Refine
Year of publication
Document Type
- Preprint (699)
- Article (638)
- Book (2)
- Working Paper (2)
- Conference Proceeding (1)
- Part of Periodical (1)
Language
- English (1343)
Has Fulltext
- yes (1343)
Is part of the Bibliography
- no (1343)
Keywords
- Heavy Ion Experiments (20)
- Hadron-Hadron Scattering (11)
- Hadron-Hadron scattering (experiments) (11)
- LHC (9)
- Heavy-ion collision (6)
- ALICE experiment (4)
- Collective Flow (4)
- Genetics (4)
- Jets (4)
- Quark-Gluon Plasma (4)
- ALICE (3)
- CRISPR/Cas9 (3)
- Elastic scattering (3)
- Jets and Jet Substructure (3)
- Psychiatric disorders (3)
- Treatment (3)
- pp collisions (3)
- schizophrenia (3)
- ADHD (2)
- Beauty production (2)
- Biogeography (2)
- Bipolar disorder (2)
- Charm physics (2)
- Collectivity (2)
- Correlation (2)
- Diffraction (2)
- Elliptic flow (2)
- Experimental nuclear physics (2)
- Experimental particle physics (2)
- Guidelines (2)
- HER2/neu (2)
- HLA class I (2)
- Heavy Ions (2)
- Heavy Quark Production (2)
- Heavy-ion collisions (2)
- Human behaviour (2)
- Immunology (2)
- Lepton-Nucleon Scattering (experiments) (2)
- MHC (2)
- Neuroscience (2)
- Particle Correlations and Fluctuations (2)
- Particle and resonance production (2)
- Particle correlations and fluctuations (2)
- Pb–Pb collisions (2)
- Polarization (2)
- Quarkonium (2)
- RHIC (2)
- Shear viscosity (2)
- Single electrons (2)
- Sweden (2)
- Trauma (2)
- chemotherapy (2)
- epigenetics (2)
- 16S (1)
- 5-Aminolävulinsäure (5-ALA) (1)
- 5-aminolevulinic acid (5-ALA) (1)
- 900 GeV (1)
- ABC transporters (1)
- ALICE detector (1)
- APM (1)
- APP processing (1)
- ATAD2 (1)
- ATPases (1)
- Actin (1)
- Activities of daily living (1)
- Acute lymphocytic leukaemia (1)
- Adult (1)
- Adult-onset ADHD (1)
- Advanced biliary tract cancer (1)
- Advanced breast cancer (1)
- Aichi targets (1)
- Aiolochroia crassa (1)
- Alliaria petiolata (1)
- Alzheimer (1)
- Anti-nuclei (1)
- Antigens/Peptides/Epitopes (1)
- Antihormone therapy (1)
- Antiretroviral therapy (1)
- Antiretrovirals (1)
- Appendectomy (1)
- Appendicitis (1)
- Arbitrage (1)
- Asymptotically Even Nonlinearity (1)
- Ataxia-telangiectasia (1)
- Atherosclerosis (1)
- Atmospheric chemistry (1)
- Atmospheric science (1)
- B-slope (1)
- BET inhibitors (1)
- BRCA1 (1)
- BRCA2 (1)
- BRD2 (1)
- BRD4 (1)
- BROMO-10 (1)
- BTC (1)
- Babesia divergens (1)
- Babesia microti (1)
- Big Five (1)
- Biochemistry and chemical biology (1)
- Biodiversity conservation (1)
- Biodiversity tools and pipelines (1)
- Biological (1)
- Black and Scholes Option Price theory (1)
- Blocked Realized Kernel (1)
- Body temperature (1)
- Boosted Jets (1)
- Borrelia (1)
- Boundary Value Problems (1)
- Bromodomänen (1)
- CAR (1)
- CDH13 (1)
- CDK4/CDK6 (1)
- CNVs (1)
- COI (1)
- CVD biomarker (1)
- CVID (1)
- CYBA/p22phox (1)
- Cancer (1)
- Cancer genomics (1)
- Carbapenem-resistente Gram-negative Bakterien (CRGN) (1)
- Carbapenemasen (1)
- Cardiomyocyte signaling pathways (1)
- Cardiomyopathy (1)
- Cardioprotection (1)
- Cardiovascular disease (1)
- Cardiovascular diseases (1)
- Cell biology (1)
- Cell membranes (1)
- Centrality Class (1)
- Centrality Selection (1)
- Charged-particle multiplicity (1)
- Charm quark spatial diffusion coefficient (1)
- Charmonia (1)
- Chemische Sonden (1)
- Child health (1)
- Chronic hepatitis C (1)
- Circadian (1)
- Cirrhosis (1)
- Classification (1)
- Climate change (1)
- Clinical Trials and Observations (1)
- Clinical variation (1)
- Closure (1)
- Coalescence (1)
- Cognitive impairment (1)
- Cold nuclear matter effects (1)
- Collective Flow, (1)
- Community dynamics (1)
- Comorbidities (1)
- Comorbidity (1)
- Comparison with QCD (1)
- Complex I (1)
- Complicated appendicitis (1)
- Conformational trapping (1)
- Conservative (1)
- Covariance Prediction (1)
- Critical point (1)
- CspA (1)
- CspZ (1)
- Cytoskeleton (1)
- DIPSHIFT (1)
- Data sharing (1)
- Data standard (1)
- Data standards (1)
- Database searching (1)
- Degenerate Linear Part (1)
- Depression (1)
- Deuteron production (1)
- Developmental trajectory (1)
- Di-hadron correlations (1)
- Diagnostic differentiation (1)
- Diagnostic markers (1)
- Dilated cardiomyopathy (1)
- Discovery (1)
- Disease Activity (1)
- Dissemination (1)
- Drug targeting (1)
- E. colo (1)
- E/I-Balance (1)
- EMT (1)
- ERBB2 (1)
- ERBB2 (HER2/neu) (1)
- Early Rheumatoid Arthritis (1)
- Ecology (1)
- Ecophysiology (1)
- Ed Diener (1)
- Elderly (1)
- Electron-pion identification (1)
- Electrophysiology (1)
- Electroweak interaction (1)
- Embolization (1)
- Ena/VASP proteins (1)
- Endothelial permeability (1)
- Entomology (1)
- Epigenetik (1)
- Epilepsy (1)
- Erythrocytes (1)
- European Society for Immunodeficiencies (ESID) (1)
- Extracellular RNA (eRNA) (1)
- Factor H (1)
- Factor Model (1)
- Femtoscopy (1)
- Ferroelectrics and multiferroics (1)
- Fibre/foam sandwich radiator (1)
- Fibromyalgia (1)
- Finite temperature field theory (1)
- Fistula (1)
- Flow (1)
- Frailty (1)
- G protein-coupled receptors (1)
- GWAS (1)
- Gadobutrol (1)
- Gadopentate dimeglumine (1)
- Gamma-Band Activity (1)
- General practitioners (1)
- German PID-NET registry (1)
- Germany (1)
- Giraffa (1)
- Groomed jet radius (1)
- Guanine nucleotide exchange factors (1)
- Guanosine triphosphatase (1)
- HBT (1)
- HEOR (1)
- HER2 c-erbB2 (1)
- HIV (1)
- HIV-1 (1)
- Hadron production (1)
- Hadron-Hadron Scattering Heavy (1)
- Hadron-hadron interactions (1)
- Hadronization (1)
- Hand-foot syndrome (1)
- Hard Scattering (1)
- Health risk analysis (1)
- Heart (1)
- Heart regeneration (1)
- Heart transplantation (1)
- Heavy Ion Experiment (1)
- Heavy flavor production (1)
- Heavy flavour production (1)
- Heavy ion collisions (1)
- Heavy ions (1)
- Heavy-flavor decay electron (1)
- Heavy-flavour decay muons (1)
- Heavy-flavour production (1)
- Heavy-ion (1)
- Hepatitis C virus (1)
- Hereditary breast and ovarian cancer (1)
- Heregulin (1)
- Hif1α (1)
- Higher moments (1)
- Hippocampus (1)
- Human (1)
- Hypertension (1)
- IgA deficiency (1)
- IgG substitution therapy (1)
- Immunodeficiency (1)
- Immunogenetics (1)
- Immunoglobulins (1)
- Immunotherapy (1)
- In vitro selection (1)
- Inclusive spectra (1)
- Index at Infinity (1)
- Individual based modeling (1)
- Induced pluripotent stem cells (1)
- Inherited arrhythmic syndrome (1)
- Intensity interferometry (1)
- Interference fragmentation function (1)
- Intra-abdominal infection (1)
- Invariant Mass Distribution (1)
- Ionisation energy loss (1)
- Ischemia–reperfusion injury (1)
- Isoxazoline Alkaloids (1)
- Italy (1)
- J/ψ suppression (1)
- Jet Physics (1)
- Jet Substructure (1)
- Jet substructure (1)
- KCGS (1)
- Katze (1)
- Lactic acidosis (1)
- Landscape genetics (1)
- Landwirtschaftlicher Betrieb (1)
- Laparoscopic appendectomy (1)
- Laparostomy (1)
- Library screening (1)
- Lipid metabolism (1)
- Liver diseases (1)
- Liver transplantation (1)
- Long distance movement (1)
- Long-Range Dependence (1)
- Luciferase (1)
- Lymphocytes (1)
- Lymphoid tissues (1)
- Lymphopenia Mortality (1)
- MACE (1)
- MET (1)
- MM-121 (1)
- MRI (1)
- Magnetic properties and materials (1)
- Marine biodiversity (1)
- Material budget (1)
- Medizinische Chemie (1)
- Meldepflicht (1)
- Membrane protein (1)
- Mena/VASP (1)
- Mesh (1)
- Metaanalysis (1)
- Metastatic (1)
- MicroRNAs (miRNAs) (1)
- Mid-rapidity (1)
- Minimum Bias (1)
- Mitochondria (1)
- Mitochondrial disorder (1)
- Mixing Frequencies (1)
- Mobile links (1)
- Molecular autopsy (1)
- Molecular biology (1)
- Molecular neuroscience (1)
- Monte Carlo (1)
- Mortality (1)
- Multi-Parton Interactions (1)
- Multi-strange baryons (1)
- Multi-wire proportional drift chamber (1)
- Multiple parton interactions (1)
- Myeloid Neoplasia (1)
- Myocardial infarction (1)
- N-methyl-D-aspartate receptor (1)
- NADPH oxidase (1)
- NK-92 (1)
- NMR (1)
- NO (1)
- Nanobody (1)
- Neolithic (1)
- Neonatal (1)
- Net-charge correlations (1)
- Net-charge fluctuations (1)
- Neural network (1)
- Nitric oxide (1)
- Non-operative (1)
- Non-trauma (1)
- Nonflow (1)
- Noninferiority (1)
- Nonperturbative effects in field theory (1)
- Nuclear modification factor (1)
- Nutrition (1)
- Oldest-old (1)
- Oncology (1)
- Open abdomen (1)
- OspE (1)
- Outcomes research (1)
- PARK2 (1)
- PDGFRβ (1)
- PID prevalence (1)
- PYTHIA (1)
- Pancreatitis (1)
- Parkinson's disease (1)
- Particle and Resonance Production (1)
- Pb–Pb (1)
- Pediatric (1)
- Peer review (1)
- Peritonitis (1)
- Personalized medicine (1)
- Phage display (1)
- Phase transitions and critical phenomena (1)
- Phosphorylation (1)
- Photodynamische Therapie (PDT) (1)
- Phylogenomics (1)
- Physiology (1)
- Platelet (1)
- Population genetics (1)
- Portfolio Optimization (1)
- Portfolios (1)
- Post-mortem genetic screening (1)
- Prediction (1)
- Predictive markers (1)
- Production Cross Section (1)
- Prognosis (1)
- Properties of Hadrons (1)
- Proton-proton collisions (1)
- Proton–proton (1)
- Proton–proton collisions (1)
- Psychiatry (1)
- QCD (1)
- Quantum field theory (1)
- Quark Deconfinement (1)
- Quark Gluon Plasma (1)
- Quark Production (1)
- Questionnaires (1)
- RMS (1)
- Rapidity Range (1)
- Re-exploration (1)
- Red blood cell transfusion (1)
- Red blood cells (1)
- Reintervention (1)
- Relativistic heavy ion physics (1)
- Relativistic heavy-ion collisions (1)
- Remote ischemic conditioning (1)
- Renal lesions (1)
- Research Article (1)
- Resolution Parameter (1)
- Rheumatoid Arthritis (1)
- Ribosome display (1)
- SNP (1)
- STAR (1)
- SVR (1)
- Safety (1)
- Schizophrenia (1)
- Seasonal variation (1)
- Seribantumab (1)
- Single muons (1)
- Small molecules (1)
- SoftDrop (1)
- Solar insolation (1)
- Sorafenib (1)
- Sozialverhalten (1)
- Species coexistence (1)
- Spectral Decomposition (1)
- Spectrin (1)
- Spin alignment (1)
- Spleen (1)
- Splitting function (1)
- Sponges (1)
- Stewardship (1)
- Stewardship and dissemination (1)
- Stochastic Analysis of Square Zero Variation Processes (1)
- Stroke (1)
- Structural biology and molecular biophysics (1)
- Structure Elucidation (1)
- Strukturbasiertes Design (1)
- Sudden cardiac death (1)
- Sudden death (1)
- Suicide (1)
- Sunlight (1)
- Surgery (1)
- Synaptic plasticity (1)
- Synthetic (1)
- Systematic Uncertainty (1)
- Systematic reviews (1)
- T-DM1 (1)
- TGF-β (1)
- TR (1)
- Technique (1)
- Thermal model (1)
- Tick-Borne diseases (1)
- Time Projection Chamber (1)
- Timing (1)
- Tools and pipelines (1)
- Tools and ressources (1)
- Tracking (1)
- Transition radiation detector (1)
- Transverse momentum (1)
- Transversity (1)
- Trigger (1)
- Triple-negative breast cancer (1)
- Uncomplicated appendicitis (1)
- VEGF receptor 2 internalization and signaling (1)
- VEGFR-2 (1)
- VEGFR-3 (1)
- VUS (1)
- Vascular emergencies (1)
- Vector Boson Production (1)
- Vesicles (1)
- Vitamin (1)
- Warzen (1)
- X-ray crystallography (1)
- Xenon-based gas mixture (1)
- acute coronary syndromes (1)
- advanced breast cancer (1)
- agreeableness (1)
- algebraic cluster model (1)
- alirocumab (1)
- alleles (1)
- anaemia (1)
- anchialine cave (1)
- androgen receptor (1)
- anticoagulants (1)
- antigen presentation (1)
- antigen processing and presentation (1)
- antihormone therapy (1)
- antiseizure medication (1)
- atherosclerosis (1)
- atrial fibrillation (1)
- autism spectrum disorder (1)
- autistic disorder (1)
- axions (1)
- azacitidine (1)
- binary nucleation (1)
- biobank (1)
- biogeographic legaciese (1)
- biomarkers (1)
- bioprinting (1)
- body-on-a-chip (1)
- bromodomain (1)
- bromodomain inhibitor (1)
- bromodomains (1)
- burden of illness (1)
- c-kit (1)
- cancer immunotherapy (1)
- carbapenem-resistant Gram-negative bacteria (CRGN) (1)
- carbapenemases (1)
- cardiocerebral resuscitation (1)
- cardiopulmonary resuscitation (1)
- cardiovascular disease (1)
- castration-resistant prostate cancer (1)
- cell-free expression (1)
- cellular therapy (1)
- chemical probes (1)
- chemogenomic set (1)
- child (1)
- children (1)
- chimeric antigen receptor (1)
- chromatin (1)
- chromium de novo assembly (1)
- citizen science (1)
- common genetic variation (1)
- complement (1)
- complexity (1)
- copy number polymorphism (1)
- cost containment (1)
- cross-linking (1)
- cryo-EM (1)
- cytokine-induced killer cells (1)
- cytotoxicity (1)
- dE/dx (1)
- dark matter experiments (1)
- demographic inference (1)
- detector (1)
- diagnosis (1)
- direct-acting antivirals (DAAs) (1)
- disease prevalence (1)
- domestication (1)
- drug discovery (1)
- druggable genome (1)
- dynamics (1)
- eNOS (1)
- early childhood (1)
- ectosomes (1)
- elderly patients (1)
- electrocardiography (1)
- endothelial cells (1)
- epigenetic (1)
- evolution (1)
- executive functions (1)
- exosomes (1)
- experimental results (1)
- extracellular vesicles (1)
- follow-up (1)
- forest classification (1)
- forest functional similarity (1)
- functional connectivity (1)
- galunisertib monohydrate (LY2157299) (1)
- gastric cancer (1)
- gene flow (1)
- genes (1)
- genetic distance (1)
- genetic diversity (1)
- genetics (1)
- genome (1)
- genome-wide association study (1)
- genotype (1)
- genotype determination (1)
- giraffe (1)
- gliomas (1)
- global change (1)
- guidelines (1)
- habitat destruction (1)
- happiness (1)
- heart-on-a-chip (1)
- heavy ion experiments (1)
- hematopoietic stem cell transplantation (1)
- hemodialysis (1)
- host-pathogen interaction (1)
- human (1)
- human papilloma virus (HPV) (1)
- humanes Papillomvirus (HPV) (1)
- insertable cardiac monitor (1)
- inter-individual variability (1)
- ion‐induced nucleation (1)
- iron metabolism (1)
- juvenile myelomonocytic leukemia (1)
- kidney disease (1)
- kidney-on-a-chip (1)
- kinase inhibitor (1)
- knapsack cryptosystems (1)
- knockout (1)
- land use (1)
- lapatinib (1)
- lattice basis reduction (1)
- lattices (1)
- leukemia (1)
- leukopenia (1)
- life satisfaction (1)
- liver-on-a-chip (1)
- low-density lipoprotein cholesterol (1)
- lung-on-a-chip (1)
- macrophage polarization (1)
- magic angle spinning (1)
- magnetoencephalography (1)
- major adverse cardiovascular events (1)
- mandatory reporting system (1)
- medicinal chemistry (1)
- membrane proteins (1)
- mentalizing (1)
- metastatic (1)
- miRNA (1)
- micro-physiological systems (1)
- microparticles (1)
- microvesicles (1)
- minimal information requirements (1)
- model system (1)
- molecular machines (1)
- multidrug-resistant Gram-negative bacteria (MRGN) (1)
- multiresistente Gram-negativen Stäbchenbakterien (MRGN) (1)
- multispecies coalescent (1)
- mutation (1)
- neural oscillations (1)
- neurodevelopment (1)
- neutropenia (1)
- next-generation sequencing (1)
- non-autonomous dynamical systems (1)
- nuclear collective model (1)
- obituary (1)
- obituary announcement (1)
- organs-on-a-chip (1)
- p+p collisions (1)
- pSMAD2 (1)
- pauli principle (1)
- perceptual closure (1)
- pericytes (1)
- pertuzumab (1)
- pharmacokinetics (1)
- phenotype (1)
- phenotypic screening (1)
- photodynamic therapy (PDT) (1)
- phylogenetic analysis (1)
- phylogenetic community distance (1)
- phylogenetic network (1)
- phylogeny (1)
- plant invasion (1)
- polymeric micelle (1)
- polymorphism (1)
- polypept(o)ide (1)
- population structure (1)
- positive psychology (1)
- precision weighting (1)
- predictive coding (1)
- primary active transporters (1)
- primary immunodeficiency (PID) (1)
- proprotein convertase subtilisin/kexin type 9 inhibition (1)
- prosocial behavior (1)
- protein kinase (1)
- quark gluon plasma (1)
- registry for primary immunodeficiency (1)
- reproducibility (1)
- research network (1)
- resistance-associated substitutions (RAS) (1)
- rhabdomyosarcoma (1)
- rigor (1)
- risk factor progression (1)
- risk factors (1)
- runs of homozygosity (1)
- seizures (1)
- sequence alignment (1)
- set-valued pullback attractors (1)
- single nucleotide polymorphism (1)
- single subject classification (1)
- skin-on-a-chip (1)
- small molecules (1)
- social exclusion (1)
- sofosbuvir (1)
- solar physics (1)
- speciation (1)
- spectra (1)
- sprouting angiogenesis (1)
- standardization (1)
- stroke prevention (1)
- structural biology (1)
- structure-based design (1)
- subjective well-being (1)
- subset sum problems (1)
- superparamagnetic iron oxide nanoparticles (1)
- surgery (1)
- switching systems (1)
- synaesthesia (1)
- temporal classification (1)
- theory of mind (1)
- tick (1)
- tip cell filopodia formation (1)
- topological entropy (1)
- trastuzumab (1)
- tropical forests (1)
- understudied kinase (1)
- velpatasvir (1)
- vessel-associated mural cells (1)
- voxilaprevir (1)
- warts (1)
- wassergefiltertes Infrarot A (wIRA) (1)
- waterfiltered infrared A (wIRA) (1)
- white and brown dwarfs (1)
- whole-genome sequencing (1)
- working memory (1)
- √sN N = 2.76 TeV (1)
Institute
- Physik (1133)
- Frankfurt Institute for Advanced Studies (FIAS) (978)
- Informatik (906)
- Medizin (106)
- Geowissenschaften (15)
- Biochemie und Chemie (11)
- Biowissenschaften (10)
- Institut für Ökologie, Evolution und Diversität (7)
- Biodiversität und Klima Forschungszentrum (BiK-F) (5)
- Senckenbergische Naturforschende Gesellschaft (5)
The dismal prognosis of pediatric and young adult patients with high-risk rhabdomyosarcoma (RMS) underscores the need for novel treatment options for this patient group. In previous studies, the tumor-associated surface antigen ERBB2 (HER2/neu) was identified as targetable in high-risk RMS. As a proof of concept, in this study, a novel treatment approach against RMS tumors using a genetically modified natural killer (NK)-92 cell line (NK-92/5.28.z) as an off-the-shelf ERBB2-chimeric antigen receptor (CAR)-engineered cell product was preclinically explored. In cytotoxicity assays, NK-92/5.28.z cells specifically recognized and efficiently eliminated RMS cell suspensions, tumor cell monolayers, and 3D tumor spheroids via the ERBB2-CAR even at effector-to-target ratios as low as 1:1. In contrast to unmodified parental NK-92 cells, which failed to lyse RMS cells, NK-92/5.28.z cells proliferated and became further activated through contact with ERBB2-positive tumor cells. Furthermore, high amounts of effector molecules, such as proinflammatory and antitumoral cytokines, were found in cocultures of NK-92/5.28.z cells with tumor cells. Taken together, our data suggest the enormous potential of this approach for improving the immunotherapy of treatment-resistant tumors, revealing the dual role of NK-92/5.28.z cells as CAR-targeted killers and modulators of endogenous adaptive immunity even in the inhibitory tumor microenvironment of high-risk RMS.
High-risk rhabdomyosarcoma (RMS) occurring in childhood to young adulthood is associated with a poor prognosis; especially children above the age of 10 with advanced stage alveolar RMS still succumb to the disease within a median of 2 years. The advent of chimeric antigen receptor (CAR)-engineered T cells marked significant progress in the treatment of refractory B cell malignancies, but experience for solid tumors has proven challenging. We speculate that this is at least in part due to the poor quality of the patient's own T cells and therefore propose using CAR-modified cytokine-induced killer (CIK) cells as effector cells. CIK cells are a heterogeneous population of polyclonal T cells that acquire phenotypic and cytotoxic properties of natural killer (NK) cells through the cultivation process, becoming so-called T-NK cells. CIK cells can be genetically modified to express CARs. They are minimally alloreactive and can therefore be acquired from haploidentical first-degree relatives. Here, we explored the potential of ERBB2-CAR-modified random-donor CIK cells as a treatment for RMS in xenotolerant mice bearing disseminated high-risk RMS tumors. In otherwise untreated mice, RMS tumors engrafted 13–35 days after intravenous tumor cell injection, as shown by in vivo bioluminescence imaging, immunohistochemistry, and polymerase chain reaction for human gDNA, and mice died shortly thereafter (median/range: 62/56–66 days, n = 5). Wild-type (WT) CIK cells given at an early stage delayed and eliminated RMS engraftment in 4 of 6 (67%) mice, while ERBB2-CAR CIK cells inhibited initial tumor load in 8 of 8 (100%) mice. WT CIK cells were detectable but not as active as CAR CIK cells at distant tumor sites. CIK cell therapies during advanced RMS delayed but did not inhibit tumor progression compared to untreated controls. ERBB2-CAR CIK cell therapy also supported innate immunity as evidenced by selective accumulation of NK and T-NK cell subpopulations in disseminated RMS tumors, which was not observed for WT CIK cells. Our data underscore the power of heterogenous immune cell populations (T, NK, and T-NK cells) to control solid tumors, which can be further enhanced with CARs, suggesting ERBB2-CAR CIK cells as a potential treatment for high-risk RMS.
Under certain conditions, secondary organic aerosol (SOA) particles can exist in the atmosphere in an amorphous solid or semi-solid state. To determine their relevance to processes such as ice nucleation or chemistry occurring within particles requires knowledge of the temperature and relative humidity (RH) range for SOA to exist in these states. In the Cosmics Leaving Outdoor Droplets (CLOUD) experiment at The European Organisation for Nuclear Research (CERN), we deployed a new in situ optical method to detect the viscous state of α-pinene SOA particles and measured their transition from the amorphous highly viscous state to states of lower viscosity. The method is based on the depolarising properties of laboratory-produced non-spherical SOA particles and their transformation to non-depolarising spherical particles at relative humidities near the deliquescence point. We found that particles formed and grown in the chamber developed an asymmetric shape through coagulation. A transition to a spherical shape was observed as the RH was increased to between 35 % at −10 °C and 80 % at −38 °C, confirming previous calculations of the viscosity-transition conditions. Consequently, α-pinene SOA particles exist in a viscous state over a wide range of ambient conditions, including the cirrus region of the free troposphere. This has implications for the physical, chemical, and ice-nucleation properties of SOA and SOA-coated particles in the atmosphere.
Under certain conditions, secondary organic aerosol (SOA) particles can exist in the atmosphere in an amorphous solid or semi-solid state. To determine their relevance to processes such as ice nucleation or chemistry occurring within particles requires knowledge of the temperature and relative humidity (RH) range for SOA to exist in these states. In the CLOUD experiment at CERN, we deployed a new in-situ optical method to detect the viscosity of α-pinene SOA particles and measured their transition from the amorphous viscous to liquid state. The method is based on the depolarising properties of laboratory-produced non-spherical SOA particles and their transformation to non-depolarising spherical liquid particles during deliquescence. We found that particles formed and grown in the chamber developed an asymmetric shape through coagulation. A transition to spherical shape was observed as the RH was increased to between 35 % at −10 ◦C and 80 % at −38 ◦C, confirming previous calculations of the viscosity transition conditions. Consequently, α-pinene SOA particles exist in a viscous state over a wide range of ambient conditions, including the cirrus region of the free troposphere. This has implications for the physical, chemical and ice-nucleation properties of SOA and SOA-coated particles in the atmosphere.
Under physiological conditions, endothelial cells and the endothelial nitric oxide (NO) synthase (eNOS) are the main source of NO in the cardiovascular system. However, several other cell types have also been implicated in the NO-dependent regulation of cell function, including erythrocytes. NO derived from red blood cells has been proposed to regulate erythrocyte membrane fluidity, inhibit platelet activation and induce vasodilation in hypoxic areas, but these proposals are highly controversial. In the current issue of Cell Communication and Signaling, an elegant study by Gambaryan et al., assayed NO production by erythrocytes by monitoring the activation of the platelet intracellular NO receptor, soluble guanylyl cyclase, and its downstream kinase protein kinase G. After systematically testing different combinations of erythrocyte/platelet suspensions, the authors found no evidence for platelet soluble guanylyl cyclase/protein kinase G activation by erythrocytes and conclude that erythrocytes do not release biologically active NO to inhibit platelet activation.
In ischemic vascular diseases, leukocyte recruitment and polarization are crucial for revascularization and tissue repair. We investigated the role of vasodilator-stimulated phosphoprotein (VASP) in vascular repair. After hindlimb ischemia induction, blood flow recovery, angiogenesis, arteriogenesis, and leukocyte infiltration into ischemic muscles in VASP−/− mice were accelerated. VASP deficiency also elevated the polarization of the macrophages through increased signal transducer and activator of transcription (STAT) signaling, which augmented the release of chemokines, cytokines, and growth factors to promote leukocyte recruitment and vascular repair. Importantly, VASP deletion in bone marrow–derived cells was sufficient to mimic the increased blood flow recovery of global VASP−/− mice. In chemotaxis experiments, VASP−/− neutrophils/monocytes were significantly more responsive to M1-related chemokines than wild-type controls. Mechanistically, VASP formed complexes with the chemokine receptor CCR2 and β-arrestin-2, and CCR2 receptor internalization was significantly reduced in VASP−/− leukocytes. Our data indicate that VASP is a major regulator of leukocyte recruitment and polarization in postischemic revascularization and support a novel role of VASP in chemokine receptor trafficking.
Endothelial tip cells are essential for VEGF-induced angiogenesis, but underlying mechanisms are elusive. The Ena/VASP protein family, consisting of EVL, VASP, and Mena, plays a pivotal role in axon guidance. Given that axonal growth cones and endothelial tip cells share many common features, from the morphological to the molecular level, we investigated the role of Ena/VASP proteins in angiogenesis. EVL and VASP, but not Mena, are expressed in endothelial cells of the postnatal mouse retina. Global deletion of EVL (but not VASP) compromises the radial sprouting of the vascular plexus in mice. Similarly, endothelial-specific EVL deletion compromises the radial sprouting of the vascular plexus and reduces the endothelial tip cell density and filopodia formation. Gene sets involved in blood vessel development and angiogenesis are down-regulated in EVL-deficient P5-retinal endothelial cells. Consistently, EVL deletion impairs VEGF-induced endothelial cell proliferation and sprouting, and reduces the internalization and phosphorylation of VEGF receptor 2 and its downstream signaling via the MAPK/ERK pathway. Together, we show that endothelial EVL regulates sprouting angiogenesis via VEGF receptor-2 internalization and signaling.
Oxidative stress attenuates the NO-cGMP pathway, e.g. in the vascular system, through scavenging of free NO radicals by superoxide O2•-, by inactivation of soluble guanylyl cyclase (sGC) via oxidation of its central Fe2+ ion, and by down-regulation of sGC protein levels. While the former pathways are well established, the molecular mechanisms underlying the latter are still obscure. Using oxidative sGC inhibitor ODQ we demonstrate rapid down-regulation of sGC protein in mammalian cells. Co-incubation with proteasomal inhibitor MG132 results in accumulation of ubiquitinated sGC whereas sGC activator BAY 58–2667 prevents ubiquitination. ODQ-induced down-regulation of sGC is mediated through selective ubiquitination of its b subunit, and BAY 58–2667 abrogates this effect. Ubiquitination of sGC-b is dramatically enhanced by E3 ligase CHIP. Our data indicate that oxidative stress promotes ubiquitination of sGC b subunit through E3 ligase CHIP, and that sGC activator 58–2667 reverts this effect, most likely through stabilization of the heme-free b subunit. Thus the deleterious effects of oxidative stress can be counter-balanced by an activator of a key enzyme of vascular homeostasis.
Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.
Background: Panic disorder is common (5% prevalence) and females are twice as likely to be affected as males. The heritable component of panic disorder is estimated at 48%. Glutamic acid dehydrogenase GAD1, the key enzyme for the synthesis of the inhibitory and anxiolytic neurotransmitter GABA, is supposed to influence various mental disorders, including mood and anxiety disorders. In a recent association study in depression, which is highly comorbid with panic disorder, GAD1 risk allele associations were restricted to females.
Methodology/Principal Findings: Nineteen single nucleotide polymorphisms (SNPs) tagging the common variation in GAD1 were genotyped in two independent gender and age matched case-control samples (discovery sample n = 478; replication sample n = 584). Thirteen SNPs passed quality control and were examined for gender-specific enrichment of risk alleles associated with panic disorder by using logistic regression including a genotype×gender interaction term. The latter was found to be nominally significant for four SNPs (rs1978340, rs3762555, rs3749034, rs2241165) in the discovery sample; of note, the respective minor/risk alleles were associated with panic disorder only in females. These findings were not confirmed in the replication sample; however, the genotype×gender interaction of rs3749034 remained significant in the combined sample. Furthermore, this polymorphism showed a nominally significant association with the Agoraphobic Cognitions Questionnaire sum score.
Conclusions/Significance: The present study represents the first systematic evaluation of gender-specific enrichment of risk alleles of the common SNP variation in the panic disorder candidate gene GAD1. Our tentative results provide a possible explanation for the higher susceptibility of females to panic disorder.
Attention-deficit/hyperactivity disorder (ADHD) is highly heritable and the most common neurodevelopmental disorder in childhood. In recent decades, it has been appreciated that in a substantial number of cases the disorder does not remit in puberty, but persists into adulthood. Both in childhood and adulthood, ADHD is characterised by substantial comorbidity including substance use, depression, anxiety, and accidents. However, course and symptoms of the disorder and the comorbidities may fluctuate and change over time, and even age of onset in childhood has recently been questioned. Available evidence to date is poor and largely inconsistent with regard to the predictors of persistence versus remittance. Likewise, the development of comorbid disorders cannot be foreseen early on, hampering preventive measures. These facts call for a lifespan perspective on ADHD from childhood to old age. In this selective review, we summarise current knowledge of the long-term course of ADHD, with an emphasis on clinical symptom and cognitive trajectories, treatment effects over the lifespan, and the development of comorbidities. Also, we summarise current knowledge and important unresolved issues on biological factors underlying different ADHD trajectories. We conclude that a severe lack of knowledge on lifespan aspects in ADHD still exists for nearly every aspect reviewed. We encourage large-scale research efforts to overcome those knowledge gaps through appropriately granular longitudinal studies.
Background: Since sorafenib has shown activity in different tumour types and gemcitabine regimens improved the outcome for biliary tract cancer (BTC) patients, we evaluated first-line gemcitabine plus sorafenib in a double-blind phase II study.
Patients and methods: 102 unresectable or metastatic BTC patients with histologically proven adenocarcinoma of gallbladder or intrahepatic bile ducts, Eastern Cooperative Oncology Group (ECOG) 0–2 were randomised to gemcitabine (1000 mg/m2 once weekly, first 7-weeks + 1-week rest followed by once 3-weeks + 1-week rest) plus sorafenib (400 mg twice daily) or placebo. Treatment continued until progression or unacceptable toxicity. Tumour samples were prospectively stained for sorafenib targets and potential biomarkers. Serum samples (first two cycles) were measured for vascular endothelial growth factors (VEGFs), vascular endothelial growth factor receptor 2 (VEGFR-2) and stromal cell-derived factor 1 (SDF1)α by enzyme-linked immunosorbent assay (ELISA).
Results: Gemcitabine plus sorafenib was generally well tolerated. Four and three patients achieved partial responses in the sorafenib and placebo groups, respectively. There was no difference in the primary end-point, median progression-free survival (PFS) for gemcitabine plus sorafenib versus gemcitabine plus placebo (3.0 versus 4.9 months, P = 0.859), and no difference for median overall survival (OS) (8.4 versus 11.2 months, P = 0.775). Patients with liver metastasis after resection of primary BTC survived longer with sorafenib (P = 0.019) compared to placebo. Patients who developed hand-foot syndrome (HFS) showed longer PFS and OS than patients without HFS. Two sorafenib targets, VEGFR-2 and c-kit, were not expressed in BTC samples. VEGFR-3 and Hif1α were associated with lymph node metastases and T stage. Absence of PDGFRβ expression correlated with longer PFS.
Conclusion: The addition of sorafenib to gemcitabine did not demonstrate improved efficacy in advanced BTC patients. Biomarker subgroup analysis suggested that some patients might benefit from combined treatment.
A detailed analysis of the chemical constituents of a Caribbean specimen of Aiolochroia crassa was performed. Five brominated products (1 -5) were isolated and one of these was a new bromotyrosine metabolite. The structure of the new compound 1 has been established from spectral studies. Compounds 1 and 2, which are the major brominated metabolites and have not been previously identified in any Aiolochroia species, could be usefully employed as chemotaxonomic markers.
The accuracy on neutron capture cross section of fissile isotopes must be improved for the design of future nuclear systems such as Gen-IV reactors and Accelerator Driven Systems. The High Priority Request List of the Nuclear Energy Agency, which lists the most important nuclear data requirements, includes also the neutron capture cross sections of fissile isotopes such as 233,235U and 239,241Pu. A specific experimental setup has been used at the CERN n_TOF facility for the measurement of the neutron capture cross section of 235U by a set of micromegas fission detectors placed inside a segmented BaF2 Total Absorption Calorimeter.
Aims: Averaged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear.
Methods and results: An individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration (n = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events.
Conclusion: Averaged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints.
Upon infection of host cells, Legionella pneumophila releases a multitude of effector enzymes into the cells cytoplasm that hijack a plethora of cellular activities, including the hosts ubiquitination pathways. Effectors belonging to the SidE-family are involved in non-canonical serine phosphoribosyl ubiquitination of host substrate proteins contributing to the formation of a Legionella-containing vacuole that is crucial in the onset of Legionnaires’ disease. This dynamic process is reversed by effectors called Dups that hydrolyse the phosphodiester in the phosphoribosyl ubiquitinated protein. We installed reactive warheads on chemically prepared ribosylated ubiquitin to generate a set of probes targeting these Legionella enzymes. In vitro tests on recombinant DupA revealed that a vinyl sulfonate warhead was most efficient in covalent complex formation. Mutagenesis and x-ray crystallography approaches were used to identify the site of covalent crosslinking to be an allosteric cysteine residue. The subsequent application of this probe highlights the potential to selectively enrich the Dup enzymes from Legionella-infected cell lysates.
We examined alterations in E/I-balance in schizophrenia (ScZ) through measurements of resting-state gamma-band activity in participants meeting clinical high-risk (CHR) criteria (n = 88), 21 first episode (FEP) patients and 34 chronic ScZ-patients. Furthermore, MRS-data were obtained in CHR-participants and matched controls. Magnetoencephalographic (MEG) resting-state activity was examined at source level and MEG-data were correlated with neuropsychological scores and clinical symptoms. CHR-participants were characterized by increased 64–90 Hz power. In contrast, FEP- and ScZ-patients showed aberrant spectral power at both low- and high gamma-band frequencies. MRS-data showed a shift in E/I-balance toward increased excitation in CHR-participants, which correlated with increased occipital gamma-band power. Finally, neuropsychological deficits and clinical symptoms in FEP and ScZ-patients were correlated with reduced gamma band-activity, while elevated psychotic symptoms in the CHR group showed the opposite relationship. The current study suggests that resting-state gamma-band power and altered Glx/GABA ratio indicate changes in E/I-balance parameters across illness stages in ScZ.
Hypofunction of the N-methyl-D-aspartate receptor (NMDAR) has been implicated as a possible mechanism underlying cognitive deficits and aberrant neuronal dynamics in schizophrenia. To test this hypothesis, we first administered a sub-anaesthetic dose of S-ketamine (0.006 mg/kg/min) or saline in a single-blind crossover design in 14 participants while magnetoencephalographic data were recorded during a visual task. In addition, magnetoencephalographic data were obtained in a sample of unmedicated first-episode psychosis patients (n = 10) and in patients with chronic schizophrenia (n = 16) to allow for comparisons of neuronal dynamics in clinical populations versus NMDAR hypofunctioning. Magnetoencephalographic data were analysed at source-level in the 1–90 Hz frequency range in occipital and thalamic regions of interest. In addition, directed functional connectivity analysis was performed using Granger causality and feedback and feedforward activity was investigated using a directed asymmetry index. Psychopathology was assessed with the Positive and Negative Syndrome Scale. Acute ketamine administration in healthy volunteers led to similar effects on cognition and psychopathology as observed in first-episode and chronic schizophrenia patients. However, the effects of ketamine on high-frequency oscillations and their connectivity profile were not consistent with these observations. Ketamine increased amplitude and frequency of gamma-power (63–80 Hz) in occipital regions and upregulated low frequency (5–28 Hz) activity. Moreover, ketamine disrupted feedforward and feedback signalling at high and low frequencies leading to hypo- and hyper-connectivity in thalamo-cortical networks. In contrast, first-episode and chronic schizophrenia patients showed a different pattern of magnetoencephalographic activity, characterized by decreased task-induced high-gamma band oscillations and predominantly increased feedforward/feedback-mediated Granger causality connectivity. Accordingly, the current data have implications for theories of cognitive dysfunctions and circuit impairments in the disorder, suggesting that acute NMDAR hypofunction does not recreate alterations in neural oscillations during visual processing observed in schizophrenia.
he family of cubic noncentrosymmetric 3-4-3 compounds has become a fertile ground for the discovery of novel correlated metallic and insulating phases. Here, we report the synthesis of a new heavy fermion compound, Ce3Bi4Ni3. It is an isoelectronic analog of the prototypical Kondo insulator Ce3Bi4Pt3 and of the recently discovered Weyl-Kondo semimetal Ce3Bi4Pd3. In contrast to the volume-preserving Pt-Pd substitution, structural and chemical analyses reveal a positive chemical pressure effect in Ce3Bi4Ni3 relative to its heavier counterparts. Based on the results of electrical resistivity, Hall effect, magnetic susceptibility, and specific heat measurements, we identify an energy gap of 65–70 meV, about eight times larger than that in Ce3Bi4Pt3 and about 45 times larger than that of the Kondo-insulating background hosting the Weyl nodes in Ce3Bi4Pd3. We show that this gap as well as other physical properties do not evolve monotonically with increasing atomic number, i.e., in the sequence Ce3Bi4Ni3−Ce3Bi4Pd3−Ce3Bi4Pt3, but instead with increasing partial electronic density of states of the 𝑑 orbitals at the Fermi energy. This work opens the possibility to investigate the conditions under which topological states develop in this series of strongly correlated 3-4-3 materials.
The family of cubic noncentrosymmetric 3-4-3 compounds has become a fertile ground for the discovery of novel correlated metallic and insulating phases. Here, we report the synthesis of a new heavy fermion compound, Ce3Bi4Ni3. It is an isoelectronic analog of the prototypical Kondo insulator Ce3Bi4Pt3 and of the recently discovered Weyl-Kondo semimetal Ce3Bi4Pd3. In contrast to the volume-preserving Pt-Pd substitution, structural and chemical analyses reveal a positive chemical pressure effect in Ce3Bi4Ni3 relative to its heavier counterparts. Based on the results of electrical resistivity, Hall effect, magnetic susceptibility, and specific heat measurements, we identify an energy gap of 65-70 meV, about 8 times larger than that in Ce3Bi4Pt3 and about 45 times larger than that of the Kondo-insulating background hosting the Weyl nodes in Ce3Bi4Pd3. We show that this gap as well as other physical properties do not evolve monotonically with increasing atomic number, i.e., in the sequence Ce3Bi4Ni3-Ce3Bi4Pd3-Ce3Bi4Pt3, but instead with increasing partial electronic density of states of the d orbitals at the Fermi energy. To understand under which condition topological states form in these materials is a topic for future studies.
The family of cubic noncentrosymmetric 3-4-3 compounds has become a fertile ground for the discovery of novel correlated metallic and insulating phases. Here, we report the synthesis of a new heavy fermion compound, Ce3Bi4Ni3. It is an isoelectronic analog of the prototypical Kondo insulator Ce3Bi4Pt3 and of the recently discovered Weyl-Kondo semimetal Ce3Bi4Pd3. In contrast to the volume-preserving Pt-Pd substitution, structural and chemical analyses reveal a positive chemical pressure effect in Ce3Bi4Ni3 relative to its heavier counterparts. Based on the results of electrical resistivity, Hall effect, magnetic susceptibility, and specific heat measurements, we identify an energy gap of 65-70 meV, about eight times larger than that in Ce3Bi4Pt3 and about 45 times larger than that of the Kondo-insulating background hosting the Weyl nodes in Ce3Bi4Pd3. We show that this gap as well as other physical properties do not evolve monotonically with increasing atomic number, i.e., in the sequence Ce3Bi4Ni3-Ce3Bi4Pd3-Ce3Bi4Pt3, but instead with increasing partial electronic density of states of the d orbitals at the Fermi energy. To understand under which condition topological states form in these materials is a topic for future studies.
On 20th January 1964, at the Colito Army Barracks just outside Dar es salaam, 15 officers of the Tanganyika Army that was inherited from the colonial state led a mutiny against the independent Tanganyika government. One group went to the State House with the intention of forcing President Julius Nyerere to accept their demands. What would have happened if they had succeeded in entering the State House and if President Nyerere had refused to accept their demands, as he most likely would have done? Anything could have happened and in the worst case scenario Tanzanias history and indeed the history of the whole of Africa would have been seriously affected. This book is about the courage and quick thinking of Peter Bwimbo, the then head of the Presidential Protection Unit and Nyereres Chief Body Guard who, alone, planned and executed an ingenious and successful evacuation of President Nyerere and Vice President Rashid Kawawa, whisking them away from the State House before the mutineers got there. By a clever ruse he convinced the ferry operators on duty before dawn to ferry them across the Kigamboni Creek. From there they walked several miles to a hiding place in a house that was offered by an ordinary citizen and where they stayed until the situation was normalised several days later.
12 hepatics and 32 mosses are reported new to Uganda, 1 moss being also new to Africa, and 1 liverwort new to mainland Africa. Ectropothecium plumigerum (Broth.) Hedenäs is a new combination (basionym: Isopterygium plumigerum Broth.) with a new synonym Taxicaulis plumirameus Müll.Hal. nom. nud., and Taxiphyllum maniae (Renauld & Paris) M. Fleisch. is a new synonym of Taxiphyllum taxirameum (Mitt.) M.Fleisch. Three mosses are removed from the Uganda list.