Human gut commensal bacteria are routinely exposed to various stresses, including therapeutic drugs, and collateral effects are difficult to predict. To systematically interrogate community-level effects of drug perturbations, we screened stool-derived communities with 707 clinically relevant small molecules. Across ∼5,000 community-drug interaction conditions, compositional and metabolomic responses were predictably impacted by nutrient competition, with certain species exhibiting improved growth due to adverse impacts on competitors.
View Article and Find Full Text PDFMicrobial community dynamics arise through interspecies interactions, including resource competition, cross-feeding and pH modulation. The individual contributions of these mechanisms to community structure are challenging to untangle. Here we develop a framework to estimate multispecies niche overlaps by combining metabolomics data of individual species, growth measurements in spent media and mathematical models.
View Article and Find Full Text PDFAntibiotic treatment significantly impacts the human gut microbiota, but quantitative understanding of how antibiotics affect community diversity is lacking. Here, we build on classical ecological models of resource competition to investigate community responses to species-specific death rates, as induced by antibiotic activity or other growth-inhibiting factors such as bacteriophages. Our analyses highlight the complex dependence of species coexistence that can arise from the interplay of resource competition and antibiotic activity, independent of other biological mechanisms.
View Article and Find Full Text PDFDiet can impact host health through changes to the gut microbiota, yet we lack mechanistic understanding linking nutrient availability and microbiota composition. Here, we use thousands of microbial communities cultured from human feces to uncover simple assembly rules and develop a predictive model of community composition upon addition of single nutrients from central carbon metabolism to a complex medium. Community membership was largely determined by the donor feces, whereas relative abundances were determined by the supplemental carbon source.
View Article and Find Full Text PDFEfforts to model the human gut microbiome in mice have led to important insights into the mechanisms of host-microbe interactions. However, the model communities studied to date have been defined or complex, but not both, limiting their utility. Here, we construct and characterize in vitro a defined community of 104 bacterial species composed of the most common taxa from the human gut microbiota (hCom1).
View Article and Find Full Text PDFMolecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression.
View Article and Find Full Text PDFAcross diverse microbiotas, species abundances vary in time with distinctive statistical behaviors that appear to generalize across hosts, but the origins and implications of these patterns remain unclear. Here, we show that many of these macroecological patterns can be quantitatively recapitulated by a simple class of consumer-resource models, in which the metabolic capabilities of different species are randomly drawn from a common statistical distribution. Our model parametrizes the consumer-resource properties of a community using only a small number of global parameters, including the total number of resources, typical resource fluctuations over time, and the average overlap in resource-consumption profiles across species.
View Article and Find Full Text PDFDuring 1995-2011, the overall incidence of hepatitis A decreased by 95% in the United States from 12 cases per 100,000 population during 1995 to 0.4 cases per 100,000 population during 2011, and then plateaued during 2012─2015. The incidence increased by 294% during 2016-2018 compared with the incidence during 2013-2015, with most cases occurring among populations at high risk for hepatitis A infection, including persons who use illicit drugs (injection and noninjection), persons who experience homelessness, and men who have sex with men (MSM) (1-3).
View Article and Find Full Text PDFThe cyanobacterium Synechococcus elongatus possesses a circadian clock in the form of a group of proteins whose concentrations and phosphorylation states oscillate with daily periodicity under constant conditions. The circadian clock regulates the cell cycle such that the timing of the cell divisions is biased toward certain times during the circadian period, but the mechanism underlying this phenomenon remains unclear. Here, we propose a mechanism in which a protein limiting for division accumulates at a rate proportional to the cell volume growth and is modulated by the clock.
View Article and Find Full Text PDFDeferiprone (DFP) is a hydroxypyridinone-derived iron chelator currently in clinical use for iron chelation therapy. DFP has also been known to elicit antiproliferative activities, yet the mechanism of this effect has remained elusive. We herein report that DFP chelates the Fe ion at the active sites of selected iron-dependent histone lysine demethylases (KDMs), resulting in pan inhibition of a subfamily of KDMs.
View Article and Find Full Text PDFTiO nanoparticles are widely used in consumer products and industrial applications, yet little is understood regarding how the inhalation of these nanoparticles impacts long-term health. This is especially important for the occupational safety of workers who process these materials. We used RNA sequencing to probe changes in gene expression and fluorescence microscopy to image intracellular reactive oxygen species (ROS) in human lung cells incubated with low, non-cytotoxic, concentrations of TiO nanoparticles.
View Article and Find Full Text PDFMost microorganisms regulate their cell size. In this article, we review some of the mathematical formulations of the problem of cell size regulation. We focus on coarse-grained stochastic models and the statistics that they generate.
View Article and Find Full Text PDFIn nature, microorganisms exhibit different volumes spanning six orders of magnitude . Despite their capability to create different sizes, a clonal population in a given environment maintains a uniform size across individual cells. Recent studies in eukaryotic and bacterial organisms showed that this homogeneity in cell size can be accomplished by growing a constant size between two cell cycle events (that is, the adder model ).
View Article and Find Full Text PDFFront Cell Dev Biol
November 2017
Organisms across all domains of life regulate the size of their cells. However, the means by which this is done is poorly understood. We study two abstracted "molecular" models for size regulation: inhibitor dilution and initiator accumulation.
View Article and Find Full Text PDFIn model bacteria, such as E. coli and B. subtilis, regulation of cell-cycle progression and cellular organization achieves consistency in cell size, replication dynamics, and chromosome positioning [1-3].
View Article and Find Full Text PDFProc Natl Acad Sci U S A
December 2016
Bacteria tightly regulate and coordinate the various events in their cell cycles to duplicate themselves accurately and to control their cell sizes. Growth of Escherichia coli, in particular, follows a relation known as Schaechter's growth law. This law says that the average cell volume scales exponentially with growth rate, with a scaling exponent equal to the time from initiation of a round of DNA replication to the cell division at which the corresponding sister chromosomes segregate.
View Article and Find Full Text PDFHematopoietic stem cell (HSC) transplantation can cure diverse diseases of the blood system, including hematologic malignancies, anemias, and autoimmune disorders. However, patients must undergo toxic conditioning regimens that use chemotherapy and/or radiation to eliminate host HSCs and enable donor HSC engraftment. Previous studies have shown that anti-c-Kit monoclonal antibodies deplete HSCs from bone marrow niches, allowing donor HSC engraftment in immunodeficient mice.
View Article and Find Full Text PDFFront Microbiol
July 2015
Bacteria are able to maintain a narrow distribution of cell sizes by regulating the timing of cell divisions. In rich nutrient conditions, cells divide much faster than their chromosomes replicate. This implies that cells maintain multiple rounds of chromosome replication per cell division by regulating the timing of chromosome replications.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
February 2015
Macrophage-mediated programmed cell removal (PrCR) is an important mechanism of eliminating diseased and damaged cells before programmed cell death. The induction of PrCR by eat-me signals on tumor cells is countered by don't-eat-me signals such as CD47, which binds macrophage signal-regulatory protein α to inhibit phagocytosis. Blockade of CD47 on tumor cells leads to phagocytosis by macrophages.
View Article and Find Full Text PDFPhys Rev E Stat Nonlin Soft Matter Phys
October 2014
We perform extensive coarse-grained (CG) Langevin dynamics simulations of intrinsically disordered proteins (IDPs), which possess fluctuating conformational statistics between that for excluded volume random walks and collapsed globules. Our CG model includes repulsive steric, attractive hydrophobic, and electrostatic interactions between residues and is calibrated to a large collection of single-molecule fluorescence resonance energy transfer data on the interresidue separations for 36 pairs of residues in five IDPs: α-, β-, and γ-synuclein, the microtubule-associated protein τ, and prothymosin α. We find that our CG model is able to recapitulate the average interresidue separations regardless of the choice of the hydrophobicity scale, which shows that our calibrated model can robustly capture the conformational dynamics of IDPs.
View Article and Find Full Text PDFH1 linker histones facilitate higher-order chromatin folding and are essential for mammalian development. To achieve high-resolution mapping of H1 variants H1d and H1c in embryonic stem cells (ESCs), we have established a knock-in system and shown that the N-terminally tagged H1 proteins are functionally interchangeable to their endogenous counterparts in vivo. H1d and H1c are depleted from GC- and gene-rich regions and active promoters, inversely correlated with H3K4me3, but positively correlated with H3K9me3 and associated with characteristic sequence features.
View Article and Find Full Text PDFPluripotent embryonic stem cells (ESCs) are known to possess a relatively open chromatin structure; yet, despite efforts to characterize the chromatin signatures of ESCs, the role of chromatin compaction in stem cell fate and function remains elusive. Linker histone H1 is important for higher-order chromatin folding and is essential for mammalian embryogenesis. To investigate the role of H1 and chromatin compaction in stem cell pluripotency and differentiation, we examine the differentiation of embryonic stem cells that are depleted of multiple H1 subtypes.
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