Lysosomes in iron metabolism, ageing and apoptosis

The lysosomal compartment is essential for a variety of cellular functions, including the normal turnover of most long-lived proteins and all organelles. The compartment consists of numerous acidic vesicles (pH ∼4 to 5) that constantly fuse and divide. It receives a large number of hydrolases (∼50) from the trans-Golgi network, and substrates from both the cells’ outside (heterophagy) and inside (autophagy). Many macromolecules contain iron that gives rise to an iron-rich environment in lysosomes that recently have degraded such macromolecules. Iron-rich lysosomes are sensitive to oxidative stress, while ‘resting’ lysosomes, which have not recently participated in autophagic events, are not. The magnitude of oxidative stress determines the degree of lysosomal destabilization and, consequently, whether arrested growth, reparative autophagy, apoptosis, or necrosis will follow. Heterophagy is the first step in the process by which immunocompetent cells modify antigens and produce antibodies, while exocytosis of lysosomal enzymes may promote tumor invasion, angiogenesis, and metastasis. Apart from being an essential turnover process, autophagy is also a mechanism by which cells will be able to sustain temporary starvation and rid themselves of intracellular organisms that have invaded, although some pathogens have evolved mechanisms to prevent their destruction. Mutated lysosomal enzymes are the underlying cause of a number of lysosomal storage diseases involving the accumulation of materials that would be the substrate for the corresponding hydrolases, were they not defective. The normal, low-level diffusion of hydrogen peroxide into iron-rich lysosomes causes the slow formation of lipofuscin in long-lived postmitotic cells, where it occupies a substantial part of the lysosomal compartment at the end of the life span. This seems to result in the diversion of newly produced lysosomal enzymes away from autophagosomes, leading to the accumulation of malfunctioning mitochondria and proteins with consequent cellular dysfunction. If autophagy were a perfect turnover process, postmitotic ageing and several age-related neurodegenerative diseases would, perhaps, not take place

Reducing the Loss of Built Heritage in Areas of Tourist Interest

Like the fruits of those seeds sown centuries ago, buildings and places are now an essential part of our cultural heritage. When their golden Age long has passed, they risk abandonment, because maintenance costs are often prohibitive, or they risk being completely transformed. So tourism could provide an important contribution to sustaining their maintenance. Tourism is an essential resource for the promotion of cultural sites and for keeping them alive. Traditional and modern technology should be employed whether for a single building or a whole village or even a small island. On the other hand, increasing exploitation of such sites may reveal itself to be a double edged sword. By attracting an uncontrolled number of visitors this could result in a more rapid decline of the resource. Some places have been radically transformed to accommodate ever increasing numbers of tourists, with detrimental results. Rather than being enriched by the authenticity of the site, mass tourism is liable to damage the authenticity that it seeks. Sometimes the final result is less authentic and the traditional spirit of the place destroyed, sacrificed to a need to comply to standard “hit and run” tourist destinations. The paper wants to present one of the many Italian cases where the need to deal with an ever growing tourist pressure has reached such a high level that intervention now becomes urgent: the small Isola Superiore of Stresa, named Fishermens’ Island located in the centre of Lago Maggiore (Italy). Some suggestions are here reported in an attempt to reduce the loss of cultural heritage in the small island as well as in other similar situation

Short Vi-polysaccharide abrogates T-independent immune response and hyporesponsiveness elicited by long Vi-CRM197 conjugate vaccine

Polysaccharide-protein conjugates have been developed to overcome the T-independent response, hyporesponsiveness to repeated vaccination, and poor immunogenicity in infants of polysaccharides. To address the impact of polysaccharide length, typhoid conjugates made with short- and long-chain fractions of Vi polysaccharide with average sizes of 9.5, 22.8, 42.7, 82.0, and 165 kDa were compared. Long-chain-conjugated Vi (165 kDa) induced a response in both wild-type and T cell-deficient mice, suggesting that it maintains a T-independent response. In marked contrast, short-chain Vi (9.5 to 42.7 kDa) conjugates induced a response in wild-type mice but not in T cell-deficient mice, suggesting that the response is dependent on T cell help. Mechanistically, this was explained in neonatal mice, in which long-chain, but not short-chain, Vi conjugate induced late apoptosis of Vi-specific B cells in spleen and early depletion of Vi-specific B cells in bone marrow, resulting in hyporesponsiveness and lack of long-term persistence of Vi-specific IgG in serum and IgG<sup>+</sup> antibody-secreting cells in bone marrow. We conclude that while conjugation of long-chain Vi generates T-dependent antigens, the conjugates also retain T-independent properties, leading to detrimental effects on immune responses. The data reported here may explain some inconsistencies observed in clinical trials and help guide the design of effective conjugate vaccines

Distinct Impact of Three Different Statins on Arteriovenous Fistula Outcomes: A Retrospective Analysis

Whether statins improve arteriovenous fistula (AVF) outcomes is still a matter of debate. Taking into consideration the existing physicochemical differences between individual drugs, this study evaluates the impact of three different statins (atorvastatin, rosuvastatin and simvastatin) on one-stage and two-stage AVF outcomes. Using a retrospective cohort of 535 patients, we analyzed the effects of each statin on primary failure and primary patency using multivariate logistic regressions and Cox proportional hazard models. Out of the three statins analyzed, only atorvastatin improved the overall primary failure of AVF (odds ratio [OR] = 0.18, p = 0.005). Comparisons between the two AVF types demonstrated that this effect was due to a prominent reduction in primary failure of one-stage (OR = 0.03; p = 0.005), but not two-stage fistulas (OR = 0.43; p = 0.25). In contrast, primary patency of two-stage (hazards ratio [HR] = 0.51; p = 0.024), but not one-stage fistulas (HR = 0.98; p = 0.95), was improved by all statins as a group, but not by individual drugs. Our results suggest that the potential benefit of statins on AVF outcomes is a drug-specific and not a class effect, and that such effect is also influenced by the type of fistula