The MRX Complex Plays Multiple Functions in Resection of Yku- and Rif2-Protected DNA Ends

The ends of both double-strand breaks (DSBs) and telomeres undergo tightly regulated 5′ to 3′ resection. Resection of DNA ends, which is specifically inhibited during the G1 cell cycle phase, requires the MRX complex, Sae2, Sgs1 and Exo1. Moreover, it is negatively regulated by the non-homologous end-joining component Yku and the telomeric protein Rif2. Here, we investigate the nuclease activities that are inhibited at DNA ends by Rif2 and Yku in G1 versus G2 by using an inducible short telomere assay. We show that, in the absence of the protective function of Rif2, resection in G1 depends primarily on MRX nuclease activity and Sae2, whereas Exo1 and Sgs1 bypass the requirement of MRX nuclease activity only if Yku is absent. In contrast, Yku-mediated inhibition is relieved in G2, where resection depends on Mre11 nuclease activity, Exo1 and, to a minor extent, Sgs1. Furthermore, Exo1 compensates for a defective MRX nuclease activity more efficiently in the absence than in the presence of Rif2, suggesting that Rif2 inhibits not only MRX but also Exo1. Notably, the presence of MRX, but not its nuclease activity, is required and sufficient to override Yku-mediated inhibition of Exo1 in G2, whereas it is required but not sufficient in G1. Finally, the integrity of MRX is also necessary to promote Exo1- and Sgs1-dependent resection, possibly by facilitating Exo1 and Sgs1 recruitment to DNA ends. Thus, resection of DNA ends that are protected by Yku and Rif2 involves multiple functions of the MRX complex that do not necessarily require its nuclease activity

Calcium Citrate Versus Calcium Carbonate in the Management of Chronic Hypoparathyroidism: A Randomized, Double-Blind, Crossover Clinical Trial

In hypoparathyroidism (HypoPT), calcium supplementation is virtually always required, although the disease is likely to be associated with an increased risk of nephrolithiasis. The use of calcium citrate (Ca-Cit) theoretically could have a positive impact on the nephrolithiasis risk because citrate salts are used to reduce this risk. Our objective was to evaluate the potential therapeutic advantage of Ca-Cit in comparison with calcium carbonate (CaCO3) in HypoPT, on nephrolithiasis risk factors, as well as to their ability to maintain desirable serum calcium levels. We also evaluated these preparations on quality of life (QOL). This randomized, double-blind, crossover trial recruited 24 adults with postsurgical chronic hypoparathyroidism at Campus Bio-Medico University of Rome. Participants were randomized 1:1 to Ca-Cit or CaCO3 for 1 month and then crossed over to the other treatment for another month. The primary outcomes were changes in albumin-adjusted serum calcium and in ion activity product of calcium oxalate levels (AP[CaOx] index). Secondary efficacy outcomes included changes in SF-36 survey score, fatigue score, constipation, and adverse events. No difference in terms of AP(CaOx) index was observed between the two groups. However, Ca-Cit was associated with a significant reduction in the oxalate/creatinine ratio compared with CaCO3 (-2.46 mmol/mol [SD 11.93] versus 7.42 mmol/mol [SD 17.63], p = 0.029). Serum calcium and phosphorus concentration was not different between the two calcium preparations. Ca-Cit was associated with less constipation (p = 0.047). No difference was found in QOL scores. Although Ca-Cit did not modify the AP(CaOx) index when compared with CaCO3, it was associated with a reduction in urinary oxalate excretion that could have a potential beneficial effect on nephrolithiasis risk. These results are likely to have clinical implications in HypoPT, particularly those who do not tolerate CaCO3 and those affected by nephrolithiasis. A longer-term experience is needed to confirm these findings. (c) 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)

Pathophysiology of Bone Fragility in Patients with Diabetes

It has been well established that bone fragility is one of the chronic complications of diabetes mellitus, and both type 1 and type 2 diabetes are risk factors for fragility fractures. Diabetes may negatively affect bone health by unbalancing several pathways: bone formation, bone resorption, collagen formation, inflammatory cytokine, muscular and incretin system, bone marrow adiposity and calcium metabolism. The purpose of this narrative review is to explore the current understanding of pathophysiological pathways underlying bone fragility in diabetics. In particular, the review will focus on the peculiar cellular and molecular system impairment that may lead to increased risk of fracture in type 1 and type 2 diabetes

Atlas of Musculoskeletal Tumors and Tumorlike LesionsThe Rizzoli Case Archive /

XXII, 387 p. 226 illus., 173 illus. in color.onli

Fin Whale (Balaenoptera physalus) Mortality along the Italian Coast between 1624 and 2021

Simple Summary We present a comprehensive overview of fin whale historical and modern mortality events that occurred between 1624 and 2021 along the Italian coast, highlighting spatial and temporal patterns and, where possible, the proximal causes of mortality. Emerging hot spot analysis shows the spatial and temporal consistency of mortality events along the northern coast of the island of Sardinia, the central coast of Tuscany and the Gulf of Trieste in the northern Adriatic Sea. The coast of Liguria and the northern coast of Tuscany are sporadic hot spots, while the central coast of Italy along the Tyrrhenian Sea as well as the coast of southern Sardinia and northern Sicily have been identified as new hot spots of mortality events for the species. While the analysis of the temporal patterns suggests a steep increase in the number of mortality events starting in the second half of the 1980s, we cannot exclude the possibility that this positive trend is the result of a strong observer bias. Conversely, recent mortality events seem to be consistent in number over the last six decades and subject to year-round seasonality. Our results show that younger and immature individuals are the fin whales most affected by ship strikes. This study supports the implementation of a conservation plan to ensure the survival of the species in the Mediterranean region. The Mediterranean Sea hosts a population of fin whale (Balaenoptera physalus), the only species of Mysticete regularly occurring in the basin. Observed and inferred mortality suggests that the population is likely declining. Accordingly, understanding the causes of mortality and assessing the health status is pivotal to the survival of this endangered population. While such studies are inherently difficult for a highly roaming species with a pelagic distribution, mortality events provide the opportunity to investigate biological and epidemiological traits linked to these events, and evaluate the footprint of human activity, especially when long-term data series exist. We present a comprehensive spatial-temporal overview of fin whale mortality events along the Italian coast encompassing four centuries (1624-2021). Time series analysis was used to highlight structural changes in the evolution of mortality through time, while spatial-temporal patterns in the distribution of mortality events were assessed through emerging hot spot analysis methods. Recent mortality events (1964-2021) were further explored to evaluate, where possible, the primary causes of mortality and to identify anthropogenic threats of conservation concerns. This long-term survey offers the basis for an understanding of the health status of this B. physalus population and provides much-needed information for developing an effective management and conservation plan for the species in the region

Inhibition of eIF6 Activity Reduces Hepatocellular Carcinoma Growth: An In Vivo and In Vitro Study

Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipids in the liver. Given the high prevalence of NAFLD, its evolution to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) is of global concern. Therapies for managing NASH-driven HCC can benefit from targeting factors that play a continuous role in NAFLD evolution to HCC. Recent work has shown that postprandial liver translation exacerbates lipid accumulation through the activity of a translation factor, eukaryotic initiation factor 6 (eIF6). Here, we test the effect of eIF6 inhibition on the progression of HCC. Mice heterozygous for eIF6 express half the level of eIF6 compared to wt mice and are resistant to the formation of HCC nodules upon exposure to a high fat/high sugar diet combined with liver damage. Histology showed that nodules in eIF6 het mice were smaller with reduced proliferation compared to wt nodules. By using an in vitro model of human HCC, we confirm that eIF6 depletion reduces the growth of HCC spheroids. We also tested three pharmacological inhibitors of eIF6 activity—eIFsixty-1, eIFsixty-4, and eIFsixty-6—and all three reduced eIF6 binding to 60S ribosomes and limited the growth of HCC spheroids. Thus, inhibition of eIF6 activity is feasible and limits HCC formation

Role of the Saccharomyces cerevisiae Rad53 Checkpoint Kinase in Signaling Double-Strand Breaks during the Meiotic Cell Cycle▿

DNA double-strand breaks (DSBs) can arise at unpredictable locations after DNA damage or in a programmed manner during meiosis. DNA damage checkpoint response to accidental DSBs during mitosis requires the Rad53 effector kinase, whereas the meiosis-specific Mek1 kinase, together with Red1 and Hop1, mediates the recombination checkpoint in response to programmed meiotic DSBs. Here we provide evidence that exogenous DSBs lead to Rad53 phosphorylation during the meiotic cell cycle, whereas programmed meiotic DSBs do not. However, the latter can trigger phosphorylation of a protein fusion between Rad53 and the Mec1-interacting protein Ddc2, suggesting that the inability of Rad53 to transduce the meiosis-specific DSB signals might be due to its failure to access the meiotic recombination sites. Rad53 phosphorylation/activation is elicited when unrepaired meiosis-specific DSBs escape the recombination checkpoint. This activation requires homologous chromosome segregation and delays the second meiotic division. Altogether, these data indicate that Rad53 prevents sister chromatid segregation in the presence of unrepaired programmed meiotic DSBs, thus providing a salvage mechanism ensuring genetic integrity in the gametes even in the absence of the recombination checkpoint