Biology subjects

Smith, H.

Publications and source records attributed to Smith, H..

36 records · Page 2Linked to original sources

bioRxiv2024

Interaction between gene expression and morphokinetic parameters in undisturbed human embryo culture

The clinical in vitro fertilisation (IVF) need for optimal culture conditions and improved selection of human embryos for transfer led to the development of time-lapse systems built into incubators to allow a stable, well-defined and undisturbed culture environment with continual monitoring of embryo development. Clinical data suggest that both undisturbed culture of embryos and selection algorithms based on time-lapse morphometric parameters can potentially improve embryo development and live birth rates. However, there remains a need to validate and understand the mechanisms underlying the potential benefits of the time-lapse technology in IVF. In this study, we compared the gene expression of human embryos grown in an undisturbed time-lapse system with a conventional incubator and showed that there is no fundamental difference in the developmental program of the undisturbed embryos, which provides important reassurance concerning the time-lapse technology. We then performed a network-based integrative analysis based on the undisturbed blastocyst transcriptomes and identified time-lapse parameter correlated genes. These showed cross talk with identified embryo development gene functional modules, suggesting potential molecular mechanisms underlying the clinical predictive capabilities of embryo time-lapse morphokinetic parameters for subsequent live birth. This study suggests methodologies for assessing the impact of additional predictive correlates of value for optimal embryo development and understanding their mechanisms of action.

developmental biology↗

bioRxiv2023

SHIELD: Skull-shaped hemispheric implants enabling large-scale-electrophysiology datasets in the mouse brain

To understand the neural basis of behavior, it is essential to measure spiking dynamics across many interacting brain regions. While new technologies, such as Neuropixels probes, facilitate multi-regional recordings, significant surgical and procedural hurdles remain for these experiments to achieve their full potential. Here, we describe a novel 3D-printed cranial-replacement implant (SHIELD) enabling electrophysiological recordings from distributed areas of the mouse brain. This skull-shaped implant is designed with customizable insertion holes, allowing dozens of cortical and subcortical structures to be recorded in a single mouse using repeated multi-probe insertions over many days. We demonstrate the procedures high success rate, biocompatibility, lack of adverse effects on behavior, and compatibility with imaging and optogenetics. To showcase the scientific utility of the SHIELD implant, we use multi-probe recordings to reveal novel insights into how alpha rhythms organize spiking activity across visual and sensorimotor networks. Overall, this method enables powerful large-scale electrophysiological measurements for the study of distributed brain computation.

neuroscience↗

bioRxiv2023

An Immuno-Epidemiological Model of Foot-and-Mouth Disease (FMD) in the African Buffalo Population with Carrier Transmission

Foot-and-mouth disease (FMD) is a highly contagious disease that spreads among cloven-hoofed animals. Although not deadly, FMD can cause major delays in meat and dairy production. One major concern is that the foot-and-mouth disease virus (FMDV) can persist in African buffalo hosts as natural reservoirs for long periods of time, causing the pathogens to reemerge in susceptible populations. In this paper, we present a novel immuno-epidemiological model of FMD in the African buffalo host populations. Upon infection, the hosts can undergo two phases, namely the acute and the carrier stages. In our model, we divide the infectious population based upon these two stages so that we can dynamically capture the immunological characteristics of both phases of the disease to better understand the carriers role in disease transmission. We first define the within-host viral-immune kinetics dependent epidemiological basic reproduction number[R] 0 and show that it is a threshold condition for the local stability of the disease-free equilibrium and existence of the endemic equilibrium. We also analytically show that the system always displays forward bifurcation with respect to between-host epidemic parameters. Later, by using a sensitivity analysis (SA) approach developed for multi-scale models, we assess the impact of the acute infection and carrier phase immunological parameters on[R] 0. Interestingly, our numerical results show that the within-carrier infected host immune kinetics parameters and the susceptible individual recruitment rates play significant roles in disease persistence, which are consistent with experimental and field studies.

systems biology↗

bioRxiv2023

Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and severe congenital brain arteriovenous malformation, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (p=4.79x10-7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (p=1.22x10-5), which cooperates with p120 RasGAP to limit Ras activation. Other probands had pathogenic variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomics defined developing endothelial cells as a key spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant exhibited constitutive endothelial Ras/ERK/MAPK activation and impaired hierarchical development of angiogenesis-regulated arterial-capillary-venous networks, but only when carrying a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have clinical implications.

genomics↗

bioRxiv2023

Dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of neural precursors and their interneuron descendants

Expansion of the cerebrospinal fluid (CSF)-filled cerebral ventricles (ventriculomegaly) is the quintessential feature of congenital hydrocephalus (CH) but also seen in autism spectrum disorder (ASD) and several neuropsychiatric diseases. PTEN is frequently mutated in ASD; here, we show PTEN is a bona fide risk gene for the development of ventriculomegaly, including neurosurgically-treated CH. Pten-mutant hydrocephalus is associated with aqueductal stenosis due to the hyperproliferation of periventricular Nkx2.1+ neural precursors (NPCs) and CSF hypersecretion from inflammation-dependent choroid plexus hyperplasia. The hydrocephalic Pten-mutant cortex exhibits ASD-like network dysfunction due to impaired activity of Nkx2.1+ NPC-derived inhibitory interneurons. Raptor deletion or post-natal Everolimus corrects ventriculomegaly, rescues cortical deficits, and increases survival by antagonizing mTORC1-dependent Nkx2.1+ cell pathology. These results implicate a dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of NPCs and their interneuron descendants. These data identify a non-surgical treatment target for hydrocephalus and have implications for other developmental brain disorders. HIGHLIGHTSO_LIPTEN de novo mutations are associated with cerebral ventriculomegaly in autism spectrum disorder (ASD) and congenital hydrocephalus (CH). C_LIO_LIPten-mutant hydrocephalus is associated with aqueductal stenosis due to the hyperproliferation of medial ganglionic eminence Nkx2.1+ neural precursors and CSF hypersecretion from inflammation-induced choroid plexus hyperplasia. C_LIO_LIThe hydrocephalic Pten-mutant cortex exhibits ASD-like network dysfunction due to impaired activity of Nkx2.1+ NPC-derived inhibitory interneurons. C_LIO_LImTORC1 inhibition via Raptor deletion or early post-natal treatment with rapamycin or everolimus increases survival and ameliorates Pten-mutant ventriculomegaly and cortical pathology. C_LI

neuroscience↗

bioRxiv2023

Oxidized phospholipid oxPAPC induces a Th1-like phenotype in regulatory T cells and inhibits their protective function in atherosclerosis

BackgroundRegulatory T cells (Tregs) are protective in atherosclerosis but reduced during disease progression due to cell death and loss of stability. However, the mechanisms of Treg dysfunction remain unknown. Oxidized phospholipids (oxPLs) are abundant in atherosclerosis and can activate innate immune cells, but there is limited information regarding their impact on T cells. Given Treg loss during atherosclerosis progression and oxPL levels in the plaque microenvironment, we sought to determine whether oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (oxPAPC), an oxPL associated with atherosclerotic plaques, alters Treg differentiation and function. MethodsNaive CD4+ T cells were cultured under Treg, Th1, and Th17 polarizing conditions with or without oxPAPC and assessed by flow cytometry. Gene expression in oxPAPC-treated Tregs was analyzed by bulk RNA sequencing. Functional studies of oxPAPC-induced Tregs were performed by co-culturing Tregs with CTV-labeled CD8+ cells in vitro. In vivo suppression of atherosclerosis was evaluated by adoptively transferring control or oxPAPC-treated Tregs to hyperlipidemic Ldlr-/- mice. ResultsCompared to controls, oxPAPC-treated Tregs were less viable but expressed higher levels of the Th1-associated markers T-bet, CXCR3, and IFN-{gamma}. Th1 and Th17 skewing cultures were unaltered by oxPAPC. IFN-{gamma} is linked to Treg instability, thus Treg polarization experiments were repeated using Ifngr1-/- CD4+ T cells. IFN{gamma}R1 deficiency did not improve cell viability in oxPAPC-treated Tregs, however, T-bet and IFN-{gamma} expression was not increased suggesting a role for IFN-{gamma} signaling. OxPAPC-treated Tregs were less suppressive in vitro, and adoptive transfer studies in hyperlipidemic Ldlr-/- mice showed that oxPAPC-induced Tregs possessed altered tissue homing and were insufficient to inhibit atherosclerosis progression. ConclusionsOxPAPC elicits Treg-specific changes that induce a Th1-like phenotype dependent on IFN-{gamma} signaling. This is biologically relevant as oxPAPC-treated Tregs are unable to reduce atherosclerosis progression in Ldlr-/- mice. This study supports a role for oxPLs in negatively impacting Treg differentiation and atheroprotective function.

immunology↗

bioRxiv2022

Seasonal polyphenism of wing colors and its influence on sulphur butterfly diversification

Seasonal variation of color patterns on butterfly wings are iconic examples of developmentally plastic traits that can influence adaptation and speciation. Yet, there are few examples of such seasonal polyphenisms that have characterized the environmental cues, ecological consequences, or genetic mechanisms involved in generating the plastic variation of wing color. Further, there is a lack of support that such plasticity may impact the adaptive diversification of butterfly wing patterns. Here, we report a case of seasonal polyphenism in pigment and structurally-based color patterns of Zerene cesonia that are strikingly similar to the color pattern divergence seen on the wings of sulphur butterflies. We show that (i) coordinated changes in temperature and photoperiod drive the plasticity, (ii) the plastic color changes impact how fast the butterflies can warm, (iii) identify spalt as likely be involved in the genetic coupling of the pigment and structurally-based color plastic response. We further show that this plastic wing changes phenocopy wing pattern divergence between Zerene species, as well as the color pattern differences known to be commonly involved in sexual selection and speciation across sulphur butterflies. Together, our results demonstrate that shared environmental cues and genetic basis for pigment and structural color plasticity may result in conditions that may have facilitated species diversification of sulphur butterflies.

evolutionary biology↗

bioRxiv2022

Phasing of de novo mutations using a scaled-up multiple amplicon long-read sequencing approach

De novo mutations (DNMs) play an important role in severe genetic disorders that reduce fitness. To better understand the role of DNMs in disease, it is important to determine the parent-of-origin and timing of the mutational events that give rise to the mutations, especially in sex-specific developmental disorders such as male infertility. However, currently available short-read sequencing approaches are not ideally suited for phasing as this requires long continuous DNA strands that span both the DNM and one or more informative SNPs. To overcome these challenges, we optimised and implemented a multiplexed long-read sequencing approach using the Oxford Nanopore technologies MinION platform. We specifically focused on improving target amplification, integrating long-read sequenced data with high-quality short-read sequence data, and developing an anchored phasing computational method. This approach was able to handle the inherent phasing challenges that arise from long-range target amplification and the normal accumulation of sequencing error associated with long-read sequencing. In total, 77 out of 109 DNMs (71%) were successfully phased and parent-of-origin identified. The majority of phased DNMs were prezygotic (90%), the accuracy of which is highlighted by the average mutant allele frequency of 49.6% and a standard error margin of 0.84%. This study demonstrates the benefits of using an integrated short-read and long-read sequencing approach for large-scale DNM phasing.

genomics↗

bioRxiv2021

A secreted proteomic footprint for stem cell pluripotency

With a view to developing a much-needed non-invasive method for monitoring the healthy pluripotent state of human stem cells in culture, we undertook proteomic analysis of the spent medium from cultured embryonic (Man-13) and induced (Rebl.PAT) human pluripotent stem cells (hPSCs). Cells were grown in E8 medium to maintain pluripotency, and then transferred to FGF2 and TGF{beta} deficient media for 48 hours to replicate an early, undirected dissolution of pluripotency. We identified a distinct proteomic footprint associated with early loss of pluripotency in both hPSC lines, and a strong correlation with changes in the transcriptome. We demonstrate that multiplexing of 4 E8- against 4 E6- enriched biomarkers provides 16 ratio abundances which are each robustly diagnostic for pluripotent state. These biomarkers were further confirmed by Western blotting which demonstrated consistent correlation with the pluripotent state across cell lines, and in response to recovery assays.

cell biology↗

bioRxiv2020

Cell-intrinsic IL4R alpha independence of large intestinal RELMα+ Ym1+ macrophages

The balance of pro-inflammatory and anti-inflammatory macrophages is critically important in enabling the development and resolution of inflammatory responses. Anti-inflammatory macrophages have been shown to be activated by IL4 and/or IL13 via the IL4R. In the context of type 2 immunity, anti-inflammatory macrophages have been defined by the expression of the signature markers RELM, CD206 and Ym1, associated with activation of macrophages via the IL4R. Despite a breadth of inflammatory pathologies associated with the large intestine, many of which feature unbalanced macrophage activation states, little is known about how large intestinal macrophages are activated. Here, we address this important knowledge gap by using a Trichuris muris infection model of resolving type 2 intestinal inflammation, in combination with transgenic mice (IL4Rfl/fl.CX3CR1Cre) and IL4R-deficient/wild-type mixed bone marrow chimaeras. These models allowed us to interrogate the role of IL4/IL13 in macrophage activation driven by inflammation of the large intestine. We make the unexpected finding that education of large intestinal macrophages towards a RELM and Ym1 expressing cell type during type 2 inflammation, does not require IL4R expression on macrophages. Thus, upregulation of RELM and Ym1 post infection is independent of macrophage IL4R expression. Further, this independence is maintained even when the mice are treated with anti-IFN{gamma} antibody to create a strongly polarised Th2 environment. In contrast to RELM and Ym1, PD-L2 expression on macrophages post infection was dependent on IL4R signalling in the macrophages. These data challenge existing paradigms, evidencing that expression of RELM and Ym1 by macrophages, typically regarded as having anti-inflammatory functions, do not always rely on IL4/IL13.

immunology↗

bioRxiv2020

Metabolic Immunomodulation, Transcriptional Regulation, and Signal Protein Expression Define the Metabotype and Effector Functions of Five Polarized Macrophage Phenotypes

Macrophages (M{Phi}s) display remarkable plasticity and the ability to activate diverse responses to a host of intracellular and external stimuli. Despite extensive characterization of M1 M{Phi}s and a broad set of M2 M{Phi}s, comprehensive characterization of metabolic shifts driving M{Phi} activation remains. Herein, we utilized an ex vivo model to produce six M{Phi} functional phenotypes. Isolated CD14+ PBMCs were differentiated into resting M0 M{Phi}s, and then polarized into M1 (IFN-{gamma}/LPS), M2a (IL-4/IL-13), M2b (IC/LPS), M2c (IL-10), and M2d (IL-6/LIF) M{Phi}s. The M{Phi}s were profiled using a bioanalyte matrix of four cell surface markers, [~]50 secreted proteins, [~]800 expressed myeloid genes, and [~]450 identified metabolites relative to M0 M{Phi}s. Signal protein and expressed gene profiles grouped the M{Phi}s into inflammatory (M1 and M2b) and wound resolution (M2a, M2c, and M2d) phenotypes; however, each had a unique metabolic profile. While both M1 and M2b M{Phi}s shared metabotype profiles consistent with an inflammatory signature; key differences were observed in the TCA cycle, FAO and OXPHOS. Additionally, M2a, M2c and M2d M{Phi}s all profiled as tissue repair M{Phi}s; however, metabotype differences were observed in multiple pathways including hexosamine, polyamine, and fatty acid metabolism. These metabolic and other key functional distinctions suggest phagocytic and proliferative functions for M2a M{Phi}s, and angiogenesis and ECM assembly capabilities for M2b, M2c and M2d M{Phi}s. By integrating metabolomics into a systems analysis of M{Phi} phenotypes, we provide the most comprehensive map of M{Phi} diversity to date, along with the global metabolic shifts driving M{Phi} functional plasticity in these phenotypes. Summary SentenceMacrophage functional plasticity of six macrophage phenotypes correlates with unique distinctions in cell-surface marker expression, signal protein secretion, transcriptomics profiles, and metabolic processes.

immunology↗

bioRxiv2020

Metagenomic data reveal diverse fungal and algal communities associated with the lichen symbiosis

Lichens have traditionally been considered the symbiotic phenotype from the interactions of a single fungal partner and one or few photosynthetic partners. However, the lichen symbiosis has been shown to be far more complex and may include a wide range of other interacting organisms, including non-photosynthetic bacteria, accessory fungi, and algae. In this study, we analyzed metagenomic shotgun sequences to better characterize lichen mycobiomes. Specifically, we inferred the range of fungi associated within lichen thalli from five groups of lichens - horsehair lichens (mycobiont=Bryoria spp.), shadow lichens (taxa in Physciaceae), rock posies (Rhizoplaca spp.), rock tripes (Umbilicaria spp.), and green rock shields (Xanthoparmelia spp.). Metagenomic reads from the multi-copy nuclear ribosomal internal transcribed spacer region, the standard DNA barcode region for fungi, were extracted, clustered, and used to infer taxonomic assignments. Our data revealed diverse lichen-associated mycobiomes, and closely related mycobionts tended to have more similar mycobiomes. Many of the members of the lichen-associated mycobiomes identified here have not previously been found in association with lichens. We found little evidence supporting the ubiquitous presence of Cystobasidiales yeasts in macrolichens, although reads representing this putative symbiotic partner were found in samples of horsehair lichens, albeit in low abundance. Our study further highlights the ecosystem-like features of lichens, with partners and interactions far from being completely understood. Future research is needed to more fully and accurately characterize lichen mycobiomes and how these fungi interact with the major lichen components - the photo- and mycobionts.

ecology↗

bioRxiv2019

In silico design of a T-cell epitope vaccine candidate for parasitic helminth infection

Trichuris trichiura is a parasite that infects 500 million people worldwide, leading to colitis, growth retardation and Trichuris dysentery syndrome. There are no licensed vaccines available to prevent Trichuris infection and current treatments are of limited efficacy. Trichuris infections are linked to poverty, reducing childrens educational performance and the economic productivity of adults. We employed a systematic, multi-stage process to identify a candidate vaccine against trichuriasis based on the incorporation of selected T cell epitopes into virus-like particles. We conducted a systematic review to identify the most appropriate in silico prediction tools to predict histocompatibility complex class II (MHC-II) molecule T-cell epitopes. These tools were used to identify candidate MHC-II epitopes from predicted ORFs in the Trichuris genome, selected using inclusion and exclusion criteria. Selected epitopes were incorporated into Hepatitis B core antigen virus-like particles (VLPs). A combined VLP vaccine containing four Trichuris MHC-II T-cell epitopes stimulated dendritic cells and macrophages to produce pro-inflammatory and anti-inflammatory cytokines. The VLPs were internalized and co-localized in the antigen presenting cell lysosomes. Upon challenge infection, mice vaccinated with the VLPs+T-cell epitopes showed a significantly reduced worm burden, and mounted Trichuris-specific IgM and IgG2c antibody responses. The protection of mice by VLPs+T-cell epitopes was characterised by the production of mesenteric lymph node (MLN)-derived Th2 cytokines and goblet cell hyperplasia. Collectively our data establishes that a combination of in silico genome-based CD4+ T cell epitope prediction, combined with VLP delivery, offers a promising pipeline for the development of an effective, safe and affordable helminth vaccine. Author SummaryThe soil transmitted helminth Trichuris trichiura is a major parasite in developing countries; development of a comprehensive vaccine has been elusive. Here we used a systematic approach based on in silico identification of MHC-II T cell epitopes from genome sequences, their incorporation into a virus-like particle (VLP), characterization of the assemblies and testing in an in vivo murine infection model. Animals vaccinated with a preparation of four different VLP-antigen fusions showed significant reductions in intestinal worm burdens and associated antibody responses consistent with protection. The results suggest that a pipeline based on in silico prediction of potent MHC-II T cell epitopes, followed by incorporation into VLPs, could be a strategy which enables rapid translation into a vaccine against Trichuris trichiura.

immunology↗

bioRxiv2019

STing: accurate and ultrafast genomic profiling with exact sequence matches

Genome-enabled approaches to molecular epidemiology have become essential to public health agencies and the microbial research community. We developed the algorithm STing to provide turn-key solutions for molecular typing and gene detection directly from next-generation sequence data of microbial pathogens. Our implementation of STing uses an innovative k-mer search strategy that eliminates the computational overhead associated with the time consuming steps of quality control, assembly, and alignment required by more traditional methods. We compared STing to six of the most widely used programs for genome-based molecular typing and demonstrate its ease of use, accuracy, speed, and efficiency. STing shows superior accuracy and performance for standard multilocus sequence typing schemes, along with larger genome-scale typing schemes, and it enables rapid automated detection of antimicrobial resistance and virulence factor genes. We hope that the adoption of STing will help to democratize microbial genomics and thereby maximize its benefit for public health.

bioinformatics↗

bioRxiv2018

Interactome comparison of human embryonic stem cell lines with the inner cell mass and trophectoderm

Human embryonic stem cells (hESCs) derived from the pluripotent Inner cell mass (ICM) of the blastocyst are fundamental tools for understanding human development, yet are not identical to their tissue of origin. To investigate this divergence we compared the transcriptomes of genetically paired ICM and trophectoderm (TE) samples with three hESC lines: MAN1, HUES3 and HUES7 at similar passage. We generated inferred interactome networks using transcriptomic data unique to the ICM or TE, and defined a hierarchy of modules (highly connected regions with shared function). We compared network properties and the modular hierarchy and show that the three hESCs had limited overlap with ICM specific transcriptome (6%-12%). However this overlap was enriched for network properties related to transcriptional activity in ICM (p=0.016); greatest in MAN1 compared to HUES3 (p=0.048) or HUES7 (p=0.012). The hierarchy of modules in the ICM interactome contained a greater proportion of MAN1 specific gene expression (46%) compared to HUES3 (28%) and HUES7 (25%) (p=9.0x10-4). These findings show that traditional methods based on transcriptome overlap are not sufficient to identify divergence of hESCs from ICM. Our approach also provides a valuable approach to the quantification of differences between hESC lines. And Manchester Academic Health Sciences Centre

developmental biology↗

bioRxiv2018

An optimized method for the isolation and the molecular characterization of cerebral microvessels in vivo

The molecular characterization of cerebral microvessels in experimental disease models has been hindered by the lack of a standardized method to reproducibly isolate intact cerebral microvessels, with consistent cellular compositions, and without the use of enzymatic digestion, which causes undesirable molecular and metabolic changes. Herein, we describe an optimized method for microvessel isolation from mouse brain cortex, which yields microvessel fragments (diameter <50 m, 89.3% 3-5 m) with consistent populations of discrete blood-brain barrier components (endothelial cells, pericytes, and astrocyte end feet), retaining high RNA integrity and protein postranslational modifications (e.g. phosphorylation). We demonstrate that this method allows the quantification of changes in gene expression in a disease model (stroke) and the activation of signalling pathways in mice subjected to drug administration. We also describe the isolation of genomic DNA and bisulfite treatment for the assessment of DNA methylation, as well as the optimization of chromatin extraction and shearing from cortical microvessels. Therefore, this protocol will be of great use to improve the understanding of the molecular mechanisms governing cerebrovascular dysfunction, which may help the development of novel therapies for stroke and other neurodegenerative diseases.

neuroscience↗

bioRxiv2017

Universal Scaling in Biochemical Networks

The application of network science to biology has advanced our understanding of the metabolism of individual organisms and the organization of ecosystems but has scarcely been applied to life at a planetary scale. To characterize planetary-scale biochemistry, we constructed biochemical networks using a global database of 28,146 annotated genomes and metagenomes, and 8,658 cataloged biochemical reactions. We uncover scaling laws governing biochemical diversity and network structure shared across levels of organization from individuals to ecosystems, to the biosphere as a whole. Comparing real biochemical networks to random chemical networks reveals the observed biological scaling is not solely a product of the biochemistry shared across life on Earth. Instead, it emerges due to how the global inventory of biochemical reactions is partitioned into individuals. We show the three domains of life are topologically distinguishable, with > 80% accuracy in predicting evolutionary domain based on biochemical network size and average topology. Taken together our results point to a deeper level of organization in biochemical networks than what has been understood so far.

systems biology↗

bioRxiv2017

Tragedy Of The Commons In The Chemostat

We present a proof of principle for the phenomenon of the tragedy of the commons that is at the center of many theories on the evolution of cooperation. We establish the tragedy in the context of a general chemostat model with two species, the cooperator and the cheater. Both species have the same growth rate function and yield constant, but the cooperator allocates a portion of the nutrient uptake towards the production of a public good -the \"Commons\" in the Tragedy-which is needed to digest the externally supplied nutrient. The cheater on the other hand does not produce this enzyme, and allocates all nutrient uptake towards its own growth. We prove that when the cheater is present initially, both the cooperator and the cheater will eventually go extinct, hereby confirming the occurrence of the tragedy. We also show that without the cheater, the cooperator can survive indefinitely, provided that at least a low level of public good or processed nutrient is available initially. Our results provide a predictive framework for the analysis of cooperator-cheater dynamics in a powerful model system of experimental evolution.

evolutionary biology↗