Taking a closer look: How to improve the design of the Solvency Support Instrument. Bertelsmann Policy Paper IPolicy PaperThe Solvency Support Instrument (SSI) is central to the European Commis-sion’s proposal to mitigate economic damage of the pandemic. It would use part of the money raised under the Recovery Instrument to provide equity support to struggling firms. It could become a powerful tool for the recovery. However, in its current form, the instrument risks provid-ing free lunch bailouts for owners and private investors without ensuring that public support secures jobs, avoids market concentration, and puts firms on a growth path more conducive with the EU’s broader industrial policy goals. To remedy these shortcomings, the instrument needs clear political criteria for equity support and better political control. Bertelsmann Policy Paper, 14 July 2020

The Solvency Support Instrument (SSI) is central to the European Commission’s proposal to mitigate economic damage of the pandemic. It would use part of the money raised under the Recovery Instrument to provide equity support to struggling firms. It could become a powerful tool for the recovery. However, in its current form, the instrument risks providing free lunch bailouts for owners and private investors without ensuring that public support secures jobs, avoids market concentration, and puts firms on a growth path more conducive with the EU’s broader industrial policy goals. To remedy these shortcomings, the instrument needs clear political criteria for equity support and better political control

Neisseria meningitidis Has Two Independent Modes of Recognizing Its Human Receptor CEACAM1

BACKGROUND: Several human-restricted gram-negative bacteria exploit carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) for host colonization. For example, Neisseria meningitidis engages these human receptors via outer membrane proteins of the colony opacity-associated (Opa) protein family triggering internalization into non-phagocytic cells. PRINCIPAL FINDINGS: We report that a non-opaque strain of N. meningitidis selectively interacts with CEACAM1, but not other CEACAM family members. Using functional assays of bacterial adhesion and internalisation, microscopic analysis, and a panel of CEACAM1 deletion mutants we demonstrate that the engagement of CEACAM1 by non-opaque meningococci occurs in a manner distinct from Opa protein-mediated association. In particular, the amino-terminal domain of CEACAM1 is necessary, but not sufficient for Opa protein-independent binding, which requires multiple extracellular domains of the human receptor in a cellular context. Knock-down of CEACAM1 interferes with binding to lung epithelial cells, whereas chemical or pharmacological disruption of host protein glycosylation does not abrogate CEACAM1 recognition by non-opaque meningococci. The previously characterized meningococcal invasins NadA or Opc do not operate in a CEACAM1-dependent manner. CONCLUSIONS: The results demonstrate a mechanistically distinct, Opa protein-independent interaction between N. meningitidis and human CEACAM1. Our functional investigations suggest the presence of a second CEACAM1-binding invasin on the meningococcal surface that associates with the protein backbone and not the carbohydrate structures of CEACAM1. The redundancy in meningococcal CEACAM1-binding factors further highlights the important role of CEACAM recognition in the biology of this human-adapted pathogen

A scalable Computer-Aided Detection system for microcalcification cluster identification in a pan-European distributed database of mammograms

A computer-aided detection (CADe) system for microcalcification cluster identification in mammograms has been developed in the framework of the EU-founded MammoGrid project. The CADe software is mainly based on wavelet transforms and artificial neural networks. It is able to identify microcalcifications in different kinds of mammograms (i.e. acquired with different machines and settings, digitized with different pitch and bit depth or direct digital ones). The CADe can be remotely run from GRID-connected acquisition and annotation stations, supporting clinicians from geographically distant locations in the interpretation of mammographic data. We report the FROC analyses of the CADe system performances on three different dataset of mammograms, i.e. images of the CALMA INFN-founded database collected in the Italian National screening program, the MIAS database and the so-far collected MammoGrid images. The sensitivity values of 88% at a rate of 2.15 false positive findings per image (FP/im), 88% with 2.18 FP/im and 87% with 5.7 FP/im have been obtained on the CALMA, MIAS and MammoGrid database respectively.Comment: 6 pages, 5 figures; Proceedings of the ITBS 2005, 3rd International Conference on Imaging Technologies in Biomedical Sciences, 25-28 September 2005, Milos Island, Greec

CCN2/CTGF promotor activity in the developing and adult mouse eye

CCN2/CTGF is a matricellular protein that is known to enhance transforming growth factor-β signaling and to induce a myofibroblast-like phenotype in a variety of cell types. Here, we investigated Ccn2/Ctgf promotor activity during development and in the adult mouse eye, using CTGFLacZ/+ mice in which the β-galactosidase reporter gene LacZ had been inserted into the open reading frame of Ccn2/Ctgf. Promotor activity was assessed by staining for β-galactosidase activity and by immunolabeling using antibodies against β-galactosidase. Co-immunostaining using antibodies against glutamine synthetase, glial fibrillary acidic protein, choline acetyltransferase, and CD31 was applied to identify specific cell types. Ccn2/Ctgf promotor activity was intense in neural crest-derived cells differentiating to corneal stroma and endothelium, and to the stroma of choroid, iris, ciliary body, and the trabecular meshwork during development. In the adult eye, a persistent and very strong promotor activity was present in the trabecular meshwork outflow pathways. In addition, endothelial cells of Schlemm’s canal, and of retinal and choroidal vessels, retinal astrocytes, Müller glia, and starburst amacrine cells were stained. Very strong promoter activity was seen in the astrocytes of the glial lamina at the optic nerve head. We conclude that CCN2/CTGF signaling is involved in the processes that govern neural crest morphogenesis during ocular development. In the adult eye, CCN2/CTGF likely plays an important role for the trabecular meshwork outflow pathways and the glial lamina of the optic nerve head

CCN2/CTGF tip the balance of growth factors towards TGF-β2 in primary open-angle glaucoma

TGF-β2 is the predominant TGF-β isoform within the eye. One function of TGF-β2 is to provide the eye with immune protection against intraocular inflammation. The beneficial function of TGF-β2 within the eye must be under tight control of a network of different factors. A disbalance of the network can result in different eye diseases. In Primary Open-Angle Glaucoma (POAG), one of the leading causes of irreversible blindness worldwide, TGF-β2 is significantly elevated in the aqueous humor and antagonistic molecules like BMPs are reduced. The changes provoke an altering of the quantity and quality of the extracellular matrix and the actin cytoskeleton in the outflow tissues, leading to an increased outflow resistance and thereby to an increased intraocular pressure (IOP), the major risk factor for primary open-angle glaucoma. The pathologic effect of TGF-β2 in primary open-angle glaucoma is mainly meditated by CCN2/CTGF. CCN2/CTGF can modulate TGF-β and BMP signaling by direct binding. The eye specific overexpression of CCN2/CTGF caused an increase in IOP and led to a loss of axons, the hallmark of primary open-angle glaucoma. CCN2/CTGF appears to play a critical role in the homeostatic balance of the eye, so we investigated if CCN2/CTGF can modulate BMP and TGF-β signaling pathways in the outflow tissues. To this end, we analyzed the direct effect of CCN2/CTGF on both signaling pathways in two transgenic mouse models with a moderate (βB1-CTGF1) and a high CCN2/CTGF (βB1-CTGF6) overexpression and in immortalized human trabecular meshwork (HTM) cells. Additionally, we investigate whether CCN2/CTGF mediates TGF-β effects via different pathways. We observed developmental malformations in the ciliary body in βB1-CTGF6 caused by an inhibition of the BMP signaling pathway. In βB1-CTGF1, we detected a dysregulation of the BMP and TGF-β signaling pathways, with reduced BMP activity and increased TGF-β signaling. A direct CCN2/CTGF effect on BMP and TGF-β signaling was shown in immortalized HTM cells. Finally, CCN2/CTGF mediated its effects on TGF-β via the RhoA/ROCK and ERK signaling in immortalized HTM cells. We conclude that CCN2/CTGF functions as a modulator of the homeostatic balance of BMP and TGF-β signaling pathways, which is shifted in primary open-angle glaucoma

Crystal Symmetry of Stripe Ordered La1.88Sr0.12CuO4

We present a combined x-ray and neutron diffraction study of the stripe ordered superconductor \lscox{0.12}. The average crystal structure is consistent with the orthorhombic $Bmab$ space group as commonly reported in the literature. This structure however is not symmetry compatible with a second order phase transition into the stripe order phase, and, as we report here numerous Bragg peaks forbidden in the $Bmab$ space group are observed. We have studied and analysed these $Bmab$-forbidden Bragg reflections. Fitting of the diffraction intensities yields monoclinic lattice distortions that are symmetry consistent with charge stripe order.Comment: 7 pages, 3 figures, 5 Table

Targeting TGF-ß in the Central Nervous System: Assessment of Cynomolgus Monkey—Toxicity and Pharmacokinetics for an LNA-Antisense Oligonucleotide

Increasingly antisense oligonucleotides (ASOs) are developed for potential treatment of CNS disorders, and due to the inability to cross the blood brain barrier, they require direct administration into the cerebrospinal fluid (CSF). In this regard, intrathecal (i.th.) administration in cynomolgus monkeys (Macaca fascicularis) is a well-established approach for preclinical safety studies. Here, we present an innovative preclinical approach that is intended to support rapid entry into clinical development with ASOs targeting the CNS. The preclinical approach comprises one non-GLP study in 26 non-human primates, followed by a pivotal GLP repeated dose toxicity study in the same species. No pivotal rodent studies were conducted, and regulatory guidance to initiate this study was met by in vitro work. The non-GLP study consists of three separate phases: Phase A determines toxicity after i.th. administrations with five escalating dose levels in a single male and female animal, respectively. Dosing is conducted on days 1, 8, 15, 22, and 29 and the experiment is terminated 36 days after start of the study. The second phase (Phase B) investigates pharmacokinetics over a 2- or 4-week period at two dose levels following single administrations in eight (8) animals (4 females, 4 males). Finally, a third phase (Phase C) investigates toxicity and pharmacokinetics after repeated (9×) dosing over a 13-week period at two dose levels in sixteen (8 females, 8 males) animals. In each phase, clinical observations and physical/neurological parameters are investigated directly pre-dose, 4 h and 24 h post-dose, respectively. In all phases, CSF and blood samples are taken pre-dose and after each dosing, for determination of test article concentration, biomarkers of tolerability and biomarkers of pharmacology. In all phases, tissue samples from the liver, kidney, spinal cord, and brain are collected for determination of NVP-13 tissue concentrations. The above concept has successfully supported first-in-human clinical trials. The entire non-GLP program is completed within less than six months and requires fewer animals in comparison to the conduct of three independent studies

Safe and Effective Cynomolgus Monkey GLP—Tox Study with Repetitive Intrathecal Application of a TGFBR2 Targeting LNA-Gapmer Antisense Oligonucleotide as Treatment Candidate for Neurodegenerative Disorders

The capability of the adult central nervous system to self-repair/regenerate was demonstrated repeatedly throughout the last decades but remains in debate. Reduced neurogenic niche activity paralleled by a profound neuronal loss represents fundamental hallmarks in the disease course of neurodegenerative disorders. We and others have demonstrated the endogenous TGFβ system to represent a potential pathogenic participant in disease progression, of amyotrophic lateral sclerosis (ALS) in particular, by generating and promoting a disequilibrium of neurodegenerative and neuroregenerative processes. The novel human/primate specific LNA Gapmer Antisense Oligonucleotide “NVP-13”, targeting TGFBR2, effectively reduced its expression and lowered TGFβ signal transduction in vitro and in vivo, paralleled by boosting neurogenic niche activity in human neuronal progenitor cells and nonhuman primate central nervous system. Here, we investigated NVP-13 in vivo pharmacology, safety, and tolerability following repeated intrathecal injections in nonhuman primate cynomolgus monkeys for 13 weeks in a GLP-toxicology study approach. NVP-13 was administered intrathecally with 1, 2, or 4 mg NVP-13/animal within 3 months on days 1, 15, 29, 43, 57, 71, and 85 in the initial 13 weeks. We were able to demonstrate an excellent local and systemic tolerability, and no adverse events in physiological, hematological, clinical chemistry, and microscopic findings in female and male Cynomolgus Monkeys. Under the conditions of this study, the no observed adverse effect level (NOAEL) is at least 4 mg/animal NVP-13

Transcytosis of Listeria monocytogenes across the intestinal barrier upon specific targeting of goblet cell accessible E-cadherin

Listeria monocytogenes targets accessible E-cadherin expressed on mucus-producing goblet cells to invade the intestinal tissue

Novel Association Strategy with Copy Number Variation for Identifying New Risk Loci of Human Diseases

Copy number variations (CNV) are important causal genetic variations for human disease; however, the lack of a statistical model has impeded the systematic testing of CNVs associated with disease in large-scale cohort.Here, we developed a novel integrated strategy to test CNV-association in genome-wide case-control studies. We converted the single-nucleotide polymorphism (SNP) signal to copy number states using a well-trained hidden Markov model. We mapped the susceptible CNV-loci through SNP site-specific testing to cope with the physiological complexity of CNVs. We also ensured the credibility of the associated CNVs through further window-based CNV-pattern clustering. Genome-wide data with seven diseases were used to test our strategy and, in total, we identified 36 new susceptible loci that are associated with CNVs for the seven diseases: 5 with bipolar disorder, 4 with coronary artery disease, 1 with Crohn's disease, 7 with hypertension, 9 with rheumatoid arthritis, 7 with type 1 diabetes and 3 with type 2 diabetes. Fifteen of these identified loci were validated through genotype-association and physiological function from previous studies, which provide further confidence for our results. Notably, the genes associated with bipolar disorder converged in the phosphoinositide/calcium signaling, a well-known affected pathway in bipolar disorder, which further supports that CNVs have impact on bipolar disorder.Our results demonstrated the effectiveness and robustness of our CNV-association analysis and provided an alternative avenue for discovering new associated loci of human diseases