Biology subjects

Bailey, J.

Publications and source records attributed to Bailey, J..

At least 19 recordsLinked to original sources

bioRxiv2026

A rapid, sensitive, and quantitative high plex biomarker digital detection platform enabled by Hypercoding

Low-cost, multiplexed, and automated assays are needed to make omic technologies more broadly accessible in clinical, research, and commercial settings. We present Hypercoding, a scalable technology for detection and quantitation of multi-omic targets. Drawing from data reliability methods in the telecommunications field, Hypercoding uses fluorescent signals from hybridization with an error-correcting code to enable detection of high-plexity targets from biological samples, such as human DNA. In the presence of the target, a linear DNA construct is circularized, immobilized, and amplified to enable single-molecule detection of a target via rapid readout cycles within a 96-well plate. We demonstrate capability for >10,000 code plexity and accurate (98.7%) genotyping of 209 pharmacogenomic variants. Furthermore, we show computation of copy number variation with whole chromosome and sub-gene resolution, as well as quantitation of target abundance down to 10 fM sensitivity with a dynamic range of up to 10 logs.

genomics↗

bioRxiv2026

Computational Analysis of Structure and Binding Energy for the Development of a Cisplatin-Loaded Protein Nanocarrier

Platinum-based drugs, such as cisplatin, are first-line chemotherapy treatments for patients with cancer. However, the success of these drugs is balanced with severe off-target toxicities and high dosing requirements, prompting the development of selective nanocarriers for targeted drug delivery. This study uses a computationally guided approach to examine the role of amino acids in cisplatin binding within proteins as nanocarriers. Using density functional theory, we quantify the binding of cisplatin to platinum-coordinating amino acids. We then rationally engineer a model MSH6 protein carrier, and evaluate the ability of MSH6 to bind cisplatin via molecular docking simulations. Structure predictions of the engineered MSH6 show that inserting the cisplatin-binding site has a limited impact on the nearby protein architecture of MSH6. Finally, we confirm and reveal cisplatins mechanism of action with DNA binding, and compare the energetic potentials of DNA binding from protein-delivered cisplatin to systemically administered cisplatin. Future studies will use these results to experimentally validate the binding of cisplatin in model protein carriers, and inform the strategic design and experimental development of a protein nanocarrier to achieve targeted drug delivery in cancer. TOC Figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=60 SRC="FIGDIR/small/699809v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@feee4org.highwire.dtl.DTLVardef@ccc34org.highwire.dtl.DTLVardef@328cd3org.highwire.dtl.DTLVardef@bb8335_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Towards an evolutionary baseline model of Plasmodium falciparum for population-genomic inference

Malaria has caused over 15.7 million deaths in the 21st century and was responsible for [~]600 thousand deaths globally in 2023 alone. Although many effective antimalarial drugs have been developed and widely adopted to reduce the occurrence and severity of the disease, recurrent resistance to the frontline treatment has been of major concern. Multiple drug resistance alleles at intermediate and high allele frequency have been identified in specific Asian and African populations of P. falciparum, the deadliest malaria parasite. With the improvement in throughput of sequencing technologies and global efforts such as the MalariaGEN project to build genomic surveillance, we now have access to tens of thousands of genomes of P. falciparum from across the world. With this data, it is becoming increasingly possible to employ powerful population genetics approaches to understand the selective pressures and demographic history of the parasite. While several empirically motivated outlier-based approaches have been employed to identify targets of drug resistance, there is a lack of a framework that jointly accounts for the multiple concurrent processes occurring in natural populations of P. falciparum. We argue that a baseline evolutionary model that accounts for simultaneously acting evolutionary processes is needed to understand patterns of genomic variation in P. falciparum populations. Here, we identify key components essential for building such a baseline model for the malaria-causing pathogen. The development of an appropriate null model will be important to test evolutionary hypotheses using genomic datasets, will provide a path forward to improve the accuracy of inference of evolutionary parameters, and will help identify new gene candidates involved in drug resistance.

evolutionary biology↗

bioRxiv2025

Umbilical Cord Blood Cell Transcriptional and Methylation Signatures at Birth Are Associated with BPD Development.

Bronchopulmonary dysplasia (BPD) is the most common respiratory disease in preterm infants born at less than 28 weeks gestation. Most existing clinical prediction models for BPD show limited accuracy in predicting BPD development when validated using external data, stressing the need for novel biomarkers to identify at-risk infants for early and effective interventions. We leveraged existing frozen umbilical cord blood samples from the Northwestern University Cord Blood Biobank (NUCord) to perform parallel transcriptional and DNA methylation profiling. BPD-associated differentially expressed genes (DEGs) in our cohort included markers previously established in clinical and animal BPD studies, such as genes related to NF-{kappa}B signaling and immune responses. We also identified that BPD development is associated with disrupted methylation signatures in microRNA genes and genes associated with glucose metabolism. Our results suggest that BPD development is associated with distinct transcriptomic and epigenetic signatures when compared with healthy term and preterm infants. These signatures may represent biomarkers measurable at birth that predict BPD development during a time window when preventative or therapeutic interventions could be applied.

genomics↗

bioRxiv2025

Geographical variation drives adaptive equilibrium of the P. falciparum sickle-associated mutations

The recent discovery of genetic mutations in Plasmodium falciparum--the most lethal malaria parasite--that enable it to overcome the protective effects of sickle cell trait, raises fundamental questions about the underlying biological and evolutionary interactions. Here we develop a geostatistical model to compare sickle haemoglobin genotype frequencies to the Plasmodium falciparum sickle-associated alleles across global populations, and find a robust association at multiple geographical scales, implying that sickle drives positive selection for these parasite mutations. A model of parasite evolution and an analysis of local haplotype patterns suggest that key features of these mutations - that they are polymorphic in all African populations and are mutually correlated despite lying in different genome regions - are caused by geographical variation in selection pressure, and that the alleles may have been maintained by balancing selection over timescales comparable to the age of the sickle mutation itself. The predicted impact of this host-parasite interaction on disease outcomes varies widely across populations, and functional data are needed to discover the biological mechanisms involved.

genetics↗

bioRxiv2025

A High-Dimensional Interfacial Wave Assay for Early Biophysical Profiling of Therapeutic Antibodies

Therapeutic antibody performance depends not only on sequence and structure, but also on how the molecule responds to physico-chemical perturbations encountered in its environment. Whereas sequence and static structure can be inferred under controlled conditions, behaviour is a conditional, multidimensional response to environment, most directly characterised by applying defined perturbations and quantifying the resulting dynamics. Conventional early-stage developability methods capture isolated dimensions of this response under near-equilibrium conditions, deferring integrated behavioural assessment to late-stage characterisation, when the cost of correction is highest. We introduce Variations in Interfacial Behaviour under Excitation (VIBE), an interfacial wave method implemented via Liquid State Intelligence (LSI), a sensing architecture that transduces molecular perturbations at the air-liquid interface into high-dimensional wave patterns. A colloidal liquid substrate operated near a thermodynamic transition couples small molecular perturbations to large dynamical responses, integrating structural flexibility, charge distribution, and surface hydrophobicity into a single behavioural readout from microgram-scale samples. Applied to antibodies previously characterised by industrial benchmarks, the primary behavioural descriptor, VIBE1, functioned as a high-precision triage tool, flagging candidates carrying multiple biophysical liabilities. In a clinical-stage cohort, the proportion of high-VIBE1 antibodies declined progressively from early trials through approval, and high-VIBE1 candidates showed an elevated clinical failure rate. Concordance analysis against estab-lished methods confirmed that VIBE1 captures a composite signal spanning hydrophobicity, polyreactivity, self-interaction, and thermal stability rather than recapitulating any single conventional readout. These findings establish interfacial wave sensing as a low-material modality for early-stage developability assessment, repositioning molecular behaviour from late-stage validation to discovery-phase characterisation.

biophysics↗

bioRxiv2025

Sulfuriferula spp. from sulfide mineral weathering environments have diverse sulfur- and iron-cycling capabilities

Microorganisms are important catalysts for the oxidation of reduced inorganic sulfur compounds. One environmentally important source of reduced sulfur is metal sulfide minerals that occur in economic mineral deposits and mine waste. Previous research found that Sulfuriferula spp. were abundant and active in long-term weathering experiments with simulated waste rock and tailings from the Duluth Complex, Northern Minnesota. We therefore isolated several strains of Sulfuriferula spp. from these long-term experiments and characterized their metabolic and genomic properties to provide insight into microbe-mineral interactions and the microbial biogeochemistry in these and other moderately acidic to circumneutral environments. The Sulfuriferula strains are all obligate chemolithoautotrophs capable of oxidizing inorganic sulfur compounds and ferrous iron. The strains grew over different pH ranges, but all grew between pH 4.5-7, matching the weathering conditions of the Duluth Complex rocks. All strains grew on the iron-sulfide mineral pyrrhotite (Fe1-xS, 0 < x < 0.125) as the sole energy source, as well as hydrogen sulfide and thiosulfate, which are products of sulfide mineral breakdown. Despite their metabolic similarities, each strain encodes a distinct pathway for the oxidation of reduced inorganic sulfur compounds as well as differences in nitrogen metabolism that reveal diverse genomic capabilities among the group. Our results show that Sulfuriferula spp. are primary producers that likely play a role in sulfide mineral breakdown in moderately acidic to circumneutral mine waste, and the metabolic diversity within the genus likely explains their success in sulfide mineral-rich and other sulfidic environments. ImportanceMetal sulfide minerals such as pyrite and pyrrhotite are one of the main sources of reduced sulfur in the global sulfur cycle. The chemolithotrophic microorganisms that break down these minerals in natural and engineered settings are catalysts for biogeochemical sulfur cycling and have important applications in biotechnological processes such as biomining or bioremediation. Sulfuriferula is a recently described genus of sulfur oxidizing bacteria that are abundant primary producers in diverse terrestrial environments, including waste rock and tailings from metal mining operations. In this study, we explored the genomic and metabolic properties of new isolates from this genus, and the implications for their ecophysiology and biotechnological potential in ore and waste from economic mineral deposits.

microbiology↗

bioRxiv2024

Incorporation of Epstein-Barr viral variation implicates significance of LMP1 in survival prediction and prognostic subgrouping in Burkitt lymphoma

While Epstein-Barr virus (EBV) plays a role in Burkitt lymphoma (BL) tumorigenesis, it is unclear if EBV genetic variation impacts clinical outcomes. From 130 publicly available whole-genome tumor sequences of EBV-positive BL patients, we used least absolute shrinkage and selection operator (LASSO) regression and Bayesian variable selection models within a Cox proportional hazards framework to select the top EBV variants, putative driver genes, and clinical features associated with patient survival time. These features were incorporated into survival prediction and prognostic subgrouping models. Our model yielded 22 EBV variants including seven in LMP1 as most associated with patient survival time. Using the top EBV variants, driver genes, and clinical features, we defined three prognostic subgroups that demonstrated differential survival rates, laying the foundation for incorporating EBV variants such as those in LMP1 as predictive biomarker candidates in future studies.

genomics↗

bioRxiv2024

Brain Vasculature Accumulates Tau and Is Spatially Related to Tau Tangle Pathology in Alzheimer's Disease

Insoluble pathogenic proteins accumulate along blood vessels in conditions of cerebral amyloid angiopathy (CAA), exerting a toxic effect on vascular cells and impacting cerebral homeostasis. In this work we provide new evidence from three-dimensional human brain histology that tau protein, the main component of neurofibrillary tangles, can similarly accumulate along brain vascular segments. We quantitatively assessed n=6 Alzheimers disease (AD), and n=6 normal aging control brains and saw that tau-positive blood vessel segments were present in all AD cases. Tau-positive vessels are enriched for tau at levels higher than the surrounding tissue and appear to affect arterioles across cortical layers (I-V). Further, vessels isolated from these AD tissues were enriched for N-terminal tau and tau phosphorylated at T181 and T217. Importantly, tau-positive vessels are associated with local areas of increased tau neurofibrillary tangles. This suggests that accumulation of tau around blood vessels may reflect a local clearance failure. In sum, these data indicate tau, like amyloid beta, accumulates along blood vessels and may exert a significant influence on vasculature in the setting of AD.

neuroscience↗

bioRxiv2023

Evolution of rarity and phylogeny determine above- and belowground biomass in plant-plant interactions

Rare species are often considered inferior competitors due to occupancy of small ranges, specific habitats, and small local populations. However, the phylogenetic relatedness and rarity level of interacting species in plant-plant interactions are not often considered when predicting the competitive response of rare plants. We used a common garden of 25 species of Tasmanian Eucalyptus, varying in rarity to allow us to differentiate the competitive abilities of rare versus common species when grown in mixtures varying in phylogenetic relatedness and rarity. We demonstrate increased biomass production of rare plant species when interacting with genetically intermediate neighbors through synergistic non-additive effects not seen in common species. Additionally, we also find that all plants, regardless of rarity status, maintain 47% greater aboveground and 69% greater belowground biomass when interacting with common species compared to the rarest species. However, species-specific interactions with one particular common species, E. globulus, yielded a 97% increase in biomass compared to average biomass yields in other interactions, suggesting the importance of E. globulus integration into rare species restoration plantings. These results are important because they suggest that the evolutionary processes driving species rarity and the phylogenetic divergence of traits interact to drive ecological dynamics of plant-plant interactions in non-additive ways. Through the ecological and evolutionary consideration of performance traits, rarity, and species-specific effects, we can more accurately predict plant-plant interaction dynamics varying in rarity and relatedness across the landscape.

ecology↗

bioRxiv2022

Sequencing by avidity enables high accuracy with low reagent consumption

We present avidity sequencing - a novel sequencing chemistry that separately optimizes the process of stepping along a DNA template and the process of identifying each nucleotide within the template. Nucleotide identification uses multivalent nucleotide ligands on dye-labeled cores to form polymerase-polymer nucleotide complexes bound to clonal copies of DNA targets. These polymer-nucleotide substrates, termed avidites, decrease the required concentration of reporting nucleotides from micromolar to nanomolar, and yield negligible dissociation rates. We demonstrate the use of avidites as a key component of a sequencing technology that surpasses Q40 accuracy and enables a diversity of applications that include single cell RNA-seq and whole human genome sequencing. We also show the advantages of this technology in sequencing through long homopolymers.

genomics↗

bioRxiv2022

Examining the early distribution of the artemisinin-resistant Plasmodium falciparum kelch13 R561H mutation in Rwanda

Artemisinin resistance mutations in Plasmodium falciparum kelch13 (Pfk13) have begun to emerge in Africa. Pfk13-R561H was the first reported African mutation found in Rwanda in 2014, but limited sampling left questions about its early distribution and origin. We detected 476 parasitemias among 1873 residual blood spots from a 2014-15 Rwanda Demographic Health Survey. We sequenced 351 samples revealing 341/351 were wild type (97.03% weighted) and 4 samples (1.34% weighted) harbored R561H which were significantly spatially clustered. Our study better defines the early distribution of R561H in Rwanda and suggests that the origin may have involved higher-transmission regions.

genomics↗

bioRxiv2022

Exposure of Greenlandic Inuit and South African VhaVenda men to the persistent DDT metabolite is associated with an altered sperm epigenome at regions implicated in paternal epigenetic transmission and developmental disease - a cross-sectional study

BackgroundThe persistent organochlorine dichlorodiphenyltrichloroethane (DDT) is banned world-wide due to its negative health effects and persistence in the environment. It is exceptionally used as an insecticide for malaria control. Exposure occurs in regions where DDT is applied, as well as in the arctic where its endocrine disrupting metabolite, p,p-dichlorodiphenyldichloroethylene (p,p-DDE) accumulates in marine mammals and fish. DDT and p,p-DDE exposures are linked to birth defects, infertility, cancer, and neurodevelopmental delays. Of particular concern is the potential of DDT use to impact the health of generations to come. Generational effects of toxicant exposures have been described in animal models and implicated germline epigenetic factors. Similar generational effects have been shown in epidemiological studies. Although advances in understanding the molecular mechanisms mediating this epigenetic inheritance have been made, there remain major knowledge gaps in how this occurs in humans. In animal and human models, DNA methylation (DNAme) has been implicated in paternal epigenetic effects. In animal models, histone H3K4 trimethylation (H3K4me3) has been shown to be responsive to the paternal environment and linked with epigenetic transmission to the embryo. Our objectives were to define the associations between p,p-DDE serum levels and alterations in the sperm methylome and H3K4me3 enrichment using next generation sequencing. We aimed to compare regions of epigenomic sensitivity between geographically diverse populations with different routes and levels of exposures, and to identify interactions between altered DNAme and H3K4me3 regions. The potential for p,p-DDE to impact the health of the next generation was explored by examining the functions of the genomic regions impacted, their roles during embryo development, and in health and disease. MethodsIn the Limpopo Province of South Africa, we recruited 247 VhaVenda South African men from 12 villages that either used indoor residual spraying with DDT for malaria control or not. We selected 49 paired blood and semen samples, from men that ranged from 18 to 32 years of age (mean 25 years). Sample inclusion was based on normal sperm counts (> 15 million/ml), normal sperm DNA fragmentation index, and testing a range of p,p-DDE exposure levels (mean 10,462.228 {+/-} 1,792.298 ng/ml). From a total of 193 samples, 47 Greenlandic Inuit blood and semen paired samples were selected from the biobank of the INUENDO cohort. The subjects ranged from 20 to 44 years of age (mean 31 years), were born in Greenland, and all had proven fertility. Sample selection was based on obtaining a range of p,p-DDE exposure levels (mean 870.734 {+/-} 134.030 ng/ml). Here we determined the molecular responses at the level of the sperm epigenome to serum p,p-DDE levels using MethylC-Capture-seq (MCC-seq) and chromatin-immunoprecipitation followed by sequencing (ChIP-seq). We identified genomic regions with altered DNA methylation (DNAme) and differential enrichment of histone H3 lysine 4 trimethylation (H3K4me3) in sperm. We used in silico analyses to discover regions of differential methylation associated with p,p-DDE levels that were predicted to be transmitted and persist in the embryo. ResultsAlterations in DNAme and H3K4me3 enrichment followed dose response-like trends, and we identified overlapping genomic regions with DNAme sensitivities in both populations. Altered DNAme and H3K4me3 in sperm occurred at transposable elements and regulatory regions involved in fertility, disease, development, and neurofunction. A subset of regions with altered sperm DNAme and H3K4me3 were predicted to persist in the pre-implantation embryo and were associated with embryonic gene expression. LimitationsThe samples were collected from remote areas of the world thus sample size is relatively small. The populations differed in the routes of exposure, timing of collection, mean age (mean of 25 versus 31 years of age in South African and Greenlandic populations respectively) and in the timing of p,p-DDE measurement. Moreover, the Greenlandic Inuit men were proven fertile whereas the fertility status of the South African men was unknown. Confounding factors such as other environmental exposures and selection bias cannot be ruled out. ConclusionsThese findings suggest that in men, DDT and p,p-DDE exposure impacts the sperm epigenome in a dose-responsive manner and may negatively impact the health of future generations through epigenetic mechanisms.

genomics↗

bioRxiv2020

Elucidating the viral and host factors enabling the cross-species transmission of primate lentiviruses from simians to humans

The HIV-1 epidemic originated from a cross-species transmission of a primate lentivirus from chimpanzees to humans near the turn of the 18th century. Simian immunodeficiency viruses have been jumping between old world monkeys in West/Central Africa for thousands of years. So why did HIV-1 only emerge in the past century? This study examined the replicative fitness, transmission, restriction, and cytopathogenicity of 26 primate lentiviruses. Pairwise competitions of these primate lentiviruses revealed that SIVcpz had the highest replicative fitness in human or chimpanzee peripheral blood mononuclear cells, even higher fitness than HIV-1 group M strains responsible for 37 million infections worldwide. In contrast the "HIV-2 lineage" (SIVsmm, SIVmac, SIVagm, and HIV-2) had the lowest replicative fitness. SIVcpz strains were less inhibited by human restriction factors than the "HIV-2 lineage" strains, a restriction that was inversely correlated with replicative fitness. SIVcpz from the chimpanzee subspecies Pan troglodytes troglodytes (Ptt) was slightly more fit in human cells than the strains from Pt schweinfurthii (Pts). However, unlike all other primate lentiviruses (including the HIV-2 lineage), SIVcpz was nonpathogenic in human tonsillar tissue and did not deplete CD4+ T-cells, consistent with the slow or nonpathogenic disease observed in chimpanzees. Despite the close phylogenetic relationship between SIVcpz_Ptt and HIV-1, this epidemic was either caused by cross species transmission of a rare, undiscovered SIVcpz strain of higher virulence or higher virulence differentially evolved among HIV-1 subtypes during the human epidemic. Author summaryInvasion of wild animal habitats by humans can have devastating consequences for the human population as evident by the HIV-1 and SARS-CoV-2 epidemics. With SARS-CoV-2, a recent zoonotic jump, likely from bats, will help to identify a coronavirus progenitor. In contrast, simian immunodeficiency virus (SIV) jumped into humans over 100 years ago from a possibly extinct sub-species of chimpanzees and/or extinct lineage of SIV. We examined replicative fitness and pathogenesis of 26 different primate lentiviruses in human and chimpanzee primary lymphoid cells from blood and within tonsils. SIV from a specific chimpanzee species and lowland gorillas were the most capable of infecting and replicating in human and chimp lymphoid cells but they did not result in the pathogenesis related to disease in humans. In contrast, SIV from other old world monkeys were pathogenic but could not replicate efficiently in human cells. We propose the main HIV-1 is derived from a distinct jump of a very rare SIV strain in chimps leading to AIDS pandemic.

microbiology↗

bioRxiv2020

Microbial activation converts neutrophils into anti-tumor effectors

Neutrophils infiltrate most solid tumors and their presence is usually correlated with suppression of anti-tumor responses, metastasis and poor prognosis. Here we used microbial bioparticles administered into the tumor microenvironment to transform neutrophils into anti-tumor effectors. Microbially activated neutrophils acquired an effector phenotype associated with pathogen killing and lost vascular endothelial growth factor expression associated with tumor growth and metastasis. They became the dominant immune cell infiltrating the tumor and inhibited tumor growth. Using intravital two-photon microscopy microbially activated neutrophils could be seen forming close contacts with tumor cells resulting in tumor tissue remodeling and tumor cell death. Thus, microbial bioparticle treatment can endow neutrophils with anti-tumor properties, suggesting that neutrophil plasticity in cancer could be exploited for tumor killing. These data highlight a pathway for the rational development of neutrophil-based cancer therapy.

immunology↗

bioRxiv2020

A zebrafish functional genomics model to investigate the role of human A20 variants in vivo

Germline loss-of-function variation in TNFAIP3, encoding A20, has been implicated in a wide variety of autoinflammatory and autoimmune conditions, with acquired somatic missense mutations linked to cancer progression. Furthermore, human sequence data reveals that the A20 locus contains ~400 non-synonymous coding variants which are largely uncharacterised. The growing number of A20 coding variants with unknown function, but potential clinical impact, poses a challenge to traditional mouse-based approaches. Here we report the development of a novel functional genomics approach that utilises the new A20-deficient zebrafish (Danio rerio) model to investigate the impact of TNFAIP3 genetic variants in vivo. Similar to A20-deficient mice, A20-deficient zebrafish are hyper-responsive to inflammatory triggers and exhibit spontaneous early lethality. While ectopic addition of human A20 rescued A20-null zebrafish from lethality, missense mutations at two conserved A20 residues, S381A and C243Y reversed this protective effect. Ser381 represents a phosphorylation site important for enhancing A20 activity that is abrogated by its mutation to alanine, or by a C243Y mutation that associates with human autoimmune disease. These data reveal an evolutionarily conserved role for A20, but also demonstrate how a zebrafish functional genomics pipeline can be utilized to investigate the in vivo significance of medically relevant TNFAIP3 gene variants. This approach could be utilised to investigate genetic variation for other conserved genes.

genetics↗

bioRxiv2018

An enriched network motif family regulates multistep cell fate transitions with restricted reversibility

Multistep cell fate transitions with stepwise changes of transcriptional profiles are common to many developmental, regenerative and pathological processes. The multiple intermediate cell lineage states can serve as differentiation checkpoints or branching points for channeling cells to more than one lineages. However, mechanisms underlying these transitions remain elusive. Here, we explored gene regulatory circuits that can generate multiple intermediate cellular states with stepwise modulations of transcription factors. With unbiased searching in the network topology space, we found a motif family containing a large set of networks can give rise to four attractors with the stepwise regulations of transcription factors, which limit the reversibility of three consecutive steps of the lineage transition. We found that there is an enrichment of these motifs in a transcriptional network controlling the early T cell development, and a mathematical model based on this network recapitulates multistep transitions in the early T cell lineage commitment. By calculating the energy landscape and minimum action paths for the T cell model, we quantified the stochastic dynamics of the critical factors in response to the differentiation signal with fluctuations. These results are in good agreement with experimental observations and they suggest the stable characteristics of the intermediate states in the T cell differentiation. These dynamical features may help to direct the cells to correct lineages during development. Our findings provide general design principles for multistep cell linage transitions and new insights into the early T cell development. The network motifs containing a large family of topologies can be useful for analyzing diverse biological systems with multistep transitions.\n\nAuthor summaryThe functions of cells are dynamically controlled in many biological processes including development, regeneration and disease progression. Cell fate transition, or the switch of cellular functions, often involves multiple steps. The intermediate stages of the transition provide the biological systems with the opportunities to regulate the transitions in a precise manner. These transitions are controlled by key regulatory genes of which the expression shows stepwise patterns, but how the interactions of these genes can determine the multistep processes were unclear. Here, we present a comprehensive analysis on the design principles of gene circuits that govern multistep cell fate transition. We found a large network family with common structural features that can generate systems with the ability to control three consecutive steps of the transition. We found that this type of networks is enriched in a gene circuit controlling the development of T lymphocyte, a crucial type of immune cells. We performed mathematical modeling using this gene circuit and we recapitulated the stepwise and irreversible loss of stem cell properties of the developing T lymphocytes. Our findings can be useful to analyze a wide range of gene regulatory networks controlling multistep cell fate transitions.

systems biology↗

bioRxiv2018

Mapping malaria by combining parasite genomic and epidemiologic data

Recent global progress in scaling up malaria control interventions has revived the goal of complete elimination in many countries. Decreasing transmission intensity generally leads to increasingly patchy spatial patterns of malaria transmission, however, and control programs must accurately identify remaining foci in order to target interventions efficiently. In particular, mosquito control interventions like bed nets and insecticide spraying are best targeted to transmission hotspots, and the role of connectivity between different pockets of local transmission becomes increasingly important since humans are able to move parasites beyond the limits of mosquito dispersal and re-introduce parasites to previously malaria-free regions. Quantifying the connectivity between regions due to human travel, measuring malaria transmission intensity in different areas, and monitoring parasite spatial spread are therefore key issues for policy-makers because they underpin the feasibility of elimination and inform the path to its attainment. To this end, recent efforts have been made to develop new approaches to incorporating human mobility into spatial epidemiological models, for example using mobile phone data, and there has been a surge of interest in collecting spatially informative parasite samples to measure the genomic signatures of parasite connectivity. Due to their complicated life-cycles, Plasmodium parasites pose unique challenges to researchers in this respect and new methods that move beyond traditional phylogenetic and population genetic tools must be developed to harness genetic information effectively. Here, we discuss the spatial epidemiology of malaria in the context of transmission-reduction interventions, and the challenges and promising directions for the development of integrated mapping, modeling, and genomic approaches that leverage disparate data sets to measure both connectivity and transmission.

epidemiology↗