Nucleosomes are recognized as key regulators of transcription. However, the relationship between slow nucleosome unwrapping dynamics and bulk transcriptional properties has not been thoroughly ...explored. Here, an agent-based model that we call the dynamic defect Totally Asymmetric Simple Exclusion Process (ddTASEP) was constructed to investigate the effects of nucleosome-induced pausing on transcriptional dynamics. Pausing due to slow nucleosome dynamics induced RNAPII convoy formation, which would cooperatively prevent nucleosome rebinding leading to bursts of transcription. The mean first passage time (MFPT) and the variance of first passage time (VFPT) were analytically expressed in terms of the nucleosome rate constants, allowing for the direct quantification of the effects of nucleosome-induced pausing on pioneering polymerase dynamics. The mean first passage elongation rate γ(hc, ho) is inversely proportional to the MFPT and can be considered to be a new axis of the ddTASEP phase diagram, orthogonal to the classical αβ-plane (where α and β are the initiation and termination rates). Subsequently, we showed that, for β = 1, there is a novel jamming transition in the αγ-plane that separates the ddTASEP dynamics into initiation-limited and nucleosome pausing-limited regions. We propose analytical estimates for the RNAPII density ρ, average elongation rate v, and transcription flux J and verified them numerically. We demonstrate that the intra-burst RNAPII waiting times tin follow the time-headway distribution of a max flux TASEP and that the average inter-burst interval Formula: see text correlates with the index of dispersion De. In the limit γ→0, the average burst size reaches a maximum set by the closing rate hc. When α≪1, the burst sizes are geometrically distributed, allowing large bursts even while the average burst size Formula: see text is small. Last, preliminary results on the relative effects of static and dynamic defects are presented to show that dynamic defects can induce equal or greater pausing than static bottle necks.
Cancer metastasis accounts for the majority of cancer-related deaths and remains a clinical challenge. Metastatic cancer cells generally resemble cells of the primary cancer, but they may be ...influenced by the milieu of the organs they colonize. Here, we show that colorectal cancer cells undergo metabolic reprogramming after they metastasize and colonize the liver, a key metabolic organ. In particular, via GATA6, metastatic cells in the liver upregulate the enzyme aldolase B (ALDOB), which enhances fructose metabolism and provides fuel for major pathways of central carbon metabolism during tumor cell proliferation. Targeting ALDOB or reducing dietary fructose significantly reduces liver metastatic growth but has little effect on the primary tumor. Our findings suggest that metastatic cells can take advantage of reprogrammed metabolism in their new microenvironment, especially in a metabolically active organ such as the liver. Manipulation of involved pathways may affect the course of metastatic growth.
Display omitted
•Colon cancer liver metastasis upregulates ALDOB, an enzyme for fructose metabolism•Metabolized fructose provides fuel for the central carbon metabolism•Targeting ALDOB or its upstream regulator GATA6 reduces liver metastasis growth•Reducing dietary fructose diminishes liver metastatic growth
Bu et al. show that, during colonization of the liver, the liver environment can cause colon cancer cells (CRC) to undergo metabolic reprogramming by upregulating aldolase B, which enhances fructose metabolism and promotes growth of CRC liver metastases. Targeting aldolase B or reducing dietary fructose reduces liver metastasis growth.
Topological management of materials at a Micro‐scale is one of the fundamental building principles of nature. This combination of material and structural properties results in marked changes in the ...properties of solids. Nowadays physicists, chemists, materials scientists and engineers explore those effects by synthesizing, characterizing, and modeling Micro‐lattice materials from all material classes. Applications have been identified in the fields of ultra‐lightweight structures, thermal equipment, electrochemical devices, high absorption capacity and bio‐repair materials. This article aims to review recent progress in the development of such advanced Micro‐lattice materials.
Topological management of materials at a Micro‐scale is one of the fundamental building principles of nature. This combination of material and structural properties results in marked changes in the properties of solids. Nowadays physicists, chemists, materials scientists and engineers explore those effects by synthesizing, characterizing, and modeling Micro‐lattice materials from all material classes. Applications have been identified in the fields of ultra‐lightweight structures, thermal equipments, electrochemical devices, high absorption capacity and bio‐repair materials. This article aims to review recent progress in the development of such advanced Micro‐lattice materials.
This paper outlines the findings of a study on a range of stainless steel and titanium alloy lattice structures manufactured using the selective laser melting technique. The effect of varying key ...manufacturing parameters on the properties of lattice strands was studied through a series of single-filament tensile tests. The resulting failure mechanisms were investigated using a scanning electron microscope. The resulting observations have shown that the properties of these lattice strands are determined by the laser energy during the manufacturing process, which in turn is controlled by the laser power and laser exposure time. The quasi-static and low-velocity penetration behaviour of lattice core-based sandwich panels has been examined, and an aluminium foam and an aluminium honeycomb were chosen to benchmark their performance. The impact resistance of the lattice core-based sandwich structures were shown to be dependent on both the manufacturing parameters and lattice unit-cell geometry of the lattice structure. The impact resistances were improved by increasing manufacturing laser energy and lattice core density. A series of drop-weight tests at velocities up to 6 m/s have shown that the penetration behaviour of the titanium alloy lattice cores and the aluminium honeycomb cores is similar.
Inflammation often induces regeneration to repair the tissue damage. However, chronic inflammation can transform temporary hyperplasia into a fertile ground for tumorigenesis. Here, we demonstrate ...that the microRNA
acts as a central safeguard to protect the inflammatory stem cell niche and reparative regeneration. Although playing little role in regular homeostasis,
deficiency leads to colon tumorigenesis after
infection.
targets both immune and epithelial cells to restrain inflammation-induced stem cell proliferation.
targets Interleukin six receptor (IL-6R) and Interleukin 23 receptor (IL-23R) to suppress T helper 17 (Th17) cell differentiation and expansion, targets chemokine CCL22 to hinder Th17 cell recruitment to the colon epithelium, and targets an orphan receptor Interleukin 17 receptor D (IL-17RD) to inhibit IL-17-induced stem cell proliferation. Our study highlights the importance of microRNAs in protecting the stem cell niche during inflammation despite their lack of function in regular tissue homeostasis.
Colorectal cancer (CRC) metastasizes mainly to the liver, which accounts for the majority of CRC‐related deaths. Here it is shown that metastatic cells undergo specific chromatin remodeling in the ...liver. Hepatic growth factor (HGF) induces phosphorylation of PU.1, a pioneer factor, which in turn binds and opens chromatin regions of downstream effector genes. PU.1 increases histone acetylation at the DPP4 locus. Precise epigenetic silencing by CRISPR/dCas9KRAB or CRISPR/dCas9HDAC revealed that individual PU.1‐remodeled regulatory elements collectively modulate DPP4 expression and liver metastasis growth. Genetic silencing or pharmacological inhibition of each factor along this chromatin remodeling axis strongly suppressed liver metastasis. Therefore, microenvironment‐induced epimutation is an important mechanism for metastatic tumor cells to grow in their new niche. This study presents a potential strategy to target chromatin remodeling in metastatic cancer and the promise of repurposing drugs to treat metastasis.
Metastasis of colorectal cancer to the liver is a leading cause of cancer‐related death. This work shows that metastatic colorectal cancer cells undergo chromatin remodeling in the liver via an HGF‐PU.1‐DPP4 axis. Pharmacological or genetic inhibition of this remodeling axis can suppress liver metastasis and prolong survival.
Stainless steel micro lattice structures, manufactured by selective laser melting, have the potential to be used as core materials in twin skinned structures. The configuration considered here is ...body centred cubic. One of the major structural performance requirements for such twin skinned structures is foreign object impact. The paper describes the series of steps taken to simulate (using DYNA) and validate the low velocity foreign object impact behaviour of twin skinned panels with micro lattice cores. This includes the validation of a three beam model for each micro strut, the modelling of node behaviour, and the modelling and validation of compressed micro lattice blocks, and of full foreign object impact panel behaviour.
Agent-based modelling (ABM) offers a framework to realistically couple subcellular signaling pathways to cellular behavior and macroscopic tissue organization. However, these models have been ...previously inaccessible to many systems biologists due to the difficulties with formulating and simulating multi-scale behavior. In this chapter, a review of the Compucell3D framework is presented along with a general workflow for transitioning from a well-mixed ODE model to an ABM. These techniques are demonstrated through a case study on the simulation of a Notch-Delta Positive Feedback, Lateral Inhibition (PFLI) gene circuit in the intestinal crypts. Specifically, techniques for gene circuit-driven hypothesis formation, geometry construction, selection of simulation parameters, and simulation quantification are presented.
PDF
