Diamond-Blackfan anemia, the archetype of ribosomopathy: How distinct is it from the other constitutional ribosomopathies?

Diamond-Blackfan anemia (DBA) was the first ribosomopathy described in humans. DBA is a congenital hypoplastic anemia, characterized by macrocytic aregenerative anemia, manifesting by differentiation blockage between the BFU-e/CFU-e developmental erythroid progenitor stages. In 50 % of the DBA cases, various malformations are noted. Strikingly, for a hematological disease with a relative erythroid tropism, DBA is due to ribosomal haploinsufficiency in 24 different ribosomal protein (RP) genes. A few other genes have been described in DBA-like disorders, but they do not fit into the classical DBA phenotype (Sankaran et al., 2012; van Dooijeweert et al., 2022; Toki et al., 2018; Kim et al., 2017 [1-4]). Haploinsufficiency in a RP gene leads to defective ribosomal RNA (rRNA) maturation, which is a hallmark of DBA. However, the mechanistic understandings of the erythroid tropism defect in DBA are still to be fully defined. Erythroid defect in DBA has been recently been linked in a non-exclusive manner to a number of mechanisms that include: 1) a defect in translation, in particular for the GATA1 erythroid gene; 2) a deficit of HSP70, the GATA1 chaperone, and 3) free heme toxicity. In addition, p53 activation in response to ribosomal stress is involved in DBA pathophysiology. The DBA phenotype may thus result from the combined contributions of various actors, which may explain the heterogenous phenotypes observed in DBA patients, even within the same family.

New KCNN4 Variants Associated With Anemia: Stomatocytosis Without Erythrocyte Dehydration.

The K+ channel activated by the Ca2+, KCNN4, has been shown to contribute to red blood cell dehydration in the rare hereditary hemolytic anemia, the dehydrated hereditary stomatocytosis. We report two de novo mutations on KCNN4, We reported two de novo mutations on KCNN4, V222L and H340N, characterized at the molecular, cellular and clinical levels. Whereas both mutations were shown to increase the calcium sensitivity of the K+ channel, leading to channel opening for lower calcium concentrations compared to WT KCNN4 channel, there was no obvious red blood cell dehydration in patients carrying one or the other mutation. The clinical phenotype was greatly different between carriers of the mutated gene ranging from severe anemia for one patient to a single episode of anemia for the other patient or no documented sign of anemia for the parents who also carried the mutation. These data compared to already published KCNN4 mutations question the role of KCNN4 gain-of-function mutations in hydration status and viability of red blood cells in bloodstream.

Do Some Super-Spreaders Spread Better? Effects of individual heterogeneity in epidemiological traits

Many high-profile outbreaks are driven by super-spreading, including HIV, MERS, Ebola, and the SARS-Cov-2 pandemic. That super-spreading is a common feature of epidemics is immutable, however, the relative importance of 2super-spreaders to the outcome of an epidemic, and the individual-level traits that lead to super-spreading, is less clear. For example, an individual may contribute disproportionately to transmission by way of an extremely high contact rate or by way of low recovery, but how these two super-spreaders differ in their effect on epidemiological dynamics is unclear. Furthermore, epidemiological traits may often covary with one another in ways that promote or inhibit super-spreading. What patterns of covariation, and between what traits, are most likely to lead to large epidemics driven by super-spreading? Using stochastic individual-based simulations of an SIR epidemiological model, we explore how variation and covariation between transmission-related traits (contact rate and infectiousness) and duration-related traits (virulence and recovery) of infected individuals affects super-spreading and peak epidemic size. We show that covariation matters when contact rate and infectiousness covary: peak epidemic size is largest when they covary positively and smallest when they covary negatively. We did not see that more super-spreading always leads to larger epidemics, rather, we show that the relationship between super-spreading and peak epidemic size is dependent on which traits are covarying. This suggests that there may not necessarily be any general relationship between the frequency of super-spreading and the size of an epidemic.

Silymarin and hepatoprotection / 中南大学学报(医学版)

OBJECTIVE@#To determine the hepatoprotective effect of silymarin with Chang cell cultures. Specifically, to investigate the antioxidant properties of silymarin and its protective function in reducing pro-apoptotic markers.@*METHODS@#Intracellular free radical levels were assessed with dichlorofluorescein (DCF) fluorescence after exposing cells to an oxidative stress of 400 μmol/L H2O2 for 20 min. Levels of cellular ATP and bax expression were examined to evaluate the protective effects of silymarin.@*RESULTS@#Silymarin significantly reduced the DCF fluorescence signal. Cell viability, assessed by the MTT assay, showed that silymarin enhanced the cell growth. Drug treatment was also associated with enhanced ATP levels, and reduced Bax and protein mRNA levels.@*CONCLUSION@#Silymarin can function as a hepatoprotectant against free radical damage due to oxidative stress. The protective nature extends to reducing levels of pro-apoptotic Bax protein. Silymarin may be a useful adjuvant for the treatment of specific liver diseases.