80 research outputs found
ARF6 CONTROLS LYSOSOMAL TRANSPORT OF APP AND Ap42 PRODUCTION
Alzheimer’s disease (AD) is characterized by the deposition of Beta-Amyloid (AP) peptide plaques in the brain. Ap peptides are generated by the sequential cleavage of the Amyloid Precursor Protein (APP). The AP42 cleavage product is the most neurotoxic form. Previous studies in our lab have uncovered a novel rapid lysosomal APP trafficking pathway that bypasses the early and late endosomal compartments. We set out to characterize this transport pathway using APP constructs with an N-terminal HA-tag, allowing us to label APP at the cell surface with a fluorescently labeled antibody. SN56 cells and mouse cortical neurons were also co-transfected with fluorescently-tagged compartment marker proteins and a panel of endocytosis regulatory proteins bearing dominant negative and constitutively activating mutations. Rapid APP internalization to lysosomes is stimulated by antibody binding and is increased when Arfl activity was inhibited, but decreased when Arfó activity was inhibited. In addition, disruption of either Arfó or Arfl was able to significantly reduce Ap42 secretion into the media. Our findings suggest that rapid APP transport to lysosomes is regulated by Arfó and is an important, and potentially targetable, mechanism that regulates A(342 production, while Arfl regulates secretion of Ap42 into the media
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Mathematical modeling of tumor growth and angiogenesis
Tumor angiogenesis plays a crucial role in cancer progression and metastasis. Mathematical modeling has emerged as a powerful tool to unravel the complex dynamics of tumor angiogenesis and to develop new therapeutic strategies. In this thesis, we focus on a comprehensive study on the mathematical modeling of tumor-induced angiogenesis, spanning from the fundamental concepts to the development of a novel hybrid model that integrates tumor growth and angiogenesis in a complex, realistic vascular network. We begin by investigating a thermodynamically consistent mixture model for avascular solid tumor growth. To simulate tumor growth, we develop a mass-conservative, adaptive, finite difference, nonlinear multigrid method that captures the evolution of tumor morphology accurately and efficiently. Next, we present a hybrid model for angiogenesis growth based on the phase-field theory. The model incorporates the dynamics of capillaries, angiogenic factors, and tip endothelial cells (TECs), along with a discrete conceptualization of filopodia that enables TECs to sense their microenvironment. Finally, we build a mathematical model of tumor-induced angiogenesis that integrates tumor growth and angiogenesis in a complex, realistic vascular network extracted from the vascularized microtumor (VMT) platform. The model combines continuum and discrete modeling approaches to capture the key biological processes involved in tumor angiogenesis, and is simulated by our new developed numerical method
Small-signal modelling of AC/MTDC hybrid power systems using Multi-Layer Component Connection Method
A fast tunable driver of light source for the TRIDENT Pathfinder experiment
TRIDENT (The tRopIcal DEep-sea Neutrino Telescope) is a proposed
next-generation neutrino telescope to be constructed in the South China Sea. In
September 2021, the TRIDENT Pathfinder experiment (TRIDENT EXplorer, T-REX for
short) was conducted to evaluate the in-situ optical properties of seawater.
The T-REX experiment deployed three digital optical modules at a depth of 3420
meters, including a light emitter module (LEM) and two light receiver modules
(LRMs) equipped with photomultiplier tubes (PMTs) and cameras to detect light
signals. The LEM emits light in pulsing and steady modes. It features a fast
tunable driver to activate light-emitting diodes (LEDs) that emit
nanosecond-width light pulses with tunable intensity. The PMTs in the LRM
receive single photo-electron (SPE) signals with an average photon number of
approximately 0.3 per 1-microsecond time window, which is used to measure the
arrival time distribution of the SPE signals. The fast tunable driver can be
remotely controlled in real-time by the data acquisition system onboard the
research vessel, allowing for convenient adjustments to the driver's parameters
and facilitating the acquisition of high-quality experimental data. This paper
describes the requirements, design scheme, and test results of the fast tunable
driver, highlighting its successful implementation in the T-REX experiment and
its potential for future deep-sea experiments
Biological Effects of Black Phosphorus Nanomaterials on Mammalian Cells and Animals
The remarkable progress of applied black phosphorus nanomaterials (BPNMs) is attributed to BP's outstanding properties. Due to its potential for applications, environmental release and subsequent human exposure are virtually inevitable. Therefore, how BPNMs impact biological systems and human health needs to be considered. In this comprehensive Minireview, the most recent advancements in understanding the mechanisms and regulation factors of BPNMs’ endogenous toxicity to mammalian systems are presented. These achievements lay the groundwork for an understanding of its biological effects, aimed towards establishing regulatory principles to minimize the adverse health impacts
Arf6 controls beta-amyloid production by regulating macropinocytosis of the Amyloid Precursor Protein to lysosomes
Alzheimer\u27s disease (AD) is characterized by the deposition of Beta-Amyloid (Aβ) peptides in the brain. Aβ peptides are generated by cleavage of the Amyloid Precursor Protein (APP) by the β - and γ - secretase enzymes. Although this process is tightly linked to the internalization of cell surface APP, the compartments responsible are not well defined. We have found that APP can be rapidly internalized from the cell surface to lysosomes, bypassing early and late endosomes. Here we show by confocal microscopy and electron microscopy that this pathway is mediated by macropinocytosis. APP internalization is enhanced by antibody binding/crosslinking of APP suggesting that APP may function as a receptor. Furthermore, a dominant negative mutant of Arf6 blocks direct transport of APP to lysosomes, but does not affect classical endocytosis to endosomes. Arf6 expression increases through the hippocampus with the development of Alzheimer\u27s disease, being expressed mostly in the CA1 and CA2 regions in normal individuals but spreading through the CA3 and CA4 regions in individuals with pathologically diagnosed AD. Disruption of lysosomal transport of APP reduces both Aβ40 and Aβ42 production by more than 30 %. Our findings suggest that the lysosome is an important site for Aβ production and that altering APP trafficking represents a viable strategy to reduce Aβ production
Pickering emulsion-enhanced interfacial biocatalysis: tailored alginate microparticles act as particulate emulsifier and enzyme carrier
A robust Pickering emulsion stabilized by lipase-immobilized alginate gel microparticles with a coating of silanized titania nanoparticles is developed for biphasic biocatalysis. The good recyclability and high stability of the proposed interfacial catalysis system have been verified, retaining about 90% of relative enzyme activity in 10 catalytic cycles with operation for 240 h. Meanwhile the Pickering emulsions remain stable during a storage time of one year. The green system can be widely applied to construct powerful platforms for enzyme or microorganism-driven interfacial catalysis
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