Lysosomal storage diseases (LSDs) comprise a group of inherited monogenic disorders characterized by lysosomal dysfunctions due to undegraded substrate accumulation. They are caused by a deficiency in specific lysosomal hydrolases involved in cellular catabolism, or non-enzymatic proteins essential for normal lysosomal functions. In LSDs, the lack of degradation of the accumulated substrate and its lysosomal storage impairs lysosome functions resulting in the perturbation of cellular homeostasis and, in turn, the damage of multiple organ systems. A substantial number of studies on the pathogenesis of LSDs has highlighted how the accumulation of lysosomal substrates is only the first event of a cascade of processes including the accumulation of secondary metabolites and the impairment of cellular trafficking, cell signalling, autophagic flux, mitochondria functionality and calcium homeostasis, that significantly contribute to the onset and progression of these diseases. Emerging studies on lysosomal biology have described the fundamental roles of these organelles in a variety of physiological functions and pathological conditions beyond their canonical activity in cellular waste clearance. Here, we discuss recent advances in the knowledge of cellular and molecular mechanisms linking lysosomal positioning and trafficking to LSDs.

Multifragment disintegration has been measured with a high efficiency detection system for the reaction Au + Au at E/A = 35 MeV. From the event shape analysis and the comparison with the predictions of a many-body trajectories calculation the data, for central collisions, are compatible with a fast emission from a unique fragment source.

Acute administration of a high level of extracellular citrate displays an anti-proliferative effect on both in vitro and in vivo models. However, the long-term effect of citrate treatment has not been investigated yet. Here, we address this question in PC3 cells, a prostate-cancer-derived cell line. Acute administration of high levels of extracellular citrate impaired cell adhesion and inhibited the proliferation of PC3 cells, but surviving cells adapted to grow in the chronic presence of 20 mM citrate. Citrate-resistant PC3 cells are significantly less glycolytic than control cells. Moreover, they overexpress short-form, citrate-insensitive phosphofructokinase 1 (PFK1) together with full-length PFK1. In addition, they show traits of mesenchymal-epithelial transition: an increase in E-cadherin and a decrease in vimentin. In comparison with PC3 cells, citrate-resistant cells display morphological changes that involve both microtubule and microfilament organization. This was accompanied by changes in homeostasis and the organization of intracellular organelles. Thus, the mitochondrial network appears fragmented, the Golgi complex is scattered, and the lysosomal compartment is enlarged. Interestingly, citrate-resistant cells produce less total ROS but accumulate more mitochondrial ROS than control cells. Consistently, in citrate-resistant cells, the autophagic pathway is upregulated, possibly sustaining their survival. In conclusion, chronic administration of citrate might select resistant cells, which could jeopardize the benefits of citrate anticancer treatment.

Intermediate-mass-fragment emission has been studied in central E/A=30 MeV ${}_{}{}^{129}{}_{}{}^{}\mathrm{Xe}$ ${+}^{\mathrm{nat}}$Cu reactions. The measured fragment multiplicities, reduced-velocity correlation functions, and emission velocities have been compared with schematic three-body trajectory calculations and with three statistical models with input based upon a dynamical BNV code. The statistical models which include expansion either explicitly or implicitly are able to generate a sufficient number of fragments. The three-body trajectory calculations indicate a mean emission time of ≊200 fm/c, consistent with sequential decay. Dynamical expanding-emitting source calculations predict a similar time scale for fragment emission and give satisfactory agreement with the experimental correlation functions if the experimental angular distributions are incorporated into the model. The Berlin multifragmentation model gives good agreement with the experimental charge distributions, and, depending upon the choice of radius parameter, can provide agreement with either the correlation functions or the fragment emission velocities, but not with both simultaneously. Although an overall good agreement is obtained in the statistical model comparisons, even in the most violent collisions the angular distributions and fragment emission velocities are incompatible with completely equilibrated decay from a single source.

A good quality scaling of the cluster size distributions is obtained for the lattice gas model using the Fisher’s ansatz for the scaling function. This scaling identifies a pseudocritical line in the phase diagram of the model that spans the whole (subcritical to supercritical) density range. The independent cluster hypothesis of the Fisher approach is shown to describe correctly the thermodynamics of the lattice only far away from the critical point.