Refine
Year of publication
Document Type
- Article (203)
- Preprint (38)
- Contribution to a Periodical (4)
Has Fulltext
- yes (245)
Is part of the Bibliography
- no (245)
Keywords
- SARS-CoV-2 (10)
- COVID-19 (5)
- Solution NMR-spectroscopy (4)
- COVID19-NMR (3)
- Covid19-NMR (3)
- Non-structural protein (3)
- risk factors (3)
- ACLF (2)
- Biomarkers (2)
- Collectivity (2)
- Correlation (2)
- Diffraction (2)
- Elastic scattering (2)
- Immunology (2)
- Mitochondria (2)
- Non-small cell lung cancer (2)
- Portal hypertension (2)
- Protein drugability (2)
- Shear viscosity (2)
- Solution NMR spectroscopy (2)
- acute myeloid leukemia (2)
- acute-on-chronic liver failure (2)
- aging (2)
- cirrhosis (2)
- inflammation (2)
- portal hypertension (2)
- (Hydroxymethyl)diphenyl(piperidinoalkyl)silanes (1)
- 32D progenitor cells (1)
- 3years (1)
- 5'-UTR (1)
- 5_SL4 (1)
- 5′-UTR (1)
- ABCB1 (1)
- ABCC1 (1)
- ADGRE1 (1)
- ALK-rearranged NSCLC (1)
- AML (1)
- Acute Myeloid Leukemia (AML) (1)
- Acute kidney injury (1)
- Advanced stage (1)
- Alpha-synuclein (1)
- Alternative oxidase (1)
- American crocodile (1)
- Angiogenesis (1)
- Angiography (1)
- Ankylosierende Spondylitis (1)
- Ankylosing spondylitis (1)
- Artificial Intelligence (1)
- Atmospheric chemistry (1)
- Axial spondyloarthritis (1)
- Axiale Spondyloarthritis (1)
- B-slope (1)
- BCOR (1)
- BCORL1 (1)
- BI1361849 (1)
- BRVO (1)
- Biodiversity Data (1)
- Biomonitoring (1)
- Blood (1)
- Blood loss (1)
- Blood plasma (1)
- Botanical Collections (1)
- Brain tumor (1)
- CAKUT (1)
- CBA (1)
- CLIF-C ACLF score (1)
- CLIF-C ACLF-R score (1)
- COPD (1)
- COVID (1)
- CV9202 (1)
- CVD biomarker (1)
- Cancer (1)
- Cardiology (1)
- Care gaps (1)
- Charged-particle multiplicity (1)
- Charm quark spatial diffusion coefficient (1)
- Cirrhosis (1)
- Climate sciences (1)
- Climate-change impacts (1)
- Clinical trial (1)
- Coalescence (1)
- Cohort studies (1)
- Cold nuclear matter effects (1)
- Colloids (1)
- Complex II (1)
- Complicated stage (1)
- Conservation (1)
- Critical point (1)
- Crocodylus acutus (1)
- Cryptic species (1)
- DME (1)
- Data sharing (1)
- Deuteron production (1)
- Devic disease (1)
- Devic syndrome (1)
- Di-hadron correlations (1)
- Diabetes (1)
- Digitization (1)
- Dimerization domain (1)
- Drug resistance (1)
- Drug targets (1)
- EMR1 (1)
- EWSR1 (1)
- Elliptic flow (1)
- Emphysema (1)
- Everolimus (1)
- Extended donor criteria (1)
- F4/80 (1)
- FOXO3a (1)
- G3BP (1)
- Gene fusion (1)
- Genetic testing (1)
- Genetics (1)
- Germany (1)
- Graft function (1)
- Graft survival (1)
- Groomed jet radius (1)
- HES (1)
- Hadronization (1)
- Haematocrit (1)
- Hashimoto’s thyroiditis (1)
- Health care (1)
- Health information (1)
- Health-seeking behaviour (1)
- Heat shock protein 27 (1)
- Heavy Ion Experiments (1)
- Heavy Quark Production (1)
- Heavy ion collisions (1)
- Heavy-Ion Collision (1)
- Heavy-flavor decay electron (1)
- Heavy-ion collisions (1)
- Helpline (1)
- Herbaria (1)
- Higher moments (1)
- Hydroxyethyl starch (1)
- Hypofractionated radiotherapy (1)
- IL-6 (1)
- ILUVIEN (1)
- Immunogenetics (1)
- Immunomonitoring (1)
- Interference fragmentation function (1)
- J/ψ suppression (1)
- JAK2V617F (1)
- Jet substructure (1)
- K3EDTA plasma sampling (1)
- Kidney transplantation (1)
- LEOSS (1)
- Lipidomics (1)
- Liver cirrhosis (1)
- Liver transplantation (1)
- Ltbp4 (1)
- MCP (1)
- MN1 (1)
- MR-proADM (1)
- Machine learning (1)
- Macrodomain (1)
- Marginal grafts (1)
- Mean erythrocyte volume (1)
- Medication Appropriateness Index (1)
- Metabolic models (1)
- Metabolic vulnerabilities (1)
- Metabolomics (1)
- Mitochondrial disease (1)
- Molecular diagnostic testing (1)
- Molecular medicine (1)
- Mortality (1)
- Multiple parton interactions (1)
- Muscarinic Antagonists (1)
- Muscarinic Receptors (1)
- NAFL (1)
- NAFLD (1)
- NASH (1)
- NMO-IgG (1)
- NMR spectroscopy (1)
- Nephrons (1)
- Net-charge correlations (1)
- Net-charge fluctuations (1)
- Neuroepithelial (1)
- Neuromyelitis optica (1)
- Neurooncology (1)
- Nrf2 (1)
- Nucleic acid-binding domain (1)
- Nucleocapsid (1)
- Number of platelets (1)
- Ocean sciences (1)
- Oncology (1)
- Organ rinse (1)
- Organ shortage (1)
- Oxidative phosphorylation (1)
- PATZ1 (1)
- PTDM (1)
- Palaeoceanography (1)
- Palaeoclimate (1)
- Parkinson’s disease (1)
- Pdgfrβ (1)
- Pediatric (1)
- Periodontitis grades B and C (1)
- Phylogeny (1)
- Polo-like kinase 3 (1)
- Portal veins (1)
- Post-transplant (1)
- Pre-analytics (1)
- Predictive model (1)
- Primary prophylaxis (1)
- Protein druggability (1)
- Proteins (1)
- Proton-proton collisions (1)
- Proton–proton collisions (1)
- Psychiatric disorders (1)
- Quality of care (1)
- Quality standards (1)
- Qualitätsstandards (1)
- Quarkonium (1)
- RHIC (1)
- RNA genome (1)
- ROS (1)
- Radical nephrectomy (1)
- Rare diseases (1)
- Registries (1)
- Renal cancer (1)
- Renal system (1)
- Research Infrastructure (1)
- Respiratory chain (1)
- Retro-IDEAL (1)
- Rho GTPases (1)
- SD-OCT (1)
- SL1 (1)
- SLC20A1 (1)
- SOFA (1)
- SPSS (1)
- STK3 (1)
- Sampling protocol (1)
- Semantics (1)
- Sepsis (1)
- Septic shock (1)
- Sila-difenidol (1)
- Sila-pridinol (1)
- SoftDrop (1)
- Splitting function (1)
- Spontaneous bacterial peritonitis (1)
- Steroid (1)
- Structural protein (1)
- Surgical and invasive medical procedures (1)
- Surgical oncology (1)
- Survival analysis (1)
- TGR(mREN2)27 (1)
- TOR inhibitor (1)
- TP53 mutation status (1)
- Tacrolimus (1)
- Taxonomy (1)
- Telemedicine (1)
- Tgfβ (1)
- Thermal model (1)
- Transversity (1)
- Trauma (1)
- UCN-01 (1)
- VEGF (1)
- Versorgungslücken (1)
- Versorgungsqualität (1)
- Volume therapy (1)
- Western diet (1)
- White blood cells (1)
- YM155 (1)
- accessory proteins (1)
- accident (1)
- acute decompensation (1)
- acute-on-chronic liver failure (ACLF) (1)
- adhesion (1)
- advanced care planning (1)
- aftercare structures (1)
- ambulatory assessment (1)
- anal carcinoma (1)
- anticonvulsants (1)
- aquaporin-4 (AQP4) antibody (1)
- bioactivity testing (1)
- bladder exstrophy-epispadias complex (1)
- bleeding (1)
- cancer (1)
- caspase-8 (1)
- cell-free expression (1)
- cell-free protein synthesis (1)
- cerebrospinal fluid (1)
- chemoradiotherapy (1)
- chronic kidney disease (1)
- chronic myeloid leukemia (1)
- clinical features (1)
- cloacal malformation (1)
- comorbidities (1)
- computed tomography (1)
- computer-assisted drug therapy (1)
- consensus (1)
- context (1)
- critically ill patients (1)
- cytarabine dose (1)
- day clinic (1)
- decompensated liver cirrhosis (1)
- differentiated thyroid carcinoma (1)
- drug resistance (1)
- dysbiosis (1)
- easyPACId (1)
- ectosomes (1)
- elderly (1)
- epidemiology (1)
- epilepsy (1)
- epileptic encephalopathies (1)
- essential thrombocythemia (ET) (1)
- exosomes (1)
- experience sampling (1)
- extracellular vesicles (1)
- functional genetics (1)
- global change (1)
- glycobiology (1)
- glycoconjugate (1)
- guidelines (1)
- habitat destruction (1)
- health information exchange (1)
- hepatic encephalopathy (1)
- homing (1)
- hospital admission (1)
- immunity (1)
- infectious disease (1)
- injury (1)
- intrinsically disordered region (1)
- kidney formation (1)
- land use (1)
- lasso regression (1)
- lethal toxin (1)
- levetiracetam (1)
- liver (1)
- liver fibrosis (1)
- liver transplantation (1)
- liver transplantation center (1)
- local control (1)
- lockdown (1)
- long-term outcome (1)
- longitudinally extensive transverse myelitis (1)
- loss-of-function (1)
- mRNA active cancer immunotherapy (1)
- macrophage (1)
- magnetic resonance imaging (1)
- male (1)
- mechanical ventilation (1)
- medication reconciliation (1)
- metabolic reprogramming (1)
- metabolic syndromes (1)
- microbiome (1)
- microdosing (1)
- microparticles (1)
- microvesicles (1)
- migration (1)
- minimal information requirements (1)
- mitosis (1)
- molecular modeling (1)
- molecular switch (1)
- monocyte chemotactic protein 1 (MCP-1) (1)
- mortality (1)
- mtDNA (1)
- multimodal complex treatment (1)
- multimorbidity (1)
- multiple chronic conditions (1)
- myeloproliferative neoplasms (MPN) (1)
- nanodiscs (1)
- natural products (1)
- networks (1)
- neuroblastoma (1)
- neurodegeneration (1)
- neurological manifestations (1)
- neutralizing antibodies (1)
- nomogram (1)
- nonstructural proteins (1)
- p+p collisions (1)
- pediatric intensive care (1)
- peptide antibiotics (1)
- peri-implantitis (1)
- personalized medicine (1)
- phage lysis proteins (1)
- polycythemia vera (PV) (1)
- polypharmacy (1)
- portosystemic shunt (1)
- post-liver transplantation management (1)
- primary myelofibrosis (PMF) (1)
- proteobacteria (1)
- proteomics (1)
- pulmonary failure (1)
- qualitative research (1)
- quality control (1)
- rare diseases (1)
- real-life study (1)
- recurrent optic neuritis (1)
- renal dysfunction (1)
- reproducibility (1)
- respiratory failure (1)
- retrovirus (1)
- rigor (1)
- risk factor progression (1)
- risk stratification (1)
- seizure (1)
- sequential ALK-inhibitor therapy (1)
- sialic acid (1)
- simplified production (1)
- sirtuin1 (1)
- situation (1)
- spike protein (1)
- spontaneous portosystemic shunt (1)
- standardization (1)
- structural proteins (1)
- survival (1)
- survivin (1)
- thromboembolism (1)
- thrombosis (1)
- toxin B (1)
- transjugular intrahepatic portosystemic shunt (TIPS) (1)
- trauma (1)
- tyrosine kinase inhibitors. (1)
- urinary tract development (1)
- variants of concern (1)
- vitamin D (1)
- vitamin D receptor (1)
- vitreous samples (1)
- zebrafish development (1)
Institute
Since 2010, an intensified ambulatory cardiology care programme has been implemented in southern Germany. To improve patient management, the structure of cardiac disease management was improved, guideline-recommended care was supported, new ambulatory medical services and a morbidity-adapted reimbursement system were set up. Our aim was to determine the effects of this programme on the mortality and hospitalisation of enrolled patients with cardiac disorders. We conducted a comparative observational study in 2015 and 2016, based on insurance claims data. Overall, 13,404 enrolled patients with chronic heart failure (CHF) and 19,537 with coronary artery disease (CAD) were compared, respectively, to 8,776 and 16,696 patients that were receiving usual ambulatory cardiology care. Compared to the control group, patients enrolled in the programme had lower mortality (Hazard Ratio: 0.84; 95% CI: 0.77–0.91) and fewer all-cause hospitalisations (Rate Ratio: 0.94; 95% CI: 0.90–0.97). CHF-related hospitalisations in patients with CHF were also reduced (Rate Ratio: 0.76; 95% CI: 0.69–0.84). CAD patients showed a similar reduction in mortality rates (Hazard Ratio: 0.81; 95% CI: 0.76–0.88) and all-cause hospitalisation (Rate Ratio: 0.94; 95% CI: 0.91–0.97), but there was no effect on CAD-related hospitalisation. We conclude that intensified ambulatory care reduced mortality and hospitalisation in cardiology patients.
Following votes in the Coniacian Working Group, the Cretaceous Subcommission and the International Commission on Stratigraphy, on May 1st, 2021, the International Union of Geological Sciences voted unanimously to ratify the Global Stratotype Section and Point (GSSP) proposal for the base of the Coniacian Stage of the Upper Cretaceous Series and Cretaceous System. The lower boundary of the Coniacian Stage is placed at the base of Bed 46 of the Salzgitter-Salder section in northern Germany. The boundary is defined by the first appearance of the inoceramid bivalve species Cremnoceramus deformis erectus (Meek) and complemented by the Navigation carbon isotope event. Additional data include the bivalve genus Didymotis, foraminifera, ammonite, nannofossil and organic-walled dinoflagellate cyst events. Three auxiliary sections (Słupia Nadbrzeżna, central Poland; Střeleč, Czech Republic; El Rosario, NE Mexico) supplement the details of the boundary record in various facies, and in differing geographic and biogeographic contexts.
Background: Conversion from calcineurin inhibitor (CNI) therapy to a mammalian target of rapamycin (mTOR) inhibitor following kidney transplantation may help to preserve graft function. Data are sparse, however, concerning the impact of conversion on posttransplant diabetes mellitus (PTDM) or the progression of pre-existing diabetes.
Methods: PTDM and other diabetes-related parameters were assessed post hoc in two large open-label multicenter trials. Kidney transplant recipients were randomized (i) at month 4.5 to switch to everolimus or remain on a standard cyclosporine (CsA)-based regimen (ZEUS, n = 300), or (ii) at month 3 to switch to everolimus, remain on standard CNI therapy or convert to everolimus with reduced-exposure CsA (HERAKLES, n = 497).
Results: There were no significant differences in the incidence of PTDM between treatment groups (log rank p = 0.97 [ZEUS], p = 0.90 [HERAKLES]). The mean change in random blood glucose from randomization to month 12 was also similar between treatment groups in both trials for patients with or without PTDM, and with or without pre-existing diabetes. The change in eGFR from randomization to month 12 showed a benefit for everolimus versus comparator groups in all subpopulations, but only reached significance in larger subgroups (no PTDM or no pre-existing diabetes).
Conclusions: Within the restrictions of this post hoc analysis, including non-standardized diagnostic criteria and limited glycemia laboratory parameters, these data do not indicate any difference in the incidence or severity of PTDM with early conversion from a CsA-based regimen to everolimus, or in the progression of pre-existing diabetes.
Trial registration: clinicaltrials.gov, NCT00154310 (registered September 2005) and NCT00514514 (registered August 2007); EudraCT (2006-007021-32 and 2004-004346-40).
Non-alcoholic fatty liver disease (NAFLD) is gaining in importance and is linked to obesity. Especially,thedevelopmentoffibrosisandportalhypertensioninNAFLDpatientsrequirestreatment. Transgenic TGR(mREN2)27 rats overexpressing mouse renin spontaneously develop NAFLD with portal hypertension but without obesity. This study investigated the additional role of obesity in this model on the development of portal hypertension and fibrosis. Obesity was induced in twelve-week old TGR(mREN2)27 rats after receiving Western diet (WD) for two or four weeks. Liver fibrosis was assessed using standard techniques. Hepatic expression of transforming growth factor-β1 (TGF-β1), collagen type Iα1, α-smooth muscle actin, and the macrophage markers Emr1, as well as the chemoattractant Ccl2, interleukin-1β (IL1β) and tumor necrosis factor-α (TNFα) were analyzed. Assessment of portal and systemic hemodynamics was performed using the colored microsphere technique. Asexpected,WDinducedobesityandliverfibrosisasconfirmedbySiriusRedandOilRed O staining. The expression of the monocyte-macrophage markers, Emr1, Ccl2, IL1β and TNFα were increasedduringfeedingofWD,indicatinginfiltrationofmacrophagesintotheliver,eventhoughthis increase was statistically not significant for the EGF module-containing mucin-like receptor (Emr1) mRNA expression levels. Of note, portal pressure increased with the duration of WD compared to animals that received a normal chow. Besides obesity, WD feeding increased systemic vascular resistance reflecting systemic endothelial and splanchnic vascular dysfunction. We conclude that transgenic TGR(mREN2)27 rats are a suitable model to investigate NAFLD development with liver fibrosis and portal hypertension. Tendency towards elevated expression of Emr1 is associated with macrophage activity point to a significant role of macrophages in NAFLD pathogenesis, probably due to a shift of the renin–angiotensin system towards a higher activation of the classical pathway. The hepatic injury induced by WD in TGR(mREN2)27 rats is suitable to evaluate different stages of fibrosis and portal hypertension in NAFLD with obesity.
Background & Aims: Spontaneous portosystemic shunts (SPSS) frequently develop in liver cirrhosis. Recent data suggested that the presence of a single large SPSS is associated with complications, especially overt hepatic encephalopathy (oHE). However, the presence of >1 SPSS is common. This study evaluates the impact of total cross-sectional SPSS area (TSA) on outcomes in patients with liver cirrhosis.
Methods: In this retrospective international multicentric study, CT scans of 908 cirrhotic patients with SPSS were evaluated for TSA. Clinical and laboratory data were recorded. Each detected SPSS radius was measured and TSA calculated. One-year survival was the primary endpoint and acute decompensation (oHE, variceal bleeding, ascites) was the secondary endpoint.
Results: A total of 301 patients (169 male) were included in the training cohort. Thirty percent of all patients presented with >1 SPSS. A TSA cut-off of 83 mm2 was used to classify patients with small or large TSA (S-/L-TSA). Patients with L-TSA presented with higher model for end-stage liver disease score (11 vs. 14) and more commonly had a history of oHE (12% vs. 21%, p <0.05). During follow-up, patients with L-TSA experienced more oHE episodes (33% vs. 47%, p <0.05) and had lower 1-year survival than those with S-TSA (84% vs. 69%, p <0.001). Multivariate analysis identified L-TSA (hazard ratio 1.66; 95% CI 1.02–2.70, p <0.05) as an independent predictor of mortality. An independent multicentric validation cohort of 607 patients confirmed that patients with L-TSA had lower 1-year survival (77% vs. 64%, p <0.001) and more oHE development (35% vs. 49%, p <0.001) than those with S-TSA.
Conclusion: This study suggests that TSA >83 mm2 increases the risk for oHE and mortality in patients with cirrhosis. Our results support the clinical use of TSA/SPSS for risk stratification and decision-making in the management of patients with cirrhosis.
Lay summary: The prevalence of spontaneous portosystemic shunts (SPSS) is higher in patients with more advanced chronic liver disease. The presence of more than 1 SPSS is common in advanced chronic liver disease and is associated with the development of hepatic encephalopathy. This study shows that total cross-sectional SPSS area (rather than diameter of the single largest SPSS) predicts survival in patients with advanced chronic liver disease. Our results support the clinical use of total cross-sectional SPSS area for risk stratification and decision-making in the management of SPSS.
Broad AOX expression in a genetically tractable mouse model does not disturb normal physiology
(2017)
Plants and many lower organisms, but not mammals, express alternative oxidases (AOXs) that branch the mitochondrial respiratory chain, transferring electrons directly from ubiquinol to oxygen without proton pumping. Thus, they maintain electron flow under conditions when the classical respiratory chain is impaired, limiting excess production of oxygen radicals and supporting redox and metabolic homeostasis. AOX from Ciona intestinalis has been used to study and mitigate mitochondrial impairments in mammalian cell lines, Drosophila disease models and, most recently, in the mouse, where multiple lentivector-AOX transgenes conferred substantial expression in specific tissues. Here, we describe a genetically tractable mouse model in which Ciona AOX has been targeted to the Rosa26 locus for ubiquitous expression. The AOXRosa26 mouse exhibited only subtle phenotypic effects on respiratory complex formation, oxygen consumption or the global metabolome, and showed an essentially normal physiology. AOX conferred robust resistance to inhibitors of the respiratory chain in organello; moreover, animals exposed to a systemically applied LD50 dose of cyanide did not succumb. The AOXRosa26 mouse is a useful tool to investigate respiratory control mechanisms and to decipher mitochondrial disease aetiology in vivo.
An important question concerning inter-areal communication in the cortex is whether these interactions are synergistic, i.e. convey information beyond what can be performed by isolated signals. In other words, any two signals can either share common information (redundancy) or they can encode complementary information that is only available when both signals are considered together (synergy). Here, we dissociated cortical interactions sharing common information from those encoding complementary information during prediction error processing. To this end, we computed co-information, an information-theoretical measure that distinguishes redundant from synergistic information among brain signals. We analyzed auditory and frontal electrocorticography (ECoG) signals in five common awake marmosets performing two distinct auditory oddball tasks, and investigated to what extent event-related potentials (ERP) and broadband (BB) dynamics exhibit redundancy and synergy for auditory prediction error signals. We observed multiple patterns of redundancy and synergy across the entire cortical hierarchy with distinct dynamics. The information conveyed by ERPs and BB signals was highly synergistic even at lower stages of the hierarchy in the auditory cortex, as well as between lower and higher areas in the frontal cortex. These results indicate that the distributed representations of prediction error signals across the cortical hierarchy can be highly synergistic.
An important question concerning inter-areal communication in the cortex is whether these interactions are synergistic, i.e. brain signals can either share common information (redundancy) or they can encode complementary information that is only available when both signals are considered together (synergy). Here, we dissociated cortical interactions sharing common information from those encoding complementary information during prediction error processing. To this end, we computed co-information, an information-theoretical measure that distinguishes redundant from synergistic information among brain signals. We analyzed auditory and frontal electrocorticography (ECoG) signals in five common awake marmosets performing two distinct auditory oddball tasks and investigated to what extent event-related potentials (ERP) and broadband (BB) dynamics encoded redundant and synergistic information during auditory prediction error processing. In both tasks, we observed multiple patterns of synergy across the entire cortical hierarchy with distinct dynamics. The information conveyed by ERPs and BB signals was highly synergistic even at lower stages of the hierarchy in the auditory cortex, as well as between auditory and frontal regions. Using a brain-constrained neural network, we simulated the spatio-temporal patterns of synergy and redundancy observed in the experimental results and further demonstrated that the emergence of synergy between auditory and frontal regions requires the presence of strong, long-distance, feedback and feedforward connections. These results indicate that the distributed representations of prediction error signals across the cortical hierarchy can be highly synergistic.
Activation of Mitochondrial complex II-dependent respiration is beneficial for α-Synucleinopathies
(2015)
Parkinson’s disease and dementia with Lewy bodies are major challenges in research and clinical medicine world-wide and contribute to the most common neurodegenerative disorders. Previously, specific mitochondrial polymorphisms have been found to enhance clearance of amyloid-β from the brain of APP-transgenic mice leading to beneficial clinical outcome. It has been discussed whether specific mitochondrial alterations contribute to disease progression or even prevent toxic peptide deposition, as seen in many neurodegenerative diseases. Here, we investigated α-synuclein-transgenic C57BL/6J mice with the A30P mutation, and a novel A30P C57BL/6J mouse model with three mitochondrial DNA polymorphisms in the ND3, COX3 and mtRNAArg genes, as found in the inbred NOD/LtJ mouse strain. We were able to detect that the new model has increased mitochondrial complex II-respiration which occurs in parallel to neuronal loss and improved motor performance, although it exhibits higher amounts of high molecular weight species of α-synuclein. High molecular weight aggregates of different peptides are controversially discussed in the light of neurodegeneration. A favourable hypothesis states that high molecular weight species are protective and of minor importance for the pathogenesis of neurodegenerative disorders as compared to the extreme neurotoxic monomers and oligomers. Summarising, our results point to a potentially protective and beneficial effect of specific mitochondrial polymorphisms which cause improved mitochondrial complex II-respiration in α-synucleinopathies, an effect that could be exploited further for pharmaceutical interventions.
The stem-loop (SL1) is the 5'-terminal structural element within the single-stranded SARS-CoV-2 RNA genome. It is formed by nucleotides 7–33 and consists of two short helical segments interrupted by an asymmetric internal loop. This architecture is conserved among Betacoronaviruses. SL1 is present in genomic SARS-CoV-2 RNA as well as in all subgenomic mRNA species produced by the virus during replication, thus representing a ubiquitous cis-regulatory RNA with potential functions at all stages of the viral life cycle. We present here the 1H, 13C and 15N chemical shift assignment of the 29 nucleotides-RNA construct 5_SL1, which denotes the native 27mer SL1 stabilized by an additional terminal G-C base-pair.
The SARS-CoV-2 virus is the cause of the respiratory disease COVID-19. As of today, therapeutic interventions in severe COVID-19 cases are still not available as no effective therapeutics have been developed so far. Despite the ongoing development of a number of effective vaccines, therapeutics to fight the disease once it has been contracted will still be required. Promising targets for the development of antiviral agents against SARS-CoV-2 can be found in the viral RNA genome. The 5′- and 3′-genomic ends of the 30 kb SCoV-2 genome are highly conserved among Betacoronaviruses and contain structured RNA elements involved in the translation and replication of the viral genome. The 40 nucleotides (nt) long highly conserved stem-loop 4 (5_SL4) is located within the 5′-untranslated region (5′-UTR) important for viral replication. 5_SL4 features an extended stem structure disrupted by several pyrimidine mismatches and is capped by a pentaloop. Here, we report extensive 1H, 13C, 15N and 31P resonance assignments of 5_SL4 as the basis for in-depth structural and ligand screening studies by solution NMR spectroscopy.
The ongoing pandemic caused by the Betacoronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) demonstrates the urgent need of coordinated and rapid research towards inhibitors of the COVID-19 lung disease. The covid19-nmr consortium seeks to support drug development by providing publicly accessible NMR data on the viral RNA elements and proteins. The SARS-CoV-2 genome encodes for approximately 30 proteins, among them are the 16 so-called non-structural proteins (Nsps) of the replication/transcription complex. The 217-kDa large Nsp3 spans one polypeptide chain, but comprises multiple independent, yet functionally related domains including the viral papain-like protease. The Nsp3e sub-moiety contains a putative nucleic acid-binding domain (NAB) with so far unknown function and consensus target sequences, which are conceived to be both viral and host RNAs and DNAs, as well as protein-protein interactions. Its NMR-suitable size renders it an attractive object to study, both for understanding the SARS-CoV-2 architecture and drugability besides the classical virus’ proteases. We here report the near-complete NMR backbone chemical shifts of the putative Nsp3e NAB that reveal the secondary structure and compactness of the domain, and provide a basis for NMR-based investigations towards understanding and interfering with RNA- and small-molecule-binding by Nsp3e.
The SARS-CoV-2 genome encodes for approximately 30 proteins. Within the international project COVID19-NMR, we distribute the spectroscopic analysis of the viral proteins and RNA. Here, we report NMR chemical shift assignments for the protein Nsp3b, a domain of Nsp3. The 217-kDa large Nsp3 protein contains multiple structurally independent, yet functionally related domains including the viral papain-like protease and Nsp3b, a macrodomain (MD). In general, the MDs of SARS-CoV and MERS-CoV were suggested to play a key role in viral replication by modulating the immune response of the host. The MDs are structurally conserved. They most likely remove ADP-ribose, a common posttranslational modification, from protein side chains. This de-ADP ribosylating function has potentially evolved to protect the virus from the anti-viral ADP-ribosylation catalyzed by poly-ADP-ribose polymerases (PARPs), which in turn are triggered by pathogen-associated sensing of the host immune system. This renders the SARS-CoV-2 Nsp3b a highly relevant drug target in the viral replication process. We here report the near-complete NMR backbone resonance assignment (1H, 13C, 15N) of the putative Nsp3b MD in its apo form and in complex with ADP-ribose. Furthermore, we derive the secondary structure of Nsp3b in solution. In addition, 15N-relaxation data suggest an ordered, rigid core of the MD structure. These data will provide a basis for NMR investigations targeted at obtaining small-molecule inhibitors interfering with the catalytic activity of Nsp3b.
COMP and TSP-4 interact specifically with the novel GXKGHR motif only found in fibrillar collagens
(2018)
COMP (cartilage oligomeric matrix protein) is a member of the thrombospondin family and forms homopentamers as well as mixed heterooligomers with its closely related family member TSP-4. COMP is long known to bind to collagens and to influence collagen fibril formation. Recent work indicates that already intracellular interaction with collagen is important for collagen secretion. However, the exact binding site of COMP on the collagen triple helix has not been described up to now. In this study we have identified a GXKGHR motif on the collagen II helix to bind to COMP, using a recombinantly expressed collagen II peptide library. This binding sequence is conserved throughout evolution and we demonstrate that TSP-4 binds to the same sequence. The identified binding motif overlaps with the recognition sites of many other collagen-binding partners (e.g. PEDF, Heparin) and also spans the lysine residues, which form collagen cross-links. COMP might thereby protect collagen helices from premature modification and cross-linking. Interestingly, this motif is only found in classical fibrillar collagens, although COMP is known to also bind other types. This might indicate that COMP has a unique interface for fibrillar collagens, thus making it an interesting target for the development of antifibrotic drugs.
Aim: Assessment of the effect of nonsurgical periodontal therapy on haematological parameters in patients with grades B (BP) and C periodontitis (CP).
Methods: Eight BP and 46 CP patients received full-mouth periodontal debridement within 48 h, if positive for Aggregatibacter actinomycetemcomitans with adjunctive systemic antibiotics (4 BP, 17 CP). Clinical data were collected prior and 12 weeks after periodontal therapy. Blood was sampled prior to and 1 day as well as 6 and 12 weeks after the first SD visit. Erythrocyte count, haemoglobin value, haematocrit (HCT), mean erythrocyte volume (MCV), mean corpuscular haemoglobin (MCH), MCH concentration (MCHC), platelets (PLT) and heat shock protein 27 (Hsp27) were assessed.
Results: Both groups showed significant clinical improvement (p < 0.05). Using univariate analysis, MCV was noticeably lower in CP than BP at all examinations, HCT only at baseline. For CP, MCHC was noticeably higher 12 weeks after SD than at baseline and 1 day (p ≤ 0.005) and Hsp27 increased noticeably at 1 day (p < 0.05). Repeated measures analysis of variance revealed African origin to be associated with lower MCV and female sex with lower MCHC.
Conclusion: Based on multivariate analysis, periodontal diagnosis (BP/CP) was not associated with haematological parameters measured in this study or serum Hsp27. In CP, nonsurgical periodontal therapy improved MCHC 12 weeks after SD. Also in CP Hsp27 was increased 1 day after SD.
Background: Critical organ shortage results in the utilization of extended donor criteria (EDC) liver grafts. These marginal liver grafts are prone to increased ischemia reperfusion injury (IRI) which may contribute to deteriorated graft function and survival. Experimental data have shown that the calcineurin inhibitor tacrolimus exerts protective effects on hepatic IRI when applied intravenously or directly as a hepatic rinse. Therefore, the aim of the present study is to examine the effects of an ex vivo tacrolimus perfusion on IRI in transplantation of EDC liver grafts.
Methods/Design: The TOP-Study (tacrolimus organ perfusion) is a randomized multicenter trial comparing the ex vivo tacrolimus perfusion of marginal liver grafts with placebo. We hypothesize that a tacrolimus rinse reduces IRI, potentially improving organ survival following transplantation of EDC livers. The study includes livers with two or more EDC, according to Eurotransplant International Foundation’s definition of EDC livers. Prior to implantation, livers randomized to the treatment group are rinsed with tacrolimus at a concentration of 20 ng/ml in 1000 ml Custodiol solution and in the placebo group with Custodiol alone. The primary endpoint is the maximum serum alanine transamninase (ALT) level within the first 48 hours after surgery; however, the study design also includes a 1-year observation period following transplantation. The TOP-Study is an investigator-initiated trial sponsored by the University of Munich Hospital. Seven other German transplant centers are participating (Berlin, Frankfurt, Heidelberg, Mainz, Münster, Regensburg, Tübingen) and aim to include a total of 86 patients.
Discussion: Tacrolimus organ perfusion represents a promising strategy to reduce hepatic IRI following the transplantation of marginal liver grafts. This treatment may help to improve the function of EDC grafts and therefore safely expand the donor pool in light of critical organ shortage.
Trial register: EudraCT number: 2010-021333-31, ClinicalTrials.gov identifier: NCT01564095
An important question concerning inter-areal communication in the cortex is whether these interactions are synergistic, i.e. convey information beyond what can be performed by isolated signals. Here, we dissociated cortical interactions sharing common information from those encoding complementary information during prediction error processing. To this end, we computed co-information, an information-theoretical measure that distinguishes redundant from synergistic information among brain signals. We analyzed auditory and frontal electrocorticography (ECoG) signals in three common awake marmosets and investigated to what extent event-related-potentials (ERP) and broadband (BB) dynamics exhibit redundancy and synergy for auditory prediction error signals. We observed multiple patterns of redundancy and synergy across the entire cortical hierarchy with distinct dynamics. The information conveyed by ERPs and BB signals was highly synergistic even at lower stages of the hierarchy in the auditory cortex, as well as between lower and higher areas in the frontal cortex. These results indicate that the distributed representations of prediction error signals across the cortical hierarchy can be highly synergistic.
Background: Pathogenesis of portal hypertension is multifactorial and includes pathologic intrahepatic angiogenesis, whereby TIPS insertion is an effective therapy of portal hypertension associated complications. While angiogenin is a potent contributor to angiogenesis in general, little is known about its impact on TIPS function over time. Methods: In a total of 118 samples from 47 patients, angiogenin concentrations were measured in portal and inferior caval vein plasma at TIPS insertion (each blood compartment n = 23) or angiographic intervention after TIPS (each blood compartment n = 36) and its relationship with patient outcome was investigated. Results: Angiogenin levels in the inferior caval vein were significantly higher compared to the portal vein (P = 0.048). Ten to 14 days after TIPS, inferior caval vein angiogenin level correlated inversely with the portal systemic pressure gradient (P<0.001), measured invasively during control angiography. Moreover, patients with TIPS revision during this angiography, showed significantly lower angiogenin level in the inferior caval vein compared to patients without TIPS dysfunction (P = 0.01). Conclusion: In cirrhosis patients with complications of severe portal hypertension, circulating levels of angiogenin are derived from the injured liver. Moreover, angiogenin levels in the inferior caval vein after TIPS may predict TIPS dysfunction.
The current outbreak of the highly infectious COVID-19 respiratory disease is caused by the novel coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2). To fight the pandemic, the search for promising viral drug targets has become a cross-border common goal of the international biomedical research community. Within the international Covid19-NMR consortium, scientists support drug development against SARS-CoV-2 by providing publicly available NMR data on viral proteins and RNAs. The coronavirus nucleocapsid protein (N protein) is an RNA-binding protein involved in viral transcription and replication. Its primary function is the packaging of the viral RNA genome. The highly conserved architecture of the coronavirus N protein consists of an N-terminal RNA-binding domain (NTD), followed by an intrinsically disordered Serine/Arginine (SR)-rich linker and a C-terminal dimerization domain (CTD). Besides its involvement in oligomerization, the CTD of the N protein (N-CTD) is also able to bind to nucleic acids by itself, independent of the NTD. Here, we report the near-complete NMR backbone chemical shift assignments of the SARS-CoV-2 N-CTD to provide the basis for downstream applications, in particular site-resolved drug binding studies.