Highlights • The first step in metastasis is invasion of tumor cells into the stroma. • Stromal collagen is dramatically remodeled during tumor progression. • Tumor cells can invade the stroma as ...single cells or collectively. • The microenvironment influences the mode and dynamics of cancer cell migration.
Human populations have experienced recent explosive growth, expanding by at least three orders of magnitude over the past 400 generations. This departure from equilibrium skews patterns of genetic ...variation and distorts basic principles of population genetics. We characterized the empirical signatures of explosive growth on the site frequency spectrum and found that the discrepancy in rare variant abundance across demographic modeling studies is mostly due to differences in sample size. Rapid recent growth increases the load of rare variants and is likely to play a role in the individual genetic burden of complex disease risk. Hence, the extreme recent human population growth needs to be taken into consideration in studying the genetics of complex diseases and traits.
Dendritic cells are specialized antigen presenting cells that bridge innate and adaptive immunity in mammals. This link between the ancient innate immune system and the more evolutionarily recent ...adaptive immune system is of particular interest in fish, the oldest vertebrates to have both innate and adaptive immunity. It is unknown whether dendritic cells co-evolved with the adaptive response, or if the connection between innate and adaptive immunity relied on a fundamentally different cell type early in evolution. We approached this question using the teleost model organism, rainbow trout (Oncorhynchus mykiss), with the aim of identifying dendritic cells based on their ability to stimulate naïve T cells. Adapting mammalian protocols for the generation of dendritic cells, we established a method of culturing highly motile, non-adherent cells from trout hematopoietic tissue that had irregular membrane processes and expressed surface MHCII. When side-by-side mixed leukocyte reactions were performed, these cells stimulated greater proliferation than B cells or macrophages, demonstrating their specialized ability to present antigen and therefore their functional homology to mammalian dendritic cells. Trout dendritic cells were then further analyzed to determine if they exhibited other features of mammalian dendritic cells. Trout dendritic cells were found to have many of the hallmarks of mammalian DCs including tree-like morphology, the expression of dendritic cell markers, the ability to phagocytose small particles, activation by toll-like receptor-ligands, and the ability to migrate in vivo. As in mammals, trout dendritic cells could be isolated directly from the spleen, or larger numbers could be derived from hematopoietic tissue and peripheral blood mononuclear cells in vitro.
Animal cell shape is controlled primarily by the actomyosin cortex, a thin cytoskeletal network that lies directly beneath the plasma membrane. The cortex regulates cell morphology by controlling ...cellular mechanical properties, which are determined by network structure and geometry. In particular, cortex thickness is expected to influence cell mechanics. However, cortex thickness is near the resolution limit of the light microscope, making studies relating cortex thickness and cell shape challenging. To overcome this, we developed an assay to measure cortex thickness in live cells, combining confocal imaging and subresolution image analysis. We labeled the actin cortex and plasma membrane with chromatically different fluorophores and measured the distance between the resulting intensity peaks. Using a theoretical description of cortex geometry and microscopic imaging, we extracted an average cortex thickness of ∼190 nm in mitotic HeLa cells and tested the validity of our assay using cell images generated in silico. We found that thickness increased after experimental treatments preventing F-actin disassembly. Finally, we monitored physiological changes in cortex thickness in real-time during actin cortex regrowth in cellular blebs. Our investigation paves the way to understanding how molecular processes modulate cortex structure, which in turn drives cell morphogenesis.
The accelerating pace of genome sequencing throughout the tree of life is driving the need for improved unsupervised annotation of genome components such as transposable elements (TEs). Because the ...types and sequences of TEs are highly variable across species, automated TE discovery and annotation are challenging and timeconsuming tasks. A critical first step is the de novo identification and accurate compilation of sequence models representing all of the unique TE families dispersed in the genome. Here we introduce RepeatModeler2, a pipeline that greatly facilitates this process. This program brings substantial improvements over the original version of RepeatModeler, one of the most widely used tools for TE discovery. In particular, this version incorporates a module for structural discovery of complete long terminal repeat (LTR) retroelements, which are widespread in eukaryotic genomes but recalcitrant to automated identification because of their size and sequence complexity. We benchmarked RepeatModeler2 on three model species with diverse TE landscapes and high-quality, manually curated TE libraries: Drosophila melanogaster (fruit fly), Danio rerio (zebrafish), and Oryza sativa (rice). In these three species, RepeatModeler2 identified approximately 3 times more consensus sequences matching with >95% sequence identity and sequence coverage to the manually curated sequences than the original RepeatModeler. As expected, the greatest improvement is for LTR retroelements. Thus, RepeatModeler2 represents a valuable addition to the genome annotation toolkit that will enhance the identification and study of TEs in eukaryotic genome sequences. RepeatModeler2 is available as source code or a containerized package under an open license (https://github.com/Dfam-consortium/ RepeatModeler, http://www.repeatmasker.org/RepeatModeler/).
MicroRNAs (miRNAs) are endogenously expressed small RNAs that regulate expression of mRNAs at the post-transcriptional level. The consequence of miRNA regulation is hypothesized to reduce the ...expression variation of target genes. However, it is possible that mutations in miRNAs and target sites cause rewiring of the miRNA regulatory networks resulting in increased variation in gene expression. By examining variation in gene expression patterns in human populations and between human and other primate species, we find that miRNAs have stabilized expression of a small number of target genes during primate evolution. Compared with genes not regulated by miRNAs, however, genes regulated by miRNAs overall have higher expression variation at the population level, and they display greater variation in expression among human ethnic groups or between human and other primate species. By integrating expression data with genotypes determined in the HapMap 3 and the 1000 Genomes Projects, we found that expression variation in miRNAs, genetic variants in miRNA loci, and mutations in miRNA target sites are important sources of elevated expression variation of miRNA target genes. A reasonable case can be made that natural selection is driving this pattern of variation.
I work to unbundle the structure of inertia into two distinct categories: resource rigidity (failure to change resource investment patterns) and routine rigidity (failure to change organizational ...processes that use those resources). Given discontinuous change, a researcher's failure to recognize these distinctions can generate conflicting findings regarding effects of threat perception on inertia. Using field data on the response of newspaper organizations to the rise of digital media, I show that a strong perception of threat helps overcome resource rigidity but simultaneously amplifies routine rigidity. I develop an interpretive model exploring mechanisms for overcoming these divergent behaviors.
Studies in mice and humans have revealed intriguing associations between host genetics and the microbiome. Here we report a 16S rRNA-based analysis of the gut microbiome in 1,126 twin pairs, a subset ...of which was previously reported. Tripling the sample narrowed the confidence intervals around heritability estimates and uncovered additional heritable taxa, some of which are validated in other studies. Repeat sampling of subjects showed heritable taxa to be temporally stable. A candidate gene approach uncovered associations between heritable taxa and genes related to diet, metabolism, and olfaction. We replicate an association between Bifidobacterium and the lactase (LCT) gene locus and identify an association between the host gene ALDH1L1 and the bacteria SHA-98, suggesting a link between formate production and blood pressure. Additional genes detected are involved in barrier defense and self/non-self recognition. Our results indicate that diet-sensing, metabolism, and immune defense are important drivers of human-microbiome co-evolution.
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•16S rRNA-based analysis of the gut microbiome in 1,126 twin pairs•Heritable bacterial taxa are temporally stable•Bifidobacterium associates with lactase gene variants; formate production links to blood pressure•Gene-microbe links involve genes related to diet, metabolism, olfaction, and defense
Does host genotype shape the microbiome? Goodrich et al. present a gut microbiome analysis of 1,126 twin pairs, which extends the association between host genetics and select bacterial taxa. Lactase nonpersistence was linked to higher levels of Bifidobacteria. Other gene/microbe links relate to diet and barrier defense.
Two-photon fluorescence microscopy (2PM)
enables scientists in various fields including neuroscience
, embryology
, and oncology
to visualize
and
tissue morphology and physiology at a cellular level ...deep within scattering tissue. However, tissue scattering limits the maximum imaging depth of 2PM within the mouse brain to the cortical layer, and imaging subcortical structures currently requires the removal of overlying brain tissue
or the insertion of optical probes
. Here we demonstrate non-invasive, high resolution,
imaging of subcortical structures within an intact mouse brain using three-photon fluorescence microscopy (3PM) at a spectral excitation window of 1,700 nm. Vascular structures as well as red fluorescent protein (RFP)-labeled neurons within the mouse hippocampus are imaged. The combination of the long excitation wavelength and the higher order nonlinear excitation overcomes the limitations of 2PM, enabling biological investigations to take place at greater depth within tissue.
The dynamics of weakly magnetized collisionless plasmas in the presence of an imposed temperature gradient along an ambient magnetic field is explored with particle-in-cell simulations and modeling. ...Two thermal reservoirs at different temperatures drive an electron heat flux that destabilizes off-angle whistler-type modes. The whistlers grow to large amplitude, δB/B_{0}≃1, and resonantly scatter the electrons, significantly reducing the heat flux. Surprisingly, the resulting steady-state heat flux is largely independent of the thermal gradient. The rate of thermal conduction is instead controlled by the finite propagation speed of the whistlers, which act as mobile scattering centers that convect the thermal energy of the hot reservoir. The results are relevant to thermal transport in high-β astrophysical plasmas such as hot accretion flows and the intracluster medium of galaxy clusters.
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