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Alkaliptosis is a recently discovered type of pH-dependent cell death used for tumor therapy. However, its underlying molecular mechanisms and regulatory networks are largely unknown. Here, we report that the acetate-activating enzyme acetyl-CoA short-chain synthase family member 2 (ACSS2) is a positive regulator of alkaliptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. Using qPCR and western blot analysis, we found that the mRNA and protein expression of ACSS2 was upregulated in human PDAC cell lines (PANC1 and MiaPaCa2) in response to the classic alkaliptosis activator JTC801. Consequently, the knockdown of ACSS2 by shRNAs inhibited JTC801-induced cell death in PDAC cells, and was accompanied by an increase in cell clone formation and a decrease in intracellular pH. Mechanically, ACSS2-mediated acetyl-coenzyme A production and subsequent histone acetylation contributed to NF-κB–dependent CA9 downregulation, and this effect was enhanced by the histone deacetylase inhibitor trichostatin A. These findings may provide new insights for understanding the metabolic basis of alkaliptosis and establish a potential strategy for PDAC treatment. [ABSTRACT FROM AUTHOR]

Ferroptosis is a form of regulated cell death characterized by oxidative injury-induced lipid peroxidation. However, the detailed protein post-translational modification regulatory mechanism of ferroptosis remains largely unknown. Here, we report that E1A binding protein P300 (EP300) acetyltransferase promotes ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells via the acetylation of heat shock protein family A (Hsp70) member 5 (HSPA5), also known as GRP78 or BIP) on the site of K353. Acetylated HSPA5 loses its ability to inhibit lipid peroxidation and subsequent ferroptotic cell death. Genetic or pharmacological inhibition of EP300-mediated HSPA5 acetylation on K353 increases PDAC cell resistance to ferroptosis. Moreover, histone deacetylase 6 (HDAC6) limits HSPA5 acetylation and subsequent ferroptosis. Collectively, these findings not only identify regulatory pathways for HSPA5 acetylation during ferroptosis, but also highlight promising strategies to increase ferroptosis sensitivity in PDAC cells. [ABSTRACT FROM AUTHOR]

The ear canal is usually described as an S-shaped funnel. In attempting to classify ear-canal shapes obtained from point clouds digitized from molds of 300 ears, the problem of designing criteria for distinguishing and organizing the canal shapes arose. In this work, we extracted features inspired by the S-shape characteristic (critical point, maximum, minimum, twist, writhe, translation, rotation) and, through them, introduced 14 types of ear-canal shapes. This classification allowed comparison of ears within a type and of ears between different types. It expanded our range of descriptors of canal shapes and unlocked perspectives for applications. [ABSTRACT FROM AUTHOR]

Cascading failures have become major threats to network robustness due to their potential catastrophic consequences, where local perturbations can induce global propagation of failures. Unlike failures spreading via direct contacts due to structural interdependencies, overload failures usually propagate through collective interactions among system components. Despite the critical need in developing protection or mitigation strategies in networks such as power grids and transportation, the propagation behavior of cascading failures is essentially unknown. Here we find by analyzing our collected data that jams in city traffic and faults in power grid are spatially long-range correlated with correlations decaying slowly with distance. Moreover, we find in the daily traffic, that the correlation length increases dramatically and reaches maximum, when morning or evening rush hour is approaching. Our study can impact all efforts towards improving actively system resilience ranging from evaluation of design schemes, development of protection strategies to implementation of mitigation programs. [ABSTRACT FROM AUTHOR]