University Children's Hospital Zurich

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    Long non-coding RNA H19X as a regulator of mononuclear cell adhesion to the endothelium in systemic sclerosis

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    OBJECTIVE To define the functional relevance of H19 X-linked co-expressed lncRNA (H19X) in endothelial cell (EC) activation as a key process in systemic sclerosis (SSc) vasculopathy. METHODS H19X expression in SSc skin biopsies was analyzed from single cell RNA sequencing (scRNA-seq) data. Differential expression and pathway enrichment analysis between cells expressing (H19Xpos) and non expressing H19X (H19Xneg) cells was performed. H19X function was investigated in human dermal microvascular EC (HDMECs) by silencing. H19X and EC adhesion molecules levels were analyzed by RT-qPCR and Western Blot after stimulation with proinflammatory cytokines. Cytoskeletal rearrangements were analyzed by fluorescent staining. Endothelial adhesion was evaluated by co-culture of HDMECs and fluorescent labelled peripheral blood mononuclear cells (PBMCs). Shedding VCAM1 was evaluated by ELISA on HDMEC supernatant. RESULTS scRNA-seq showed significant upregulation of H19X in SSc compared with healthy EC. In HDMEC, H19X was consistently induced by type I and II interferons. H19X knockdown lead to a significant decrease of the mRNA of several adhesion molecules. Particularly, vascular cell adhesion protein 1 (VCAM1) was significantly reduced at protein and mRNA levels. Co-expression analysis of the scRNA-seq data confirmed a higher expression of VCAM1 in (H19Xpos) EC. EC were also strongly associated with the 'cell adhesion molecule' pathway. Moreover, VCAM1 downstream pathway displayed less activation following H19X knockdown. Contractility of HDMEC, PBMC adhesion to HDMEC and VCAM1 shedding were also reduced following H19X knockdown. CONCLUSIONS lncRNA H19X may contribute to EC activation in SSc vasculopathy, acting as a regulator of expression of adhesion molecules in EC

    A multilingual gold standard for translation spotting of German compounds and their corresponding multiword units in English, French, Italian and Spanish

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    This article describes a new word alignment gold standard for German nominal compounds and their multiword translation equivalents in English, French, Italian, and Spanish. The gold standard contains alignments for each of the ten language pairs, resulting in a total of 8,229 bidirectional alignments. It covers 362 occurrences of 137 different German compounds randomly selected from the corpus of European Parliament plenary sessions, sampled according to the criteria of frequency and morphological complexity. The standard serves for the evaluation and optimisation of automatic word alignments in the context of spotting translations of German compounds. The study also shows that in this text genre, around 80% of German noun types are morphological compounds indicating potential multiword units in their parallel equivalents

    Effect of Omega-3 Polyunsaturated Fatty Acid Supplementation on Lipid Mediator Profiles

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    Lipid mediators are bioactive lipids, produced from polyunsaturated fatty acids (PUFAs), that are important regulators of inflammation. Inflammatory lipid mediators such as leukotriene B4 (LTB4) and 2-series prostanoids aid in the recruitment of leukocytes and are produced from the n-6 PUFA, arachidonic acid (AA). Conversely, the resolution of inflammation is coordinated by a group of lipid mediators termed “specialized pro-resolving mediators” (SPMs) which include lipoxins (LX) produced from AA, as well as n-3 PUFA-derived resolvins (D-series (RvD) or E-series), maresins (MaR), and protectins (PD). Increased intake of n-3 PUFAs is associated with many health benefits, and replacement of the n-6 PUFA rich soybean oil typically used in total parenteral nutrition (TPN) with an n-3 PUFA rich oil is known to prevent TPN-associated liver disease. The benefits of n-3 PUFAs are assumed to come primarily from the increased production of SPMs. Therefore, measurements of lipid mediators provide valuable insight into the inflammatory conditions in a given system

    De novo variants in ATXN7L3 lead to developmental delay, hypotonia and distinctive facial features

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    Deubiquitination is critical for the proper functioning of numerous biological pathways such as DNA repair, cell cycle progression, transcription, signal transduction, and autophagy. Accordingly, pathogenic variants in deubiquitinating enzymes (DUBs) have been implicated in neurodevelopmental disorders (ND) and congenital abnormalities. ATXN7L3 is a component of the DUB module of the SAGA complex, and two other related DUB modules, and serves as an obligate adaptor protein of 3 ubiquitin-specific proteases (USP22, USP27X or USP51). Through exome sequencing and GeneMatching, we identified nine individuals with heterozygous variants in ATXN7L3. The core phenotype included global motor and language developmental delay, hypotonia, and distinctive facial characteristics including hypertelorism, epicanthal folds, blepharoptosis, a small nose and mouth, and low-set posteriorly rotated ears. In order to assess pathogenicity, we investigated the effects of a recurrent nonsense variant [c.340C>T; p.(Arg114Ter)] in fibroblasts of an affected individual. ATXN7L3 protein levels were reduced, and deubiquitylation was impaired, as indicated by an increase in histone H2Bub1 levels. This is consistent with the previous observation of increased H2Bub1 levels in Atxn7l3-null mouse embryos, which have developmental delay and embryonic lethality. In conclusion, we present clinical information and biochemical characterization supporting ATXN7L3 variants in the pathogenesis of a rare syndromic ND

    Developmental anatomy of the thalamus, perinatal lesions, and neurological development

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    The thalamic nuclei develop before a viable preterm age. GABAergic neuronal migration is especially active in the third trimester. Thalamic axons meet cortical axons during subplate activation and create the definitive cortical plate in the second and third trimesters. Default higher-order cortical driver connections to the thalamus are then replaced by the maturing sensory networks, in a process that is driven by first-order thalamic neurons. Surface electroencephalographic activity, generated first in the subplate and later in the cortical plate, gradually show oscillations based on the interaction of the cortex with thalamus, which is controlled by the thalamic reticular nucleus. In viable newborn infants, in addition to sensorimotor networks, the thalamus already contributes to visual, auditory, and pain processing, and to arousal and sleep. Isolated thalamic lesions may present as clinical seizures. In addition to asphyxia and stroke, infection and network injury are also common. Cranial ultrasound can be used to classify neonatal thalamic injuries based on functional parcelling of the mature thalamus. We provide ample illustration and a detailed description of the impact of neonatal focal thalamic injury on neurological development, and discuss the potential for neuroprotection based on thalamocortical plasticity

    Competing States in the Unconventional Superconductor La2x_{2-x}Srx_xCuO4_4

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    In strongly correlated systems, phases and states are often highly intertwined. New insights can be gained by influencing the interplay of the phenomena, for example, by temperature, magnetic field, or strain. Benefiting from all three tuning knobs, we contributed to the research on the intriguing phase diagram of (La-based) cuprates. The experiments were mostly carried out at x-ray diffraction and angle-resolved photoemission endstations of state-of-the-art synchrotrons. The first pair of interacting states examined was the superconducting gap and the pseudogap. In a high-resolution angle-resolved photoemission spectroscopy study, we extract the evolution of the antinodal gap as a function of temperature. The gap increases below the pseudogap onset. From the linear decrease with temperature below the superconducting transition at TCT_C we deduce, that the two orders are competing. Lowering the temperature, integrated spectral weight reduces in the pseudogap state, but starts to regain already before the onset of superconductivity. Thus, superconductivity and the pseudogap interact with a third energy scale, possibly linked to charge order. Charge order upon application of compressive pressure in La2x_{2-x}Srx_xCuO4_4 (LSCO) x0.12x\approx0.12 was investigated by diffraction for the greater part of the here presented work. Stripe order in LSCO manifests in the (h,0,)(h, 0, \ell) and (0,k,)(0, k, \ell) planes, where h,k,h, k, \ell are the Miller indices. If pressure is applied along the Cu-O direction, stripe order peaks enhance by a factor of two in the direction perpendicular to the strain. They are suppressed to the background in the direction along the strain. Uniaxial pressure along the Cu-O direction lifts the domain degeneracy of both spin and charge order domains. This on one hand determines the fundamental symmetry of charge and spin order to be uniaxial stripes instead of a checkerboard structure. On the other hand, it confirms that the two orders in LSCO are strongly intertwined. By comparing experimentally measured and simulated diffraction patterns, we showed, that the space group of LSCO in the charge ordered state is not orthorhombic as the average crystal structure, but monoclinic. In another hard x-ray diffraction study, we applied pressure along the cc-axis of LSCO x0.12x\approx0.12. Within the superconducting phase, the charge order amplitude raises with strain, while it is not affected in the normal state. Adding a magnetic field along the cc-axis to the system, we initially, without pressure, reproduce the well-known augmentation of charge order below TCT_C as superconductivity is weakened. Charge order in LSCO with strain along the cc-axis and fields up to 10\,T is still boosted within the superconducting phase. However, the increase is lower than if there was solely the magnetic field. The magnetic field does not have an effect in the normal state. Our observations point towards uniaxial cc-axis strain in LSCO coupling directly to the competing interaction of superconductivity and charge order

    A Perspective on the MARS2 Trial

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    INTRODUCTION The phase 3 randomized controlled trial of extended pleurectomy decortication and chemotherapy versus chemotherapy alone for pleural mesothelioma (PM) (MARS2) reported "extended pleurectomy decortication was associated with worse survival to 2 years, and more serious adverse events for individuals with resectable PM, compared with chemotherapy alone." These results have led to considerable discourse regarding the future role of surgery for PM, and there has not been unanimity in the mesothelioma surgical community regarding the trial interpretation. This "perspective" evaluates MARS2 using internationally renowned PM experts who either agreed with the trial interpretation or who found issues with its conduct which may have influenced the results. METHODS A facilitator (HP) worked with team leaders (GW, IO) to assemble individuals offering opinions regarding the trial and its conclusions. Arguments agreeing or not agreeing with the trial interpretation were written only after publication of the full trial. Once both arguments were received by the facilitator, the individual team manuscripts were combined and sent to each team allowing editing for changes in perceived factual errors. FINDINGS Insightful arguments include (but were not limited to) the difficulties yet advantages of randomization, quality assurance, selection of histologic subtypes, the timing of randomization, use of preoperative staging, statistical methods, and reasons for surgical mortality. CONCLUSIONS The decision to operate for PM in the future will continue to be defined by consensus guidelines and health payer willingness, and the interpretation of MARS2 may play an important role in modulating the role of surgery in the future

    Effects of Biologics on Temporomandibular Joint Inflammation in Juvenile Idiopathic Arthritis

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    OBJECTIVE This prospective study investigates the efficacy of biologics in combination with methotrexate or leflunomide on juvenile idiopathic arthritis (JIA)- related temporomandibular joint (TMJ) arthritis measured by magnetic resonance imaging (MRI)-based inflammation score and deformity score. METHODS A prospective single center observational cohort study of 18 consecutive patients were performed between September 2018- April 2023. Inclusion criteria were: 1) Diagnosis of JIA, 2) MRI-verified TMJ arthritis leading to treatment with tumor necrosis factor inhibitor (TNFi), 3) MRI at 6 and 24 months after treatment initiation, 4) clinical follow-up contemporary with the MRI by a pediatric rheumatologist and an orthodontist. RESULTS We included 18 patients (89% females). At time of first MRI median age was 13.2 years (IQR 11.3-16.9), median disease duration was 7.8 years (IQR 3.4-11.1) and 4 received MTX/leflunomide. During the observation period, significant improvements were observed in TMJ movement pain (p=0.01), morning stiffness (p=0.004), opening capacity (p=0.03) and maximal incisal opening (p=0.006). The inflammation score decreased significantly from median 2 (IQR 1-3) at baseline to median 1(IQR 0-2) at 24 months, p=0.009. In 17 out of 36 TMJs (48%), the deformity score improved or remained stable and no significant increase in the median score was observed. CONCLUSION This is the first prospective observational study with evidence to support that the orofacial signs, symptoms and MRI-derived inflammation score in TMJ arthritis can be reduced by treatment with TNFi

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