacterium smegmatis as a model, we combined membrane biophysics, layer-resolved lipidomics, and membrane-drug interaction analyses to characterize envelope adaptation under oxygen limitation. Hypoxia induced asymmetric remodelling of the cell envelope, with the inner membrane becoming more ordered and less hydrated, while the outer membrane exhibited increased fluidity and hydration. Lipidomic analyses revealed corresponding membrane-specific changes, including enrichment of saturated, tightly packed lipids in the inner membrane and unsaturated, inverted-conical lipids in the outer membrane. Functionally, hypoxic cells showed reduced envelope permeability and decreased susceptibility to rifampicin, while membrane partitioning studies suggested reduced rifampicin association with hypoxia-adapted inner membranes. We identify asymmetric envelope remodeling as a previously unrecognized principle of bacterial adaptation to environmental stress. Rather than responding as a uniform structure, the mycobacterial envelope undergoes coordinated but divergent remodeling in its constituent membrane layers during hypoxia. This spatially resolved response couples inner membrane rigidification with outer membrane fluidization, generating a functionally specialized envelope architecture that simultaneously preserves membrane integrity, modulates permeability, and reduces antibiotic association. These findings suggest that membrane asymmetry is not merely a structural feature of complex bacterial envelopes but an actively regulated adaptive strategy that links environmental sensing to stress resilience and antimicrobial tolerance

biophysics↗

bioRxiv2024

Cold stress involves CBF dependent regulatory pathway to remodel wood formation in Eucalyptus gunnii hybrids.

While being the most planted tree worldwide, most Eucalyptus species are sensitive to frost. Long-term exposure to cold temperatures, among other abiotic cues, triggers modification of secondary xylem differentiation in Eucalyptus, but the molecular mechanisms behind it remain unknown. Overexpression of key players of cold signalling pathway, the CRT-repeat binding factors (CBF), not only causes the expected increase in freezing tolerance but also remodels wood in a similar trend to cold acclimation, making it a good candidate for wood functional adaptation to cold stress. To gain insight in CBF role in cold-induced secondary cell wall (SCW) remodelling, we used both targeted and untargeted methodologies to show that chilling and freezing temperatures induced the deposition of a thick SCW with alterations in lignin and polysaccharides composition as well as modifications of wood anatomy in a Eucalyptus cold-tolerant hybrid. Using co-expression network approaches, we identified CBF transcription factors (TFs) as a regulatory hub in xylem cold response. Direct targets of the CBF TFs were identified by DAPseq and unravelled promising candidates involved in SCW deposition and hormonal signalling pathways. Our results shed new light on the interplay between cold response and wood formation, bringing new evidence for the role of the cell wall in trees tolerance to abiotic stresses.

plant biology↗

bioRxiv2024

C-terminally encoded peptides promoting root symbiotic nodulation in legume plants also promote the root arbuscular mycorrhizal symbiotic interaction

C-terminally encoded peptides (CEPs) are small secreted signalling peptides that promote in legumes the root nitrogen-fixing nodulation symbiosis depending on soil mineral nitrogen availability1. In Medicago truncatula, their action is mediated by the Leucine-rich repeat receptor-like protein kinase COMPACT ROOT ARCHITECTURE 2 (CRA2)2-4. As most land plants, under inorganic phosphate (Pi) limitation, M. truncatula establishes another root endosymbiotic interaction with arbuscular fungi, the arbuscular mycorrhizal symbiosis (AMS). Because this interaction is beneficial for the plant but has a high energetic cost, it is tightly controlled by host plants to limit AMS infections mainly depending on Pi availability5. We show in this study that the expression of a subset of CEP encoding genes is enhanced in the low Pi conditions that favour AMS colonization, and that overexpression of the low Pi-induced MtCEP1 gene, previously shown to promote the nitrogen-fixing root nodulation symbiosis, enhances the AMS colonization from the initial entry point of the fungi. Conversely, a loss-of-function mutation of the CRA2 receptor required for mediating CEP peptides action2 decreases the AMS interaction capacity from the same initial fungal entry stage. Transcriptomic analyses revealed that the cra2 mutant is negatively affected in the regulation of key Pi transport and response genes as well as in the biosynthesis of strigolactone (SL) hormones that are required for establishing the AMS interaction. Accordingly, SL contents were drastically decreased in cra2 mutant roots. Overall, we showed that the CEP/CRA2 pathway promotes, in legume plants, both root nodulation and AMS depending on soil mineral nutrients availability. In briefThe establishment and maintenance of root nodule and arbuscular mycorrhizal symbioses (AMS) in legume plants is tightly regulated respectively by nitrogen and phosphate availability. Pedinotti and Teyssendier de la Serve et al. show that the CEP/CRA2 pathway, previously known to promote root competence to nodulate under low nitrogen conditions, also enhances AMS establishment by controlling the expression of Pi homeostasis and strigolactone (SL) hormone biosynthesis genes, as well as SL accumulation. HighlightsO_LIA subset of M. truncatula CEP genes is induced by AMS-promoting low phosphate conditions. C_LIO_LIThe CEP1 peptides positively regulate AMS establishment, while the cra2 CEP receptor loss of function mutants display a reduced AMS colonization. C_LIO_LIThe CEP/CRA2-dependent regulation of AMS acts through downstream signals distinct from the ones involved in root nodule symbiosis regulation. The CEP/CRA2 pathway regulates AMS establishment by controlling Pi homeostasis and strigolactone (SL) hormone biosynthesis genes, as well as SL accumulation. C_LI

plant biology↗

bioRxiv2024

Large- and Small-Animal Studies of Safety, Pharmacokinetics (PK), and Biodistribution of Inflammasome-Targeting Nanoligomer in the Brain and Other Target Organs

Immune malfunction or misrecognition of healthy cells and tissue, termed autoimmune disease, is implicated in more than 80 disease conditions and multiple other secondary pathologies. While pan-immunosuppressive therapies like steroids offer some relief for systemic inflammation for some organs, many patients never achieve remission and such drugs do not cross the blood-brain barrier making them ineffective for tackling neuroinflammation. Especially in the brain, unintended activation of microglia and astrocytes is hypothesized to be directly or indirectly responsible for Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), Parkinsons Disease (PD), and Alzheimers Disease (AD). Recent studies have also shown that targeting inflammasome and specific immune targets can be beneficial for these diseases. Further, our previous studies have shown targeting NF-{kappa}B and NLRP3 through brain penetrant Nanoligomer cocktail SB_NI_112 (abbreviated to NI112) can be therapeutic for several neurodegenerative diseases. Here we show safety-toxicity studies, followed by pharmacokinetics (PK) and biodistribution in small- (mice) and large-animal (dog) studies of this inflammasome-targeting Nanoligomer cocktail NI 112. We conducted studies using four different routes of administration: intravenous (IV), subcutaneous (SQ), intraperitoneal (IP), and intranasal (IN), and identified the drug concentration over time using inductively coupled plasma mass spectrometry (ICP-MS) in the blood serum, the brain (including different brain regions), and other target organs like liver, kidney, and colon. Our results indicate the Nanoligomer cocktail has a strong safety profile, and shows high biodistribution (F [~]0.98) and delivery across multiple routes of administration. Further analysis showed high brain bioavailability with a ratio of NI112 in brain tissue to blood serum [~]30%. Our model accurately shows dose scaling, translation between different routes of administration, and interspecies scaling. These results provide an excellent platform for human clinical translation and predicting therapeutic dosage between different routes of administration.

pharmacology and toxicology↗

bioRxiv2023

Improved detection and phylogenetic analysis of plant proteins containing LysM domains.

Plants perceive N-acetyl-d-glucosamine-containing oligosaccharides that play a role in the interaction with bacteria and fungi, both pathogenic and symbiotic, through cell-surface receptors that belong to the Receptor-Like Kinase (RLK) or Receptor-Like Protein (RLP) families. Structurally characterised proteins from these families have been shown to contain a tight bundle of three LysM domains in their extracellular domain. However, the identification of LysM domains of RLK/Ps using sequence based methods has led to some ambiguity, as some proteins have been annotated with one or only two LysM domains. This missing annotation was likely produced by the failure of the LysM hidden Markov model (HMM) from the PFAM database to correctly identify some LysM domains in proteins of plant origin. In this work, we provide improved HMMs for LysM domain detection in plants, that were built from the structural alignment of manually curated LysM domain structures from PDB and AlphaFold. Furthermore, we evaluated different sets of ligand-specific HMMs that were able to correctly classify a limited set of fully characterised RLK/Ps by their ligand specificity. In contrast, the phylogenetic analysis of the extracellular region of RLK/Ps, or of their individual LysM domains, was unable to discriminate these proteins by their ligand specificity. The HMMs reported here will allow a more sensitive detection of plant proteins containing LysM domains and help improve their characterisation.

plant biology↗

bioRxiv2023

Spatial autocorrelation dimension as a potential determinant for the temporal persistence of human atrial and ventricular fibrillation.

Background: Despite being central to atrial fibrillation (AF) and ventricular fibrillation (VF) mechanisms and therapy, the factors governing AF and VF termination are poorly understood. It has been noted that ratio of system size (L) and the two-point spatial correlation length ({xi}2) are associated with time until termination in transient spatiotemporally chaotic systems, but the relationship between these characteristics and termination has not been systematically studied in human AF and VF. Objective: We aimed assess whether the time to cardiac fibrillation termination can be predicted using a novel estimator, the spatial autocorrelation dimension (Di), defined as the ratio of L and {xi}2, in human AF and VF. Methods: Di was computed and compared in a multi-centre, multi-system study with data for sustained versus spontaneously terminating human AF/VF. VF data was collected during coronary-bypass surgery; and AF data during clinically indicated AF ablation. We analyzed: i) VF mapped using a 256-electrode epicardial sock (n=12pts); ii) AF mapped using a 64-electrode constellation basket-catheter (n=15pts); iii) AF mapped using a 16-electrode HD-grid catheter (n=42pts). To investigate temporal fibrillation persistence, the response of AF-episodes to flecainide (n=7pts) was also studied. Results: Spontaneously terminating fibrillation demonstrated a lower Di (P<0.001 all systems). Lower Di was also seen in paroxysmal compared to persistent AF (P=0.002). Post-flecainide, Di decreased over time (P<0.001). Lower Di was also associated with longer-lasting episodes of AF/VF (R2>0.90, P<0.05 in all cases). Using k-means clustering, two distinct clusters and their centroids were identified i) a cluster of spontaneously terminating episodes, and ii) a cluster of sustained epochs. Conclusion: Di predicts the temporal persistence of cardiac fibrillation. This finding provides potentially important insights into a possible common pathway to termination and therapeutic approaches.

physiology↗

bioRxiv2022

A morphological basis for path dependent evolution of visual systems

Path dependence influences macroevolutionary predictability by constraining potential outcomes after stochastic evolutionary events. Although demonstrated in laboratory experiments, the basis of path dependence is difficult to demonstrate in natural systems because of a lack of independent replicates. Here we show two types of complex distributed visual systems each recently evolved twice within chiton mollusks, demonstrating rapid and path dependent evolution. The type of visual system a chiton lineage evolves is constrained by the number of openings for optic nerves in its shell plates: lineages with more openings evolve visual systems with thousands of eyespots, whereas those with fewer evolve visual systems with hundreds of shell eyes. These macroevolutionary outcomes shaped by path dependence are both deterministic and stochastic because possibilities are restricted yet not entirely predictable. One-Sentence SummaryMultiple convergent origins of visual systems show macroevolution of complex traits can be rapid and contingent upon pre-existing structures

evolutionary biology↗

bioRxiv2021

Drosophila primary microRNA-8 encodes a microRNA encoded peptide (miPEP) acting in parallel of miR-8

BackgroundRecent genome-wide studies of many species reveal the existence of a myriad of RNAs differing in size, coding potential and function. Among these are the long non-coding RNAs, some of them producing functional small peptides via the translation of short ORFs. It now appears that any kind of RNA presumably has a potential to encode small peptides. Accordingly, our team recently discovered that plant primary transcripts of microRNAs (pri-miRNAs) produce small regulatory peptides (miPEPs) involved in auto-regulatory feedback loops enhancing their cognate microRNA expression which in turn controls plant development. Here we investigate whether this regulatory feedback loop is present in Drosophila melanogaster. ResultsWe perform a survey of ribosome profiling data and reveal that many pri-miRNAs exhibit ribosome translation marks. Focusing on miR-8, we show that pri-miR-8 can produce a miPEP-8. Functional assays performed in Drosophila reveal that miPEP-8 affects development when overexpressed or knocked down. Combining genetic and molecular approaches as well as genome-wide transcriptomic analyses, we show that miR-8 expression is independent of miPEP-8 activity and that miPEP-8 acts in parallel to miR-8 to regulate the expression of hundreds of genes. ConclusionTaken together, these results reveal that several Drosophila pri-miRNAs exhibit translation potential. Contrasting with the mechanism described in plants, these data shed light on the function of yet un-described pri-microRNA encoded peptides in Drosophila and their regulatory potential on genome expression.

developmental biology↗

bioRxiv2020

Under pressure: phenotypic divergence and convergence associated with microhabitat adaptations in Triatominae

BackgroundTriatomine bugs, the vectors of Chagas disease, associate with vertebrate hosts in highly diverse ecotopes. When these blood-sucking bugs adapt to new microhabitats, their phenotypes may change. Although understanding phenotypic variation is key to the study of adaptive evolution and central to phenotype-based taxonomy, the drivers of phenotypic change and diversity in triatomines remain poorly understood. Methods/FindingsWe combined a detailed phenotypic appraisal (including morphology and morphometrics) with mitochondrial cytb and nuclear ITS2 DNA-sequence analyses to study Rhodnius ecuadoriensis populations from across the species range. We found three major, naked-eye phenotypic variants. Southern-Andean bugs (SW Ecuador/NW Peru) from house and vertebrate-nest microhabitats are typical, light-colored, small bugs with short heads/wings. Northern-Andean bugs (W Ecuador wet-forest palms) are dark, large bugs with long heads/wings. Finally, northern-lowland bugs (coastal Ecuador dry-forest palms) are light-colored and medium-sized. Wing and (size-free) head shapes are similar across Ecuadorian populations, regardless of habitat or naked-eye phenotype, but distinct in Peruvian bugs. Bayesian phylogenetic and multispecies-coalescent DNA-sequence analyses strongly suggest that Ecuadorian and Peruvian populations are two independently-evolving lineages, with little within-lineage structuring/differentiation. ConclusionsWe report sharp naked-eye phenotypic divergence of genetically similar Ecuadorian R. ecuadoriensis (house/nest southern-Andean vs. palm-dwelling northern bugs; and palm-dwelling Andean vs. lowland); and sharp naked-eye phenotypic similarity of typical, yet genetically distinct, southern-Andean bugs from house and nest (but not palm) microhabitats (SW Ecuador vs. NW Peru). This remarkable phenotypic diversity within a single nominal species likely stems from microhabitat adaptations possibly involving predator-driven selective pressure (yielding substrate-matching camouflage coloration) and a shift from palm-crown to vertebrate-nest microhabitats (yielding smaller bodies and shorter heads and wings). These findings shed new light on the origins of phenotypic diversity in triatomines, warn against excess reliance on phenotype-based triatomine-bug taxonomy, and confirm the Triatominae as an informative model-system for the study of phenotypic change under ecological pressure. Author summaryTriatomine bugs feed on the blood of vertebrates including humans and transmit the parasite that causes Chagas disease. The bugs, of which 150+ species are known, are highly diverse in size, shape, and color. Some species look so similar that they are commonly confused, whereas a few same-species populations look so different that they were thought to be separate species. Despite the crucial role of naked-eye phenotypes in triatomine-bug identification and classification (which are essential for vector control-surveillance), the origins of this variation remain unclear. Here, we describe a striking case of phenotypic divergence, with genetically similar bugs looking very different from one another, and phenotypic convergence, with bugs from two genetically distinct populations (likely on their way to speciation) looking very similar - and all within a single nominal species, Rhodnius ecuadoriensis. Phenotypically divergent populations occupy different ecological regions (wet vs. dry) and microhabitats (palm-crowns vs. vertebrate nests), whereas convergent populations occupy man-made and nest (but not palm) microhabitats. These findings suggest that triatomines can respond to ecological novelty by changing their external, naked-eye phenotypes as they adapt to new microhabitats. We therefore warn that phenotypic traits such as overall size or color may confound triatomine-bug species identification and classification.

evolutionary biology↗

bioRxiv2019

The genetic architecture of Parkinson disease in Spain: characterizing population-specific risk, differential haplotype structures, and providing etiologic insight

BackgroundThe Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases.\n\nObjectivesTo perform the largest Parkinson disease (PD) genome-wide association study (GWAS) restricted to a single country.\n\nMethodsWe performed a GWAS for both risk of PD and age-at-onset (AAO) in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations and burden analyses.\n\nResultsWe identified a novel population-specific GWAS signal at PARK2 associated with AAO. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence via two-sample Mendelian randomization in expression and methylation datasets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls.\n\nConclusionsOur data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain.

neuroscience↗

bioRxiv2019

Renewal theory provides a universal quantitative framework to characterise the continuous regeneration of rotational events in cardiac fibrillation

BackgroundCardiac fibrillation is thought to be maintained by rotational activity, with pivoting regions called phase singularities (PSs). Despite a century of research, no clear quantitative framework exists to model the fundamental processes responsible for the continuous formation and destruction of rotors in fibrillation.\n\nObjectiveWe conducted a multi-modality, multi-species study of AF/VF under the hypothesis that PS formation/destruction in fibrillation can be modelled as self-regenerating renewal processes, producing exponential distributions of inter-event times governed by constant rate-parameters defined by the prevailing properties of the system.\n\nMethodsPS formation/destruction was studied and cross-validated in 5 models, using basket recordings and optical mapping from: i) human persistent AF (n = 20), ii) tachypaced sheep AF (n = 5), iii) rat AF (n = 4), iv) rat VF (n = 11) and v) computer simulated AF (SIM). Hilbert phase maps were constructed. PS lifetime data were fitted by exponential probability distribution functions (PDFs) computed using maximum entropy theory, and the rate parameter ({lambda}) determined. A systematic review was conducted to cross-validate with source data from literature.\n\nResultsPS destruction/formation distributions showed good fits to an exponential in all systems (R2 [≥] 0.90). In humans,{lambda} = 4.6%/ms (95%CI,4.3,4.9)), sheep 4.4%/ms (95%CI,4.1,4.7)), rat AF 38%/ms (95%CI,22,55), rat VF 46%/ms (95%CI,31.2,60.2) and SIM 5.4%/ms (95%CI,4.1,6.7). All PS distributions identified through systematic review were exponential with {lambda} comparable to experimental data.\n\nConclusionThese results provide a universal quantitative framework to explain rotor formation and destruction in AF/VF, and a platform for therapeutic advances in cardiac fibrillation.

physiology↗

bioRxiv2018

Local Cortical Activity Of Distant Brain Areas Can Time-Lock To The Respiratory Rhythm In The Freely Behaving Rat

An important unresolved question about neural processing is the mechanism by which distant brain areas coordinate their activities and relate their local processing to global neural events. A potential candidate for the local-global integration are slow rhythms such as respiration, which is also linked to sensory exploration. In this article, we asked if there are modulations of local cortical processing which are time-locked to (peripheral) sensory-motor exploratory rhythms. We studied rats freely behaving on an elevated platform where they would display exploratory and rest behaviors. Concurrent with behavior, we monitored orofacial sampling rhythms (whisking and sniffing) and local field potentials (LFP) from olfactory bulb, dorsal hippocampus, primary motor cortex, primary somatosensory cortex and primary visual cortex. We defined exploration as simultaneous whisking and sniffing above 5 Hz and found that this activity peaked at about 8 Hz. We considered rest as the absence of whisking and sniffing, and in this case, mean respiration occurred at about 3 Hz. We found a consistent shift across all areas toward these rhythm peaks accompanying behavioral state changes. We also found, across areas, that LFP gamma (70-100 Hz) amplitude could phase-lock to the animals respiratory rhythm, a finding indicative of respiration-locked changes in local processing. The respiratory rhythm, although occurring at the same frequencies of hippocampal theta, was not spectrally coherent with it, implying a different oscillator. Our results are consistent with the notion of respiration as a binder or integrator of activity between distant brain regions.

neuroscience↗

bioRxiv2017

Numb prevents a complete EMT by modulating Notch signalling

Epithelial-Mesenchymal Transition (EMT) plays key roles during embryonic development, wound healing, and cancer metastasis. Cells in a partial EMT or hybrid epithelial/mesenchymal (E/M) phenotype tend to exhibit collective cell migration, forming clusters of circulating tumour cells - the primary drivers of metastasis. Activation of cell-cell signalling pathways such as Notch fosters a partial or complete EMT, yet the mechanisms enabling cluster formation remain poorly understood. Using an integrated computational-experimental approach, we examine the role of Numb - an inhibitor of Notch intercellular signalling - in mediating EMT and clusters formation of hybrid E/M cells. Knockdown of Numb in stable hybrid E/M cells H1975 results in a full EMT, thereby showing that Numb acts as a brake for a full EMT. Consistent with this observation, we show via a mathematical model that Numb inhibits a full EMT by stabilizing a hybrid E/M phenotype. Thus, Numb can behave as a phenotypic stability factor by modulating Notch-driven EMT. By generalizing the mathematical model to a multi-cell level, Numb is predicted to alter the balance of hybrid E/M versus mesenchymal cells in clusters, potentially resulting in a higher tumour-initiation ability. Finally, Numb correlates with a poor survival in multiple independent lung and ovarian cancer datasets, hence confirming its relationship with increased cancer aggressiveness.\n\nMajor Findings: we adopt an integrative computational-experimental approach to identify that Numb, an inhibitor of Notch signalling, can stabilize a hybrid epithelial/mesenchymal (E/M) phenotype. We show that knockdown of Numb in H1975 cells that display a stable hybrid E/M state is sufficient to destabilize a hybrid E/M state and push them to a full EMT phenotype. Next, we develop a mechanism-based mathematical model that recapitulates this ability of Numb in maintaining a hybrid E/M state, and predicts that Numb can alter the relative frequency of hybrid E/M and mesenchymal cells at a tissue level or in clusters of circulating tumor cells (CTCs) - the primary drivers of metastasis. Finally, we show that across cancer types, Numb correlates with worse patient survival, thus reinforcing the emerging notion that a hybrid E/M, but not necessarily a completely mesenchymal, phenotype associates with elevated tumour progression.

cancer biology↗

bioRxiv2017

FGF4 Retrogene On CFA12 Is Responsible For Chondrodystrophy And Intervertebral Disc Disease In Dogs

Chondrodystrophy in dogs is defined by dysplastic, shortened long bones and premature degeneration and calcification of intervertebral discs. Independent genome-wide association analyses for skeletal dysplasia (short limbs) within a single breed (pBonferroni=0.0072) and intervertebral disc disease (IVDD) across breeds (pBonferroni=4.02x10-10) both identified a significant association to the same region on CFA12. Whole genome sequencing identified a highly expressed FGF4 retrogene within this shared region. The FGF4 retrogene segregated with limb length and had an odds ratio of 51.23 (95% CI = 46.69, 56.20) for IVDD. Long bone length in dogs is a unique example of multiple disease-causing retrocopies of the same parental gene in a mammalian species. FGF signaling abnormalities have been associated with skeletal dysplasia in humans, and our findings present opportunities for both selective elimination of a medically and financially devastating disease in dogs and further understanding of the ever-growing complexity of retrogene biology.

genetics↗