Separable Utility and Taste-Independence: An Escape Route from the Opportunity Paradox Via Preference Domain Restriction

AbstractThe microtubule-associated protein tau has a critical role in Alzheimer’s disease and other tauopathies. A proposed pathomechanism in the progression of tauopathies is the trans-synaptic spreading of tau seeds, with a role for exosomes which are secretory nanovesicles generated by late endosomes. Our previous work demonstrated that brain-derived exosomes isolated from tau transgenic rTg4510 mice encapsulate tau seeds with the ability to induce tau aggregation in recipient cells. We had also shown that exosomes can hijack the endosomal pathway to spread through interconnected neurons. Here, we reveal how tau seeds contained within internalized exosomes exploit mechanisms of lysosomal degradation to escape the endosome and induce tau aggregation in the cytosol of HEK293T-derived ‘tau biosensor cells’. We found that the majority of the exosome-containing endosomes fused with lysosomes to form endolysosomes. Exosomes induced their permeabilization, irrespective of the presence of tau seeds, or whether the exosomal preparations originated from mouse brains or HEK293T cells. We also found that permeabilization is a conserved mechanism, operating in both non-neuronal tau biosensor cells and primary neurons. However, permeabilization of endolysosomes only occurred in a small fraction of cells, which supports the notion that permeabilization occurs by a thresholded mechanism. Interestingly, tau aggregation was only induced in cells that exhibited permeabilization, presenting this as an escape route of exosomal tau seeds into the cytosol. Overexpression of RAB7, which is required for the formation of endolysosomes, strongly increased tau aggregation. Conversely, inhibition of lysosomal function with alkalinizing agents, or by knocking-down RAB7, decreased tau aggregation. Together, we conclude that the enzymatic activities of lysosomes permeabilize exosomal and endosomal membranes, thereby facilitating access of exosomal tau seeds to cytosolic tau to induce its aggregation. Our data underscore the importance of endosomal membrane integrity in mechanisms of cellular invasion by misfolded proteins that are resistant to lysosomal degradation.

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Optimal Installation Location of Escape Route Signs at T-Type Intersections

Sustainability ◽

10.3390/su13147903 ◽

2021 ◽

Vol 13 (14) ◽

pp. 7903

Author(s):

Young-Hoon Bae ◽

Jong-Yeong Son ◽

Ryun-Seok Oh ◽

Hye-Kyoung Lee ◽

Yoon-Ha Lee ◽

...

Keyword(s):

Decision Making ◽

University Students ◽

Simon Effect ◽

Visual Stimuli ◽

Escape Route ◽

Emergency Evacuations ◽

The Right

This study analyzed the decision-making times (DMTs) of participants at T-type indoor intersections according to the horizontal/vertical installation locations and the arrow directions of escape route signs. A total of 120 university students participated in the study. We analyzed the DMTs and following rates (FRs) required for the participants to observe the visual stimuli of the signs installed in front of the T-type indoor intersections and then properly select a path according to the arrow direction of the signs. The results are as follows: (1) the participants exhibited shorter DMTs for the right arrow direction of the signs, (2) the Simon effect occurred when the horizontal installation location of the signs was more than 60 cm away from the center of the T-type indoor intersection on both sides, (3) the DMTs of participants increased when the vertical installation location of the signs was low. Finally, we proposed an optimal installation location of the signs to support the shortest DMTs at T-type indoor intersections. It is expected that the results of this study will provide a database of DMTs, based on the locations of the signs during emergency evacuations, and will be utilized to improve the installation guidelines and regulations of signs.

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The MEK5/ERK5 Pathway in Health and Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22147594 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7594

Author(s):

Rupesh Paudel ◽

Lorenza Fusi ◽

Marc Schmidt

Keyword(s):

Mechanical Stress ◽

Fluid Shear Stress ◽

Therapy Resistance ◽

Escape Route ◽

Resistance Pathway ◽

Stress Response Pathway ◽

Mitogen Activated Protein ◽

Health And Disease ◽

Potential Risks ◽

And Oxidative Stress

The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid shear stress, high osmolarity, and oxidative stress. Physiologically, it is mainly known as a mechanoreceptive pathway in the endothelium, where it transduces the various vasoprotective effects of laminar blood flow. However, it also maintains integrity in other tissues exposed to mechanical stress, including bone, cartilage, and muscle, where it exerts a key function as a survival and differentiation pathway. Beyond its diverse physiological roles, the MEK5/ERK5 pathway has also been implicated in various diseases, including cancer, where it has recently emerged as a major escape route, sustaining tumor cell survival and proliferation under drug stress. In addition, MEK5/ERK5 dysfunction may foster cardiovascular diseases such as atherosclerosis. Here, we highlight the importance of the MEK5/ERK5 pathway in health and disease, focusing on its role as a protective cascade in mechanical stress-exposed healthy tissues and its function as a therapy resistance pathway in cancers. We discuss the perspective of targeting this cascade for cancer treatment and weigh its chances and potential risks when considering its emerging role as a protective stress response pathway.

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