RA-specific expression profiles and new candidate genes

Objective: To identify rheumatoid arthritis- (RA)-specific profiles of differentially expressed genes. Methods: Synovial tissues from RA and osteoarthritis (OA) patients and from normal joints were selected according to their disease-characteristic histology. Gene expression was analyzed using DNA microarrays (GeneChip; Unigene-array) and representational difference analysis (RDA). Data were validated on larger cohorts of patients by RT-PCR. Results: Nine hundred and eighty genes were significantly regulated in RA synovial tissue as compared with non-RA. Specialized cluster analysis identified a set of 312 genes as sufficient of unequivocally discriminating RA from non-RA patterns (class discovery). Genes of highest regulation were associated with leukocyte activation (chemokines, chemokine receptors, B- and T-cell genes), endothelial and angiogenic activation, tissue destruction and remodelling [MMP-3, BMP-4, TIMPs]. Interestingly, a large set of genes was down-regulated in RA (TGF-β superfamily, apoptosis-related genes, transcription factors). Osteopontin-like genes (n=46) — up-regulated in RA — and glutathione peroxidase-3-like genes (n=85) — down-regulated in RA — yielded the highest correlation coefficients (>0.94). Megakaryocyte stimulating factor (MSF), down-regulated in a subset of RA, may hold the key to subclassification: a loss-of-function mutation in the MSF-encoding gene leads to synovial hyperplasia in camptodactyly–arthropathy–coxa vara–pericarditis syndrome, and, as in RA, also to pericardial involvement. A further candidate, vitamin-D3-up-regulated protein-1 (VDUP-1), is regulated like MSF and predisposes to premature coronary artery disease when mutated, again a feature of a subset of RA. Conclusion: RA specific gene profiles were identified and are useful to improve diagnostics of the disease. Novel gene candidates not yet in the focus of RA pathogenesis have been identified that are likely to further the understanding of RA

Identification of Y-Box Binding Protein 1 As a Core Regulator of MEK/ERK Pathway-Dependent Gene Signatures in Colorectal Cancer Cells

Transcriptional signatures are an indispensible source of correlative information on disease-related molecular alterations on a genome-wide level. Numerous candidate genes involved in disease and in factors of predictive, as well as of prognostic, value have been deduced from such molecular portraits, e.g. in cancer. However, mechanistic insights into the regulatory principles governing global transcriptional changes are lagging behind extensive compilations of deregulated genes. To identify regulators of transcriptome alterations, we used an integrated approach combining transcriptional profiling of colorectal cancer cell lines treated with inhibitors targeting the receptor tyrosine kinase (RTK)/RAS/mitogen-activated protein kinase pathway, computational prediction of regulatory elements in promoters of co-regulated genes, chromatin-based and functional cellular assays. We identified commonly co-regulated, proliferation-associated target genes that respond to the MAPK pathway. We recognized E2F and NFY transcription factor binding sites as prevalent motifs in those pathway-responsive genes and confirmed the predicted regulatory role of Y-box binding protein 1 (YBX1) by reporter gene, gel shift, and chromatin immunoprecipitation assays. We also validated the MAPK-dependent gene signature in colorectal cancers and provided evidence for the association of YBX1 with poor prognosis in colorectal cancer patients. This suggests that MEK/ERK-dependent, YBX1-regulated target genes are involved in executing malignant properties

The German National Pandemic Cohort Network (NAPKON): rationale, study design and baseline characteristics

Schons M, Pilgram L, Reese J-P, et al. The German National Pandemic Cohort Network (NAPKON): rationale, study design and baseline characteristics. European Journal of Epidemiology . 2022.The German government initiated the Network University Medicine (NUM) in early 2020 to improve national research activities on the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic. To this end, 36 German Academic Medical Centers started to collaborate on 13 projects, with the largest being the National Pandemic Cohort Network (NAPKON). The NAPKON's goal is creating the most comprehensive Coronavirus Disease 2019 (COVID-19) cohort in Germany. Within NAPKON, adult and pediatric patients are observed in three complementary cohort platforms (Cross-Sectoral, High-Resolution and Population-Based) from the initial infection until up to three years of follow-up. Study procedures comprise comprehensive clinical and imaging diagnostics, quality-of-life assessment, patient-reported outcomes and biosampling. The three cohort platforms build on four infrastructure core units (Interaction, Biosampling, Epidemiology, and Integration) and collaborations with NUM projects. Key components of the data capture, regulatory, and data privacy are based on the German Centre for Cardiovascular Research. By April 01, 2022, 34 university and 40 non-university hospitals have enrolled 5298 patients with local data quality reviews performed on 4727 (89%). 47% were female, the median age was 52 (IQR 36-62-) and 50 pediatric cases were included. 44% of patients were hospitalized, 15% admitted to an intensive care unit, and 12% of patients deceased while enrolled. 8845 visits with biosampling in 4349 patients were conducted by April 03, 2022. In this overview article, we summarize NAPKON's design, relevant milestones including first study population characteristics, and outline the potential of NAPKON for German and international research activities.Trial registration https://clinicaltrials.gov/ct2/show/NCT04768998 . https://clinicaltrials.gov/ct2/show/NCT04747366 . https://clinicaltrials.gov/ct2/show/NCT04679584. © 2022. The Author(s)

Perinatal asphyxia: current status and approaches towards neuroprotective strategies, with focus on sentinel proteins

Delivery is a stressful and risky event menacing the newborn. The mother-dependent respiration has to be replaced by autonomous pulmonary breathing immediately after delivery. If delayed, it may lead to deficient oxygen supply compromising survival and development of the central nervous system. Lack of oxygen availability gives rise to depletion of NAD+ tissue stores, decrease of ATP formation, weakening of the electron transport pump and anaerobic metabolism and acidosis, leading necessarily to death if oxygenation is not promptly re-established. Re-oxygenation triggers a cascade of compensatory biochemical events to restore function, which may be accompanied by improper homeostasis and oxidative stress. Consequences may be incomplete recovery, or excess reactions that worsen the biological outcome by disturbed metabolism and/or imbalance produced by over-expression of alternative metabolic pathways. Perinatal asphyxia has been associated with severe neurological and psychiatric sequelae with delayed clinical onset. No specific treatments have yet been established. In the clinical setting, after resuscitation of an infant with birth asphyxia, the emphasis is on supportive therapy. Several interventions have been proposed to attenuate secondary neuronal injuries elicited by asphyxia, including hypothermia. Although promising, the clinical efficacy of hypothermia has not been fully demonstrated. It is evident that new approaches are warranted. The purpose of this review is to discuss the concept of sentinel proteins as targets for neuroprotection. Several sentinel proteins have been described to protect the integrity of the genome (e.g. PARP-1; XRCC1; DNA ligase IIIα; DNA polymerase β, ERCC2, DNA-dependent protein kinases). They act by eliciting metabolic cascades leading to (i) activation of cell survival and neurotrophic pathways; (ii) early and delayed programmed cell death, and (iii) promotion of cell proliferation, differentiation, neuritogenesis and synaptogenesis. It is proposed that sentinel proteins can be used as markers for characterising long-term effects of perinatal asphyxia, and as targets for novel therapeutic development and innovative strategies for neonatal care

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Reducing DMU fuel consumption by means of hybrid energy storage

Purpose: This paper discusses a hybrid energy storage concept and its control strategy for hydro-mechanical DMUs. The hybrid energy storage consists of double layer capacitors and batteries. The new concept aims on reducing fuel consumption and avoiding unhealthy emissions during idling in station area. Methods: Development of a hybrid propulsion concept and control strategy requires adequate methods for modeling system behavior. The simulation environment Dymola is used to develop and evaluate the control strategy and for dimensioning the system components. Results: Simulations indicated fuel savings of up to 13% depending on track characteristics. Measurements of a scaled storage system in a HiL-environment showed good accordance of the simulated and measured behavior of battery and double layer capacitor. Conclusions: The newly developed storage system and its control strategy enable reduction of fuel consumption and unhealthy emissions in station areas

Transient simulation of moving ion clouds in time-of-flight ion mobility spectrometers operating with DC and AC fields

Ion mobility spectrometers can be divided by their principle of ion separation. For example, classical drift tube time-of-flight Ion Mobility Spectrometers (IMS) separate ions by the absolute value of their low field ion mobility; Field Asymmetric Ion Mobility Spectrometers (FAIMS) separate ions by the field dependence of their ion mobility. However, the low field mobilities and the field dependence of the mobility vary only within a limited range for different ions, leading to a limited peak capacity of stand-alone drift tube IMS and FAIMS. Combining both types leads to orthogonal data and thus enhances the selectivity in comparison with stand-alone devices. In this work, a new approach of enhancing the separation power of a classical drift tube IMS by integrating a field asymmetric waveform ion separation region in longitudinal direction into the drift tube is discussed. This additional separation region is realized by superimposing the constant drift field of a drift tube IMS with an asymmetric parallel AC field using two additional grids inside the drift tube. Since the ions are exposed alternately to high field and low field strengths on their way through the additional separation region, the resulting drift time is affected. Hence, two ion species having the same low-field mobility, but showing a different field dependence of the mobility have different drift times in the enhanced IMS. In order to analyze the ion movement inside such a modified ion mobility spectrometer, the finite element method (FEM) software Comsol Multiphysics is used. Therefore, an existing drift tube IMS model which perfectly agrees with experimental results and considers field inhomogenieties, diffusion, Coulomb repulsion and ion losses at metallic surfaces, is expanded in order to simulate the ion movement in AC fields. This enhanced model provides visualization of the location and shape of the ion cloud during DC/AC operation. Particular attention is given to the increased broadening of the ion cloud due to field inhomogenieties in the additional AC field. Furthermore, ion losses inside the drift tube caused by the AC field and the additional grids are considered. In this work, simulations are used to theoretically investigate our new separation approach to give a first impression of the possible analytical performance. The final publication is available at Springer via https://doi.org/10.1007/s12127-015-0179-7