Feeding the Dragon. An Eschatological Motif in Medieval Europe

This book consists of six original essays concerning two popular eschatological motifs of medieval Europe: the devouring devil, especially in the guise of a dragon, and the zoomorphic mouth of hell, arguably a distinctive English adaptation of the anthropomorphic mouth of hell of classical antiquity. Over a time span ranging from late antiquity to the late Middle Ages and stretching across three languages, Latin, Old English, and Old Norse, the topos of the devouring demonic monster, a veritable commonplace across cultures and ages, is investigated in a variety of texts, including the Holy Scripture, homiletic and hagiographic works by authors such as Augustine of Hippo, Gregory the Great, and Ælfric of Eynsham, and apocryphal writings, e.g. the Seven Heavens Apocryphon and the Gospel of Nicodemus, especially its latter section, the Descensus Christi ad inferos. By detailing the creative interaction of a wide range of influences and the various practices of appropriation and adaptation of a vast stock of source material, both ultimate and intermediate, the contributions afford relevant case studies of the densely interlingual and intertextual modes of textual production, transmission, and reception in the European Middle Ages. Advancing our understanding of the cultural and textual networks of the period, this book will prove an important resource for anyone interested in the dynamic process of mediation between past and present, pagan and Christian, orthodoxy and apocrypha, exotic and local that makes up medieval literary and figurative culture

Isotopic and spin selectivity of H_2 adsorbed in bundles of carbon nanotubes

Due to its large surface area and strongly attractive potential, a bundle of carbon nanotubes is an ideal substrate material for gas storage. In addition, adsorption in nanotubes can be exploited in order to separate the components of a mixture. In this paper, we investigate the preferential adsorption of D_2 versus H_2(isotope selectivity) and of ortho versus para(spin selectivity) molecules confined in the one-dimensional grooves and interstitial channels of carbon nanotube bundles. We perform selectivity calculations in the low coverage regime, neglecting interactions between adsorbate molecules. We find substantial spin selectivity for a range of temperatures up to 100 K, and even greater isotope selectivity for an extended range of temperatures,up to 300 K. This isotope selectivity is consistent with recent experimental data, which exhibit a large difference between the isosteric heats of D_2 and H_2 adsorbed in these bundles.Comment: Paper submitted to Phys.Rev. B; 17 pages, 2 tables, 6 figure

Blockade of IGF2R improves muscle regeneration and ameliorates Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a debilitating fatal X-linked muscle disorder. Recent findings indicate that IGFs play a central role in skeletal muscle regeneration and development. Among IGFs, insulinlike growth factor 2 (IGF2) is a key regulator of cell growth, survival, migration and differentiation. The type 2 IGF receptor (IGF2R) modulates circulating and tissue levels of IGF2 by targeting it to lysosomes for degradation. We found that IGF2R and the store-operated Ca2+ channel CD20 share a common hydrophobic binding motif that stabilizes their association. Silencing CD20 decreased myoblast differentiation, whereas blockade of IGF2R increased proliferation and differentiation in myoblasts via the calmodulin/calcineurin/NFAT pathway. Remarkably, anti-IGF2R induced CD20 phosphorylation, leading to the activation of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) and removal of intracellular Ca2+. Interestingly, we found that IGF2R expression was increased in dystrophic skeletal muscle of human DMD patients and mdx mice. Blockade of IGF2R by neutralizing antibodies stimulated muscle regeneration, induced force recovery and normalized capillary architecture in dystrophic mdx mice representing an encouraging starting point for the development of new biological therapies for DMD

Anti-tumor efficacy assessment of the sigma receptor pan modulator RC-106. A promising therapeutic tool for pancreatic cancer

Introduction: Pancreatic cancer (PC) is one of the most lethal tumor worldwide, with no prognosis improvement over the past 20-years. The silent progressive nature of this neoplasia hampers the early diagnosis, and the surgical resection of the tumor, thus chemotherapy remains the only available therapeutic option. Sigma receptors (SRs) are a class of receptors proposed as new cancer therapeutic targets due to their over-expression in tumor cells and their involvement in cancer biology. The main localization of these receptors strongly suggests their potential role in ER unfolded protein response (ER-UPR), a condition frequently occurring in several pathological settings, including cancer. Our group has recently identified RC-106, a novel pan-SR modulator with good in vitro antiproliferative activities toward a panel of different cancer cell lines. In the present study, we investigated the in vitro properties and pharmacological profile of RC-106 in PC cell lines with the aim to identify a potential lead candidate for the treatment of this tumor. Methods: Pancreatic cancer cell lines Panc-1, Capan-1, and Capan-2 have been used in all experiments. S1R and TMEM97/S2R expression in PC cell lines was quantified by Real-Time qRT-PCR and Western Blot experiments. MTS assay was used to assess the antiproliferative effect of RC-106. The apoptotic properties of RC-106 was evaluated by TUNEL and caspase activation assays. GRP78/BiP, ATF4, and CHOP was quantified to evaluate ER-UPR. Proteasome activity was investigated by a specific fluorescent-based assay. Scratch wound healing assay was used to asses RC-106 effect on cell migration. In addition, we delineated the in vivo pharmacokinetic profile and pancreas distribution of RC-106 in male CD-1 mice. Results: Panc-1, Capan-1, and Capan-2 express both SRs. RC-106 exerts an antiproliferative and pro-apoptotic effect in all examined cell lines. Cells exposure to RC-106 induces the increase of the expression of ER-UPR related proteins, and the inhibition of proteasome activity. Moreover, RC-106 is able to decrease PC cell lines motility. The in vivo results show that RC-106 is more concentrated in pancreas than plasma. Conclusion: Overall, our data evidenced that the pan-SR modulator RC-106 is an optimal candidate for in vivo studies in animal models of PC

Contouring of emerging organs-at-risk (OARS) of the female pelvis and interobserver variability. A study by the Italian association of radiotherapy and clinical oncology (AIRO)

Purpose: To provide straightforward instructions for daily practice in delineating emerging organs-at-risk (OARs) of the female pelvis and to discuss the interobserver variability in a two-step multicenter study.Methods and materials: A contouring atlas with anatomical boundaries for each emerging OAR was realized by radiation oncologists and radiologists who are experts in pelvic imaging, as per their knowledge and clinical practice. These contours were identified as quality benchmarks for the analysis subsequently carried out. Radiation oncologists not involved in setting the custom-built contouring atlas and interested in the treatment of gynecological cancer were invited to participate in this 2-step trial. In the first step all participants were supplied with a selected clinical case of locally advanced cervical cancer and had to identify emerging OARs (Levator ani muscle; Puborectalis muscle; Internal anal sphincter; External anal sphincter; Bladder base and trigone; Bladder neck; Iliac Bone Marrow; Lower Pelvis Bone Marrow; Lumbosacral Bone Marrow) based on their own personal knowledge of pelvic anatomy and experience. The suggested OARs and the contouring process were then presented at a subsequent webinar meeting with a contouring laboratory. Finally, in the second step, after the webinar meeting, each participant who had joined the study but was not involved in setting the benchmark received the custom-built contouring atlas with anatomical boundaries and was requested to delineate again the OARs using the tool provided. The Dice Similarity Coefficient (DSC) and the Jaccard Similarity Coefficient (JSC) were used to evaluate the spatial overlap accuracy of the different volume delineations and compared with the benchmark; the Hausdorff distance (HD) and the mean distance to agreement (MDA) to explore the distance between contours. All the results were reported as sample mean and standard deviation (SD). Results: Fifteen radiation oncologists from different Institutions joined the study. The participants had a high agreement degree for pelvic bones sub-structures delineation according to DICE (IBM: 0.9 +/- 0.02; LPBM: 0.91 +/- 0.01). A moderate degree according to DICE was showed for ovaries (Right: 0.61 +/- 0.16, Left: 0.72 +/- 0.05), vagina (0.575 +/- 0.13), bladder sub-structures (0.515 +/- 0.08) and EAS (0.605 +/- 0.05), whereas a low degree for the other sub-structures of the anal-rectal sphincter complex (LAM: 0.345 +/- 0.07, PRM: 0.41 +/- 0.10, and IAS: 0.4 +/- 0.07).Conclusion: This study found a moderate to low level of agreement in the delineation of the female pelvis emerging OARs, with a high degree of variability among observers. The development of delineation tools should be encouraged to improve the routine contouring of these OARs and increase the quality and consistency of radiotherapy planning

Oral ribose supplementation in dystroglycanopathy:A single case study

Three forms of muscular dystrophy-dystroglycanopathies are linked to the ribitol pathway. These include mutations in the isoprenoid synthase domain-containing protein (ISPD), fukutin-related protein (FKRP), and fukutin (FKTN) genes. The aforementioned enzymes are required for generation of the ribitol phosphate linkage in the O-glycan of alpha-dystroglycan. Mild cases of dystroglycanopathy present with slowly progressive muscle weakness, while in severe cases the eyes and brain are also involved. Previous research showed that ribose increased the intracellular concentrations of cytidine diphosphate-ribitol (CDP-ribitol) and had a therapeutic effect. Here, we report the safety and effects of oral ribose supplementation during 6 months in a patient with limb girdle muscular dystrophy type 2I (LGMD2I) due to a homozygous FKRP mutation. Ribose was well tolerated in doses of 9 g or 18 g/day. Supplementation with 18 g of ribose resulted in a decrease of creatine kinase levels of 70%. Moreover, metabolomics showed a significant increase in CDP-ribitol levels with 18 g of ribose supplementation (p &lt; 0.001). Although objective improvement in clinical and patient-reported outcome measures was not observed, the patient reported subjective improvement of muscle strength, fatigue, and pain. This case study indicates that ribose supplementation in patients with dystroglycanopathy is safe and highlights the importance for future studies regarding its potential effects.</p