From bench to bedside

The adaptive immune system has been the main focus of immunological strategies in oncology with only more recent approaches targeting innate immunity. Endosomal toll-like receptors (TLR-7, TLR-9) activate innate immune responses by signaling damage-associated molecular patterns (DAMP) from decaying tumor cells. This has led to the development of DNA-based TLR-9 agonists, which induce antitumor activity through innate and subsequent adaptive immune responses. Early clinical trials with CpG-ODN as TLR-9 agonists were associated with unfavorable tolerability and narrow clinical efficacy, leading to failure in pivotal trials. dSLIM®, the active ingredient of MGN1703, is a DNA-based, radically different molecular alternative to CpG-ODN, which results in genuine antitumor immunomodulation. Preclinical and clinical studies of MGN1703 have confirmed that this TLR-9 agonist has therapeutic potential in a variety of solid tumors, while long-term treatment with high doses was very well tolerated. A pivotal trial of first-line maintenance treatment with MGN1703 in patients with metastatic colorectal cancer is underway

Blue native DIGE as a tool for comparative analyses of protein complexes

Differential gel electrophoresis (DIGE) is based on pre-labeling of different protein fractions and their subsequent co-electrophoresis in a single gel. Cyanine based "CyDye DIGE Fluor minimal dyes" are used for the labeling reaction and 2D IEF/SDS PAGE is the preferential electrophoresis system for protein separation. The DIGE technology allows elimination of inconsistencies based on gel to gel variations and furthermore allows exact quantification of proteins separated by gel electrophoresis. Here we report applications of the DIGE technology in combination with another 2D gel system, Blue native/SDS PAGE. "Blue native DIGE" offers (i) systematic and quantitative comparison of protein complexes of related protein fractions, (ii) structural investigation of protein complexes, (iii) assignment of protein complexes to subcellular fractions like organelles and (iv) electrophoretic mapping of isoforms of subunits of protein complexes with respect to a larger proteome. The potential of "Blue native DIGE" is illustrated by analysis of organellar fractions from the plant Arabidopsis thaliana and the alga Polytomella. Use of the DIGE technology for topological investigations is discussed

The Initial Slope of the Variogram, Foundation of the Trabecular Bone Score, Is Not or Is Poorly Associated With Vertebral Strength.

Trabecular bone score (TBS) rests on the textural analysis of dual-energy X-ray absorptiometry (DXA) to reflect the decay in trabecular structure characterizing osteoporosis. Yet, its discriminative power in fracture studies remains incomprehensible because prior biomechanical tests found no correlation with vertebral strength. To verify this result possibly owing to an unrealistic setup and to cover a wide range of loading scenarios, the data from three previous biomechanical studies using different experimental settings were used. They involved the compressive failure of 62 human lumbar vertebrae loaded 1) via intervertebral discs to mimic the in vivo situation ("full vertebra"); 2) via the classical endplate embedding ("vertebral body"); or 3) via a ball joint to induce anterior wedge failure ("vertebral section"). High-resolution peripheral quantitative computed tomography (HR-pQCT) scans acquired from prior testing were used to simulate anterior-posterior DXA from which areal bone mineral density (aBMD) and the initial slope of the variogram (ISV), the early definition of TBS, were evaluated. Finally, the relation of aBMD and ISV with failure load (Fexp ) and apparent failure stress (σexp ) was assessed, and their relative contribution to a multilinear model was quantified via ANOVA. We found that, unlike aBMD, ISV did not significantly correlate with Fexp and σexp , except for the "vertebral body" case (r(2) = 0.396, p = 0.028). Aside from the "vertebra section" setup where it explained only 6.4% of σexp (p = 0.037), it brought no significant improvement to aBMD. These results indicate that ISV, a replica of TBS, is a poor surrogate for vertebral strength no matter the testing setup, which supports the prior observations and raises a fortiori the question of the deterministic factors underlying the statistical relationship between TBS and vertebral fracture risk. © 2015 American Society for Bone and Mineral Research

Identification of a Novel Modulator of Thyroid Hormone Receptor-Mediated Action

Diabetes is characterized by reduced thyroid function and altered myogenesis after muscle injury. Here we identify a novel component of thyroid hormone action that is repressed in diabetic rat muscle. Methodology/Principal Findings. We have identified a gene, named DOR, abundantly expressed in insulin-sensitive tissues such as skeletal muscle and heart, whose expression is highly repressed in muscle from obese diabetic rats. DOR expression is up-regulated during muscle differentiation and its loss-of-function has a negative impact on gene expression programmes linked to myogenesis or driven by thyroid hormones. In agreement with this, DOR enhances the transcriptional activity of the thyroid hormone receptor TRa1. This function is driven by the N-terminal part of the protein. Moreover, DOR physically interacts with TR a1 and to T3-responsive promoters, as shown by ChIP assays. T3 stimulation also promotes the mobilization of DOR from its localization in nuclear PML bodies, thereby indicating that its nuclear localization and cellular function may be related. Conclusions/Significance. Our data indicate that DOR modulates thyroid hormone function and controls myogenesis. DOR expression is down-regulated in skeletal muscle in diabetes. This finding may be of relevance for the alterations in muscle function associated with this disease

Identification of a novel modulator of thyroid hormone receptor-mediated action

Diabetes is characterized by reduced thyroid function and altered myogenesis after muscle injury. Here we identify a novel component of thyroid hormone action that is repressed in diabetic rat muscle. Methodology/Principal Findings. We have identified a gene, named DOR, abundantly expressed in insulin-sensitive tissues such as skeletal muscle and heart, whose expression is highly repressed in muscle from obese diabetic rats. DOR expression is up-regulated during muscle differentiation and its loss-of-function has a negative impact on gene expression programmes linked to myogenesis or driven by thyroid hormones. In agreement with this, DOR enhances the transcriptional activity of the thyroid hormone receptor TRa1. This function is driven by the N-terminal part of the protein. Moreover, DOR physically interacts with TR a1 and to T3-responsive promoters, as shown by ChIP assays. T3 stimulation also promotes the mobilization of DOR from its localization in nuclear PML bodies, thereby indicating that its nuclear localization and cellular function may be related. Conclusions/Significance. Our data indicate that DOR modulates thyroid hormone function and controls myogenesis. DOR expression is down-regulated in skeletal muscle in diabetes. This finding may be of relevance for the alterations in muscle function associated with this disease

Graph Data-Models and Semantic Web Technologies in Scholarly Digital Editing

This volume is based on the selected papers presented at the Workshop on Scholarly Digital Editions, Graph Data-Models and Semantic Web Technologies, held at the Uni- versity of Lausanne in June 2019. The Workshop was organized by Elena Spadini (University of Lausanne) and Francesca Tomasi (University of Bologna), and spon- sored by the Swiss National Science Foundation through a Scientific Exchange grant, and by the Centre de recherche sur les lettres romandes of the University of Lausanne. The Workshop comprised two full days of vibrant discussions among the invited speakers, the authors of the selected papers, and other participants.1 The acceptance rate following the open call for papers was around 60%. All authors – both selected and invited speakers – were asked to provide a short paper two months before the Workshop. The authors were then paired up, and each pair exchanged papers. Paired authors prepared questions for one another, which were to be addressed during the talks at the Workshop; in this way, conversations started well before the Workshop itself. After the Workshop, the papers underwent a second round of peer-review before inclusion in this volume. This time, the relevance of the papers was not under discus- sion, but reviewers were asked to appraise specific aspects of each contribution, such as its originality or level of innovation, its methodological accuracy and knowledge of the literature, as well as more formal parameters such as completeness, clarity, and coherence. The bibliography of all of the papers is collected in the public Zotero group library GraphSDE20192, which has been used to generate the reference list for each contribution in this volume. The invited speakers came from a wide range of backgrounds (academic, commer- cial, and research institutions) and represented the different actors involved in the remediation of our cultural heritage in the form of graphs and/or in a semantic web en- vironment. Georg Vogeler (University of Graz) and Ronald Haentjens Dekker (Royal Dutch Academy of Sciences, Humanities Cluster) brought the Digital Humanities research perspective; the work of Hans Cools and Roberta Laura Padlina (University of Basel, National Infrastructure for Editions), as well as of Tobias Schweizer and Sepi- deh Alassi (University of Basel, Digital Humanities Lab), focused on infrastructural challenges and the development of conceptual and software frameworks to support re- searchers’ needs; Michele Pasin’s contribution (Digital Science, Springer Nature) was informed by his experiences in both academic research, and in commercial technology companies that provide services for the scientific community. The Workshop featured not only the papers of the selected authors and of the invited speakers, but also moments of discussion between interested participants. In addition to the common Q&A time, during the second day one entire session was allocated to working groups delving into topics that had emerged during the Workshop. Four working groups were created, with four to seven participants each, and each group presented a short report at the end of the session. Four themes were discussed: enhancing TEI from documents to data; ontologies for the Humanities; tools and infrastructures; and textual criticism. All of these themes are represented in this volume. The Workshop would not have been of such high quality without the support of the members of its scientific committee: Gioele Barabucci, Fabio Ciotti, Claire Clivaz, Marion Rivoal, Greta Franzini, Simon Gabay, Daniel Maggetti, Frederike Neuber, Elena Pierazzo, Davide Picca, Michael Piotrowski, Matteo Romanello, Maïeul Rouquette, Elena Spadini, Francesca Tomasi, Aris Xanthos – and, of course, the support of all the colleagues and administrative staff in Lausanne, who helped the Workshop to become a reality. The final versions of these papers underwent a single-blind peer review process. We want to thank the reviewers: Helena Bermudez Sabel, Arianna Ciula, Marilena Daquino, Richard Hadden, Daniel Jeller, Tiziana Mancinelli, Davide Picca, Michael Piotrowski, Patrick Sahle, Raffaele Viglianti, Joris van Zundert, and others who preferred not to be named personally. Your input enhanced the quality of the volume significantly! It is sad news that Hans Cools passed away during the production of the volume. We are proud to document a recent state of his work and will miss him and his ability to implement the vision of a digital scholarly edition based on graph data-models and semantic web technologies. The production of the volume would not have been possible without the thorough copy-editing and proof reading by Lucy Emmerson and the support of the IDE team, in particular Bernhard Assmann, the TeX-master himself. This volume is sponsored by the University of Bologna and by the University of Lausanne. Bologna, Lausanne, Graz, July 2021 Francesca Tomasi, Elena Spadini, Georg Vogele

Human Endometrial CD98 Is Essential for Blastocyst Adhesion

BACKGROUND: Understanding the molecular basis of embryonic implantation is of great clinical and biological relevance. Little is currently known about the adhesion receptors that determine endometrial receptivity for embryonic implantation in humans. METHODS AND PRINCIPAL FINDINGS: Using two human endometrial cell lines characterized by low and high receptivity, we identified the membrane receptor CD98 as a novel molecule selectively and significantly associated with the receptive phenotype. In human endometrial samples, CD98 was the only molecule studied whose expression was restricted to the implantation window in human endometrial tissue. CD98 expression was restricted to the apical surface and included in tetraspanin-enriched microdomains of primary endometrial epithelial cells, as demonstrated by the biochemical association between CD98 and tetraspanin CD9. CD98 expression was induced in vitro by treatment of primary endometrial epithelial cells with human chorionic gonadotropin, 17-β-estradiol, LIF or EGF. Endometrial overexpression of CD98 or tetraspanin CD9 greatly enhanced mouse blastocyst adhesion, while their siRNA-mediated depletion reduced the blastocyst adhesion rate. CONCLUSIONS: These results indicate that CD98, a component of tetraspanin-enriched microdomains, appears to be an important determinant of human endometrial receptivity during the implantation window

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe