Refine
Has Fulltext
- yes (547)
Is part of the Bibliography
- yes (547)
Year of publication
- 2016 (547) (remove)
Document Type
- Journal article (547) (remove)
Language
- English (547) (remove)
Keywords
- inflammation (7)
- vision (7)
- Drosophila melanogaster (6)
- Fabry disease (6)
- breast cancer (6)
- phosphorylation (6)
- genetics (5)
- mice (5)
- DNA methylation (4)
- Drosophila (4)
- Pain (4)
- chronic kidney disease (4)
- deep brain stimulation (4)
- event-related potentials (4)
- gene expression (4)
- heterochromatin (4)
- immunofluorescence (4)
- lymphocytes (4)
- oxidative stress (4)
- 5-Methylcytosine (3)
- Boron (3)
- Cancer genetics (3)
- DNA (3)
- DNA damage (3)
- Enzyme replacement therapy (3)
- LHC (3)
- MRI (3)
- Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) (3)
- NLO Computations (3)
- Neuromyelitis optica spectrum disorders (NMOSD) (3)
- Optic neuritis (3)
- Staphylococcus aureus (3)
- Treatment (3)
- Trypanosoma brucei (3)
- attention (3)
- biodiversity (3)
- biomarker (3)
- c-Fos (3)
- case report (3)
- circadian rhythms (3)
- collagens (3)
- colorectal cancer (3)
- cytokines (3)
- dopamine (3)
- electronic properties and materials (3)
- flow cytometry (3)
- humans (3)
- hyperexpression techniques (3)
- ischemic stroke (3)
- metabolism (3)
- monocytes (3)
- multiple sclerosis (3)
- ovarian cancer (3)
- platelets (3)
- polymers (3)
- prostate cancer (3)
- sRNA (3)
- AAA (2)
- ADHD (2)
- Adult (2)
- Antisense RNA (2)
- Anura (2)
- Apoptosis (2)
- Aspergillus fumigatus (2)
- Autism spectrum disorders (2)
- Autoantibodies (2)
- B cells (2)
- BDNF (2)
- Bone-marrow-transplantation (2)
- CMV (2)
- Candida albicans (2)
- Carcinogenicity (2)
- Cell therapy (2)
- Cells (2)
- Central nervous system (2)
- Cerebrospinal fluid (2)
- Chemotherapy (2)
- Diagnosis (2)
- Dionaea muscipula (2)
- Diseases (2)
- Down syndrome (2)
- Dyes (2)
- EEG (2)
- Enzyme induction (2)
- Expression (2)
- Fluorescence (2)
- Gene (2)
- Genetics research (2)
- Genome (2)
- Germany (2)
- Guidelines (2)
- HIV (2)
- HKT transporter (2)
- Humans (2)
- IAPS (2)
- In-vitro (2)
- Infections (2)
- Inflammation (2)
- Longitudinally extensive transverse myelitis (LETM) (2)
- MDD (2)
- MEG (2)
- MODIS (2)
- MRSA (2)
- MS (2)
- Mechanisms (2)
- Merkel cell carcinoma (2)
- Metabolism (2)
- Mice (2)
- Model (2)
- Multiple bonds (2)
- Multiple sclerosis (2)
- Neurotrophic factors (2)
- Outcome survey (2)
- P300 (2)
- PET (2)
- PRRT (2)
- Parkinson's disease (2)
- Parkinson’s disease (2)
- Phase-II (2)
- RNA interference (2)
- Randomized controlled-trial (2)
- Rehabilitation (2)
- Relapse (2)
- Reproductive toxicity (2)
- Silicones (2)
- Spermatogenesis (2)
- Systems (2)
- Therapy (2)
- Thyroid cancer (2)
- Transcriptome (2)
- Validation (2)
- absorption spectra (2)
- activation (2)
- adaption (2)
- adenosine (2)
- adulthood (2)
- adversity (2)
- animal behavior (2)
- animal model (2)
- antagonist (2)
- apoptosis (2)
- arabidopsis thaliana (2)
- bacteria (2)
- behavioral conditioning (2)
- bevacizumab (2)
- biological locomotion (2)
- biology (2)
- biomarkers (2)
- c-Myc (2)
- cancer treatment (2)
- cardiac hypertrophy (2)
- cardiomyopathy (2)
- change detection (2)
- chemotherapy (2)
- children (2)
- circadian clock (2)
- condensed matter physics (2)
- crystal structure (2)
- cytotoxicity (2)
- database (2)
- detoxification (2)
- diffusion (2)
- discussion report (2)
- disease (2)
- electroencephalography (2)
- environmental exposure (2)
- enzyme replacement therapy (2)
- epithelial cells (2)
- excited states (2)
- exercise (2)
- extracellular matrix (2)
- eye movements (2)
- fear (2)
- fear conditioning (2)
- fluorescence (2)
- fluorescence microscopy (2)
- gastric cancer (2)
- gene-expression (2)
- genome (2)
- genotype (2)
- heat stress (2)
- honey bees (2)
- host-pathogen interactions (2)
- imaging (2)
- in-vivo (2)
- innate immune system (2)
- insect brain (2)
- insulin (2)
- interaction (2)
- learning (2)
- leukemia (2)
- lipidomics (2)
- lung cancer (2)
- lyso-Gb3 (2)
- macrophage (2)
- macrophages (2)
- magnetic resonance imaging (2)
- mammalian genomics (2)
- maternal exposure (2)
- memory (2)
- men who have sex with men (2)
- metallic trace elements (2)
- microRNA (2)
- mouse (2)
- mouse models (2)
- movement disorders (2)
- multiple myeloma (2)
- mushroom body (2)
- mutation (2)
- neuroinflammation (2)
- neuromelanin (2)
- neuronal plasticity (2)
- neurons (2)
- neutrino astronomy (2)
- next generation sequencing (2)
- nonsmooth optimization (2)
- obesity (2)
- pain (2)
- pancreatic cancer (2)
- panic disorder (2)
- parietal hypoactivation (2)
- perception (2)
- photoperiodism (2)
- phylogenetic trees (2)
- plants (2)
- platelet activation (2)
- platelet aggregation (2)
- potassium (2)
- prenatal exposure (2)
- protein expression (2)
- protein-protein interaction (2)
- quantum dots (2)
- quantum mechanics (2)
- quantum physics (2)
- receptor tyrosine kinases (2)
- rehabilitation (2)
- repositories (2)
- retinoblastoma protein (2)
- risk factors (2)
- salinity stress (2)
- schizophrenia (2)
- semiconductors (2)
- sequestration (2)
- serotonin (2)
- serotonin transporter (2)
- sexual selection (2)
- signaling (2)
- simulation (2)
- sodium (2)
- solar cells (2)
- spintronics (2)
- stem cells (2)
- surfactants (2)
- synapses (2)
- temperature (2)
- temporoparietal junction (2)
- tissue engineering (2)
- tool (2)
- topological insulators (2)
- transcription factors (2)
- visualization (2)
- walking (2)
- xylem loading (2)
- 12-oxo-phytodienoic acid (1)
- 177Lu (1)
- 18F-FDG PET/CT (1)
- 1H-Magnetic resonance spectroscopy (1H-MRS) (1)
- 1st-line treatment (1)
- 2-Generation reproduction (1)
- 2-loop level (1)
- 2-photon absorption (1)
- 2-step IMRT (1)
- 2015 (1)
- 3D fluoroscopy (1)
- 3D mapping (1)
- 3D object recognition (1)
- 5-Fluorouracil (1)
- 5-HTT knockout mice (1)
- 5-HTTLPR (1)
- 6-percent hydroxyethyl starch (1)
- AC Stark effect (1)
- AIDS (1)
- AIRWAYS ICPs (1)
- ANTARES telescope (1)
- AP-1 (1)
- ARIA (1)
- AT/RT (1)
- Action potentials (1)
- Activation (1)
- Acute lymphocytic leukaemia (1)
- Acyrthosiphon pisum (1)
- Adamantiades-Behçet disease (1)
- Addison's disease (1)
- Adipokine (1)
- Adolescence (1)
- Adolescents (1)
- Adrenocortial carcinomas (1)
- Adult patients (1)
- Affective processing (1)
- Ag-DNA (1)
- Agalsidase beta (1)
- Aggression (1)
- Aggressive behaviour (1)
- Aging (1)
- Agoraphobia (1)
- Agricultural intensification (1)
- Alpha therapy (1)
- Alpha-Galactosidase (1)
- Alpha-synuclein oligomers (1)
- Alternative test methods (1)
- Alvis (1)
- Alzheimer disease (1)
- Alzheimer's disease (1)
- Alzheimers disease (1)
- Alzheimers-disease (1)
- Alzheimer’s disease (1)
- Amphibians (1)
- Amplification (1)
- Amygdala (1)
- Amyloid-beta oligomers; (1)
- Amyotrophic-lateral-sclerosis (1)
- Anas crecca (1)
- Anderson-Fabry Disease (1)
- Angiopoietin-2 (1)
- Angiopoietin-like 4 (1)
- Animal models (1)
- Annotation (1)
- Anorexia nervosa (1)
- Antibody index (1)
- Antisocial behavior (1)
- Anxiety (1)
- Anxiety sensitivity (1)
- Aphthae (1)
- Aquaporin-4 antibodies (AQP4-Ig, NMO-IgG)G (1)
- Aquaporin-4 antibodies (AQP4-IgG) (1)
- Aquaporin-4 antibodies (AQP4-IgG, NMO-IgG) (1)
- Arabidopsis (1)
- Arabidopsis thaliana (1)
- Arabidopsis-thaliana (1)
- Archaea (1)
- Aromatic-hydrocarbon (1)
- Aromaticity (1)
- Arthropods (1)
- Assay (1)
- Association (1)
- Ataxia (1)
- Atomic force microscopy (1)
- Atrial natriuretic peptide (1)
- Attention Deficit Hyperactivity Disorder (ADHD) (1)
- Autism (1)
- Autoimmune diseases (1)
- Autoimmunity (1)
- Autoinflammation (1)
- Aversive events (1)
- Aversive tension (1)
- Avoidance behavior (1)
- Axon degeneration (1)
- Axon growth (1)
- Axon guidance (1)
- Axonal transport (1)
- Azathioprine (1)
- B cell (1)
- B-B bond (1)
- B-cells (1)
- BCL6 (1)
- BDNF Val66Met (1)
- BMP-2 (1)
- BMP-2 delivery (1)
- BRAF (1)
- BRCA1 (1)
- BRCA1/2 (1)
- BRCA2 (1)
- BRENDA (1)
- BSTA (1)
- Bacteria (1)
- Bacterial meningitis (1)
- Bacterial symbionts (1)
- Barkhof criteria (1)
- Barratt Impulsiveness Scale (1)
- Bee abundance (1)
- Behçet’s disease (1)
- Berry phase (1)
- Beta-catenin (1)
- Big picture (1)
- Biocompatibility (1)
- Biodegradable polymer scaffolds (1)
- Biogenic (1)
- Biradicals (1)
- Blood pressure (1)
- Bone disease (1)
- Bone marrow transplantantation (1)
- Bone morphogenetic protein-2 (1)
- Bone tissue engineering (1)
- Bor (1)
- Bose gas (1)
- Bose-Fermi (1)
- Bound-states (1)
- Bradyrhizobium (1)
- Bragg-reflection waveguide (1)
- Brain (1)
- Brain Computer Interface (1)
- Brainstem encephalitis (1)
- Breaking (1)
- Breast cancer (1)
- Breath tests (1)
- Broca (1)
- B‐cell lymphoma (1)
- C2-toxin (1)
- CA19-9 (1)
- CD11b+ myeloid cells (1)
- CD39 (1)
- CD73 (1)
- CD8 (1)
- CDH13 Expression (1)
- CDH13 mRNA (1)
- CHIP (1)
- CKD (1)
- CML (1)
- COD movements (1)
- COPD (1)
- CO\(_{2}\) exposure (1)
- CO\(_{2}\) signaling (1)
- CSF (1)
- CSI (1)
- Cadherin (CDH13) (1)
- Calcineurin-NFATsignaling (1)
- Campylobacter jejuni (1)
- Canada (1)
- Cancer (1)
- Carbon (1)
- Carcinoma cells (1)
- Cardiology (1)
- Cardiovascular disease (1)
- Cardiovascular magnetic-resonance (1)
- Case-Control Studies (1)
- Cell lung canger (1)
- Cell replacement therapy (1)
- Cell reprogramming (1)
- Cell signalling (1)
- Cell-based assays (1)
- Cellular prion protein (1)
- Central hyperactivity (1)
- Central nervous system infection (1)
- Central venous-pressure (1)
- Ceramide (1)
- Cerebellitis (1)
- Cerebral-ischemia (1)
- Cervical cancer (1)
- ChIP-sequencing (1)
- Charcot-Marie-Tooth (1)
- Chemerin (1)
- Chemerin processing (1)
- Chemicals (1)
- Childhood (1)
- Childhood medulloblastoma (1)
- Childrens-cancer (1)
- China (1)
- Chlorophyll fluorescence (1)
- Chromophores (1)
- Chromosomes (1)
- Chronic kidney disease (1)
- Chronic neuropathic pain (1)
- Chronic respiratory diseases (1)
- Chronic stress (1)
- Cimex lectularius (1)
- Clinical Genetics (1)
- Clinical practice guidelines (1)
- Clinical remission (1)
- Clinical trial (1)
- Cocalodinae (1)
- Cognitive Therapy (1)
- Cohort study (1)
- Coleoptera: Chrysomelidae (1)
- Collaboration (1)
- Colony growth (1)
- Combinatorial Background (1)
- Conditioning evidence (1)
- Conduct disorder (1)
- Conjugate arc therapy (1)
- Conjugated polymers (1)
- Context (1)
- Contextual fear (1)
- Contrast-enhanced CT (1)
- Copaxone® (1)
- Coronary artery disease (1)
- Cortical plasticity (1)
- Cotransporter 2 inhibition (1)
- Couch tracking (1)
- Critically-ill patients (1)
- Cruzi (1)
- Cvi-0 (1)
- Cyclic GMP (1)
- Cyclic electron transport (1)
- Cycloaddition (1)
- Cystic-fibriosis (1)
- Cytokine GM-CSF (1)
- Cytokine receptors (1)
- Cytokines (1)
- Cytoskeleton (1)
- Cytotoxic (1)
- Cytotoxic T lymphocytes (1)
- D313Y genotype (1)
- DAMGO (1)
- DARPA (1)
- DNA Methylation (1)
- DNA binding (1)
- DNA metabolism (1)
- DNA methylation dynamics (1)
- DNA sequencing (1)
- DNA-based species delimitation (1)
- DNA-encapsulated silver nanoclusters (1)
- DOTATOC (1)
- DPF3a (1)
- DYT1 (1)
- Danio-rerio (1)
- Dark Matter (1)
- Deficit/hyperactivity disorder (1)
- Dendritic cells (1)
- Densities (1)
- Dentate granule cells (1)
- Design (1)
- Devic syndrome (1)
- Devic’s syndrome (1)
- Diabetes mellitus (1)
- Diagnostic approach (1)
- Diborane (1)
- Dictyostelium discoideum (1)
- Differential RNA-sequencing (1)
- Diisononyl phthalate (1)
- Dimers (1)
- Dionaea-muscipula ellis (1)
- Diplopia Internuclear ophthalmoplegia (INO) (1)
- Disease gene prioritization (1)
- Disease genetics (1)
- Disease prevalence (1)
- Distress (1)
- Diversity (1)
- Dorsolateral prefrontal cortex (1)
- Dose reduction (1)
- Double-blind (1)
- Draize eye test (1)
- Drosha (1)
- Drosophilia (1)
- Drug development (1)
- Drug metabolism (1)
- Drug-free remission (1)
- Duchenne muscular dystrophy (1)
- Dystonia (1)
- E3 ligase (1)
- EANM (1)
- EBV (1)
- EDS (1)
- EIP on AHA (1)
- ELISPOT (1)
- ESTARFM (1)
- EU‐RHAB Registry (1)
- Early posterior negativity (1)
- Eating disorder (1)
- Ecological momentary assessment (1)
- Ecologically important traits (1)
- Edema (1)
- Effectors in plant pathology (1)
- Ehlers-Danlos syndrome (1)
- Elective cesarean-section (1)
- Electroencephalography (1)
- Electrophysiology (1)
- Embryonic stem cell (1)
- Emission (1)
- Emotion (1)
- Emotion regulation (1)
- Emotional expression (1)
- Endothelial growth-factor (1)
- Endothelium (1)
- Energy depletion (1)
- Energy transfer (1)
- Entanglement (1)
- Enteric nervous system (1)
- Enteric neuropathies (1)
- Enterovirus (1)
- Environment (1)
- Environmental enrichment (1)
- Epidemiological study (1)
- Epidemiology (1)
- Epidermal growth-factor (1)
- Epidermis (1)
- Epigenesis (1)
- Epigenetics (1)
- Episkin (1)
- Epitaxy (1)
- Epitope (1)
- Escherichia coli K1 (1)
- Ethanol (1)
- European Innovation Partnership on Active and Healthy Ageing (1)
- Event (1)
- Event-related potential (1)
- Evoked potentials (1)
- Exciton-polariton condensate (1)
- Excitons (1)
- Exercise (1)
- Exosome (1)
- Extracorporeal Membrane Oxygenation (1)
- Eye gaze (1)
- F-18-FDG PET/CT (1)
- FANCM (1)
- FE (1)
- FISH-CLEM (1)
- FOLFIRI (1)
- FOLFOX (1)
- FP-CIT SPECT (1)
- FRET (1)
- FRET sensors (1)
- FT-IR spectroscopy (1)
- FWGE (1)
- FXIIa inhibitor rHA-Infestin (1)
- Fabry cardiomyopathy (1)
- Fabry nephropathy (1)
- Fabry-associated pain (1)
- Faces and scenes (1)
- Facial nerve palsy (1)
- Factor receptor (1)
- Familial Alzheimers-disease (1)
- FeS proteins (1)
- Female (1)
- Fermi liquid (1)
- Ferrite (1)
- Fetal brain development (1)
- Fibroblasts (1)
- Fiels-effect transistors (1)
- Fischer 344 rats (1)
- Flash relaxation kinetics (1)
- Flow cytometry (1)
- Fluorescein angiography (1)
- Fluorouracil (1)
- Foragers (1)
- Fourier-transform spectroscopy (1)
- FoxQ2 (1)
- Frequency-response areas (1)
- Fresh Freeze Plasma (1)
- Frontal cortex (1)
- Functionalization (1)
- Fungal (1)
- Fungal host response (1)
- Förster resonance energy transfer (1)
- G Protein (1)
- G protein coupled receptors (1)
- G-protein coupled receptors (1)
- GABP (1)
- GLA mutation (1)
- GPCR (1)
- GWAS (1)
- GaAsSb (1)
- Galactic Ridge (1)
- Galactosidase-A gene (1)
- Gamma (1)
- Gaze perception (1)
- Gene expression profiling (1)
- Gene-expression (1)
- Genetic (1)
- Genitoanal region (1)
- Genome assembly (1)
- Genome comparison (1)
- Genome re-annotation (1)
- Genome-wide association studies (1)
- Genomics data sets (1)
- Genotype–phenotype correlations (1)
- Gifsy-1 (1)
- Gimbaled tracking (1)
- Glatiramer acetate (1)
- Glucose metabolism (1)
- Glucose uptake (1)
- Glucosyltransferase (1)
- Glutamatergic synapses (1)
- Glutathione (1)
- GlyR receptors (1)
- Glycaemic control (1)
- Golgi (1)
- Graft versus Tumor (1)
- Graft-versus-leukemia (1)
- Graphene nanoribbons (1)
- Group B Streptococcus (1)
- Growth; BMP-2 (1)
- Guanylyl cyclase-A (1)
- Guideline (1)
- Guillain-Barré-Syndrom (1)
- Guinea pig model (1)
- Gα\(_{i1}\), Gα\(_{i2}\) and Gα\(_{i3}\) activation (1)
- H-1-NMR spectroscopy (1)
- HEY repressors (1)
- HFpEF (1)
- HFrEF (1)
- HIV infection (1)
- HIV infections (1)
- HIV neurocognitive impairment (1)
- HIV-1 subtype AG (1)
- HKT1 (1)
- HPV (1)
- Habitats (1)
- Haloferax volcanii (1)
- Hamburg (1)
- Head-injury (1)
- Hearing loss (1)
- Hearing-loss (1)
- Heart (1)
- Helicobacter pylori (1)
- Hemodynamic depression (1)
- Hemoglobin A1C (1)
- Hepatitis B virus (1)
- Hepatitis C (1)
- Herpes simplex encephalitis (1)
- Herpes simplex virus (1)
- Heterocycles (1)
- Heterocyclische Verbindungen (1)
- Higgs Boson (1)
- Higgs Mass (1)
- Higgs-boson (1)
- High efficiency (1)
- High performance (1)
- High-dose chemotherapy (1)
- High-spontaneous rate (1)
- Highlights Lecture (1)
- Hippocampus (1)
- Hirschsprung disease (1)
- Hirschsprung disease liability (1)
- Histologic grade (1)
- Hoechst 33342 (1)
- Homeostatic plasticity (1)
- Horizontal transfer (1)
- Hormesis (1)
- Hospitalization (1)
- Host adaptation (1)
- Hsp90 (1)
- Hueter interval (1)
- Human CDH13 (1)
- Human Physiome (1)
- Human Resource Management (1)
- Human and murine cancer cells (1)
- Human immunodefiency virus (1)
- Human prefrontal cortex (1)
- Hydrogen-peroxide (1)
- Hydroxymethyluracil (1)
- Hymenoptera (1)
- Hypertonic saline 7.5-percent (1)
- Hypertrophic cardiomyopathy (1)
- Hypertrophic pyloric-stenosis (1)
- IBA-1 (1)
- IGRT (1)
- IL-1 beta (1)
- IL-1 blockade (1)
- IL-10 (1)
- IL-12 family (1)
- IMAT (1)
- IMRT (1)
- IPND criteria (1)
- IVIg (1)
- Identification (1)
- IgE (1)
- IgE sensitazion (1)
- Illumina Human Exome Bead Chip (1)
- Image interpretation (1)
- Imatinib (1)
- Immune tolerance (1)
- Immunocompromised patient (1)
- Immunotherapy (1)
- In vitro skin irritation testing (1)
- In-vivo (1)
- InSAR (1)
- Incomplete contracts (1)
- Indian muntjac (1)
- Inferior Vena Cava (1)
- Inferior colliculus (1)
- Infliximab (1)
- Influenzae type B (1)
- Information (1)
- Information Integration Theory (1)
- Inhibitory glycine receptor (1)
- Inner hair cell (1)
- Insect hosts (1)
- Insects (1)
- Insulating thin films (1)
- Insulator surfaces (1)
- Insulin therapy (1)
- Intelligent mobile system (1)
- Intensity (1)
- Interactive Tree Of Life (iTOL) (1)
- Interband cascade lasers (1)
- Interferon beta (1)
- Interleukin IL-6 (1)
- Intermediate filaments (1)
- Internal transcription start site (1)
- International consensus diagnostic criteria for neuromyelitis optica spectrum disorders (1)
- Intestinal pseudoobstruction (1)
- Intracellular domain (1)
- Intractable nausea and vomiting (1)
- Intravascular coagulation (1)
- Invasion (1)
- Invasive Aspergillosis (1)
- Invasive fungal-infections (1)
- Iran (1)
- IsrK (1)
- JR11 (1)
- Jak kinases (1)
- Janus kinase (1)
- Jasmonate perception (1)
- Jasmonic acid (1)
- Joint ownership (1)
- Josephson effect (1)
- Joubert syndrome (1)
- Jurkat T cells (1)
- Jurkat cells (1)
- K2–K model (1)
- KAT/HAT (1)
- Kenyon cells (1)
- Kidney function (1)
- Kohlberg (1)
- L. reuteri (1)
- LASP1 (1)
- LED (1)
- LIN-5 (1)
- LITAF (1)
- LPS (1)
- Lacking neurofilaments (1)
- Lactated ringers solution (1)
- Lag time (1)
- Landsat (1)
- Large T antigen (1)
- Large multicenter ADHD (1)
- Latin America (1)
- Leaderless transcript (1)
- Lectins (1)
- Lepidoptera (1)
- Light Supersymmetric Particle (1)
- Light-emitting diodes (1)
- Lipid (1)
- Lipid metabolism (1)
- Liposomal amphotericin-B (1)
- Liquid-crystalline (1)
- Liver cirrhosis (1)
- Localized states (1)
- Locomotor activity (1)
- Locus (1)
- Long-range order (1)
- Longitudinally extensive transverse myelitis (1)
- Low-dose acyclovir (1)
- LpxC inhibitors (1)
- Luxembourg (1)
- Lynx lynx (1)
- MACVIA (1)
- MAG3 (1)
- MAPK pathway (1)
- MDSCs (1)
- MHC class I chain-related protein (1)
- MIZ1 (1)
- MLC tracking (1)
- MMQ cells (1)
- MOG-IgG (1)
- MPACT (1)
- MPK12 (1)
- MR (1)
- MRI criteria (1)
- MSSM (1)
- MU-M (1)
- MYC (1)
- MYCN (1)
- Macrophage (1)
- Magnetic resonance imaging (1)
- Major abdominal surgery (1)
- Male breast cancer (1)
- Male intromittent organ (1)
- Malignant melanoma (1)
- Management (1)
- Mandibular condyle (1)
- Mandibular continuity defects (1)
- Manifestation (1)
- Marcus inverted region (1)
- Marrow stromal cells (1)
- Mass (1)
- Mast cells (1)
- Matrix (1)
- McDonald criteria (1)
- Medical overuse (1)
- Medical students (1)
- Medicalization (1)
- Medulloblastoma (1)
- Meiosis (1)
- Melanoma B16 (1)
- Mellitus (1)
- Meningococcal serogroup C (1)
- Meningococci (1)
- Mesenchymal stem cells (1)
- Mesenchymal stem/stromal cells (1)
- Mesenchymal transition (1)
- Mesocestoides corti (1)
- Messenger RNA (1)
- Methicillin resistant Staphylococcus aureus (1)
- Methodological quality (1)
- Methotrexate (1)
- Methylation (1)
- Methylome (1)
- MgAl LDH (1)
- Microcavity (1)
- Microenvironment (1)
- Microorganisms (1)
- Microtubules (1)
- Mid-infrared photoluminescence (1)
- Midline (1)
- Mindfulness (1)
- Minimal supersymmetric model (1)
- Missense mutation (1)
- Mitomycin C (1)
- Mitsunobu (1)
- Molecular Imaging (1)
- Molecular beam epitaxy (1)
- Molecular-dynamics (1)
- Molecular-weight heparin (1)
- Molecules (1)
- Monoamine Oxidase/genetics (1)
- Morbus Fabry (1)
- Mortality (1)
- Motivation (1)
- Motoneuron disease (1)
- Mouse model (1)
- Mt. Kinabalu (1)
- Mud (1)
- Multibranched structures (1)
- Multicenter randomized-trial (1)
- Multiple drug resistance (1)
- Multiple myeloma (1)
- Mutations (1)
- Myelin oligodendrocyte glycoprotein (MOG) antibodies (1)
- Myelitis (1)
- Myeloma (1)
- Myocardial fibrosis (1)
- Myocardial perfusion (1)
- Müller cells (1)
- N-Myc (1)
- N-heterocyclic carbenes (1)
- N-oleoyl serinol (1)
- N100 (1)
- N170 (1)
- NDI-H (1)
- NEUROWIND (1)
- NFkB-relatedgenes (1)
- NGS (1)
- NK cells (1)
- NLO computations (1)
- NMD (1)
- NMO-IgG (1)
- NMOSD (1)
- NMR (1)
- NMR-spectroscopy (1)
- NO (1)
- NPU (1)
- NSCLC (1)
- NSG mice (1)
- Nanda-Hamner (1)
- Nanoparticles (1)
- Nasonia courtship (1)
- Natalizumab (1)
- Natural-history data (1)
- Neisseria gonorrhoeae (1)
- Neisseria meningitidis (1)
- Nesting resources (1)
- Netrin (1)
- Network (1)
- Neural crest cells (1)
- Neurofilament (1)
- Neuroinfectiology (1)
- Neuromyelitis optica (NMO) (1)
- Neuromyelitis optica antibodies (NMO-IgG) (1)
- Neurosciences (1)
- Neurotropathic Factor (1)
- Neutrino Telescope (1)
- Neutrophil (1)
- Nitric-oxide (1)
- Nodule (1)
- Non-coding RNAs (1)
- Normal breast (1)
- Nrf2 (1)
- NuMA (1)
- Nurses (1)
- OCB (1)
- OCSVM (1)
- OCT angiography (1)
- OECD guideline (1)
- OPS201 (1)
- Oesling (1)
- Ofatumumab (1)
- Oilseed rape (1)
- Olfr1393 (1)
- Oligoclonal bands (1)
- Oncology (1)
- Oncolytic action (1)
- One-photon (1)
- Oogenesis (1)
- Open source reconstructed epidermis (1)
- Openfield test (1)
- Opsins (1)
- Optical properties (1)
- Oral antidiabetic drugs (1)
- Oral squamous cell carcinoma (1)
- Organ motion (1)
- Osteoarthritis (1)
- Osteoarthrosis (1)
- Osteogenic precursor cells (1)
- Outcome (1)
- Overdiagnosis (1)
- Oxidative stress (1)
- Oxide synthase gene (1)
- Oxygen (1)
- P300 speller (1)
- P75 Neurotrophin receptor (1)
- PARROT (1)
- PBI cyclophane (1)
- PDE (1)
- PDGF (1)
- PET/CT (1)
- PI3K isoforms (1)
- PI3K/Akt/mTOR (1)
- PICD (1)
- PKB/Akt phosphorylation (1)
- PSMA (1)
- PUMP (1)
- Paediatric (1)
- Palladium-catalyzed silaboration (1)
- Panic Disorder/genetics (1)
- Panic Disorder/therapy (1)
- Parametric down-conversion (1)
- Parasite (1)
- Parkinson disease (1)
- Pathogenicity (1)
- Pathogens (1)
- Pathology (1)
- Pathway (1)
- Patient-centered care (1)
- Patterns (1)
- Peptidase inhibitor 16 (PI16) (1)
- Peptidoglycan recognition (1)
- Peripheral nervous system (1)
- Perovskite (1)
- Personality (1)
- Phosphorylation (1)
- Photochemistry (1)
- Photosystem I (1)
- Physics and instrumentation (1)
- Pinus sylvestris L. (1)
- Pitrakinra (1)
- Placebo (1)
- Placebo-controlled trial (1)
- Plant utricularia-gibba (1)
- Plants (1)
- Plasma extravasation (1)
- Plasma-membrane (1)
- Pleistocene (1)
- Pluripotency (1)
- Pneumococci (1)
- Pneumocystis-carinii-pneumonia (1)
- Podocarpus National Park (1)
- Poecilia reticulata (1)
- Polarimetric Synthetic Aperture Radar (PolSAR) (1)
- Polistine wasps (1)
- Polycistronic mRNA (1)
- Polymerase chain raction (1)
- Polyphasic fluorescence rise (1)
- Polyphenols (1)
- Poor-prognosis (1)
- Porphyrin arrays (1)
- Positron-emission-tomography (1)
- Potential-energy curves (1)
- Pou2af1 (1)
- Preclinical evaluation (1)
- Predict fluid responsiveness (1)
- Pregnancy (1)
- Primary cell lines (1)
- Primary endosymbiont (1)
- Primitive neuroectodermal (1)
- Programmed cell-death (1)
- Progressive motor neuronopathy (1)
- Progressive multifocal leukoencephalopathy (1)
- Progressive supranuclear palsy (1)
- Prolactin (1)
- Promoter (1)
- Promoter prediction (1)
- Property rights approach (1)
- Prostate-cancer (1)
- Protease inhibition (1)
- Protein (1)
- Protein function prediction (1)
- Protein kinase B (1)
- Protein transduction (1)
- Proteogenomics (1)
- Pulmonary Embolism (1)
- Pulmonary hypertension (1)
- Puls-pressure variation (1)
- Purification (1)
- QTL analysis (1)
- Qualitative representation and reasoning (1)
- Quantum wells (1)
- RARRES2 (1)
- RHE (1)
- RNA (1)
- RNA isolation (1)
- RNA polymerase (1)
- RNA sequencing (RNA-Seq) (1)
- RNA-SEQ data (1)
- RNA-binding proteins (1)
- RNA-seq (1)
- RNAseq (1)
- ROS (1)
- RU(CO)(3)CL(GLYCINATE) (1)
- RU-(II) complexes (1)
- Racial differences (1)
- Radarsat-2 (1)
- Radionuclide Therapy (1)
- Radionuclide therapy (1)
- Radiopharmacy (1)
- Radiotherapy (1)
- Rapid evolution (1)
- Rat (1)
- Rat mynteric plexus (1)
- Rating scale (1)
- Rats (1)
- RbdB (1)
- Reaction kinetics and dynamics (1)
- Real-time PCR (1)
- Recurrent medulloblastoma (1)
- Redox environment (1)
- Regenerative medicine (1)
- Regulatory T cells (1)
- Regulatory T-cells (1)
- Regulatory-cells (1)
- Reirradiation (1)
- Relapsing-remitting MS (1)
- Remotely Operate Vehicle (1)
- Reproduction (1)
- Respiratory insufficiency (1)
- Respiratory syncytial virus (1)
- Responses (1)
- Retinal arterial macroaneurysms (1)
- Reveals (1)
- Rhabdoid 2007 (1)
- Rheumatoid arthritis (1)
- Rhodopsins (1)
- Rhombencephalitis (1)
- Richness (1)
- Rictor-mTOR complex (1)
- Rituximab (1)
- Robertsonian translocation chromosomes (1)
- Robotic tracking (1)
- Ru(II)–Fe(II)–Ru(II) complex (1)
- S-HT (1)
- SABR (1)
- SAP47 gene (1)
- SAR (1)
- SBRT (1)
- SCD (1)
- SCORE (1)
- SEM (1)
- SERT (1)
- SFRP (1)
- SGLT2 inhibitor (1)
- SPECT (1)
- SSRI (1)
- SSTR (1)
- STAT3 activation (1)
- SUMO2 (1)
- SVM (1)
- Saccharomyces cerevisiae (1)
- Salmonella Typhimurium (1)
- Salmonella enterica (1)
- Salmonella-enteritidis (1)
- Sap47 (1)
- Sarah (1)
- Scaling up (1)
- Schizophrenia (1)
- Schnitzler syndrome (1)
- Schwann cell dedifferentiation (1)
- Screening questionnaire (1)
- SdsR (1)
- Secondary tumours (1)
- Seeds (1)
- Selective attention (1)
- Selen (1)
- Selenium (1)
- Senescence (1)
- Sentinel-1 (1)
- Septal bulge (1)
- Sequence Analysis (1)
- Sequence identity (1)
- Si-rhodamine (1)
- Signal transduction (1)
- Simulations (1)
- Single nucleotide change (1)
- Sinorhizobium fredii (1)
- Sinus floor augmentation (1)
- Six3/6 Wnt (1)
- Skin (1)
- Skin cancer screening (1)
- Slow-transit constipation (1)
- Small fiber dysfunction (1)
- Smartphones (1)
- SnRK1 (1)
- Social anxiety (1)
- Social entrainment (1)
- Social support (1)
- Social work (1)
- Sound detection threshold (1)
- South Africa (1)
- Spectrum (1)
- Speedcourt (1)
- Spheno (1)
- Spin echo (1)
- Spinal Muscular-arthropy (1)
- Spontaneous facial EMG (1)
- Sputter deposition (1)
- Squamous-cell carcinoma (1)
- Sracking (1)
- Stage distribution (1)
- Stat3 (1)
- State (1)
- Stathmin (1)
- Stem cells (1)
- Stem cells plasticity (1)
- Strains (1)
- Stratified scree (1)
- Streptococcus suis (1)
- Stress (1)
- Stress prevention (1)
- Stress responses (1)
- Stroke (1)
- Sturge-Weber syndrom (1)
- Supersymmetry Breaking (1)
- Suppression (1)
- Surface states (1)
- Survival (1)
- Survival analysis (1)
- Susceptibility loci (1)
- Sustainable HRM (1)
- Sustained attention (1)
- Syap1 localization (1)
- Synaptic plasticity (1)
- Synovitis (1)
- Synthetic Aperture Radar (SAR) (1)
- System involvement (1)
- T cell differentiation (1)
- T cells (1)
- T lymphocytes (1)
- T-cells (1)
- TBI (1)
- TCR diversity (1)
- TGF-β1 (1)
- TIG2 (1)
- TLR2 (1)
- TLR4 (1)
- TLR9 (1)
- TNF (1)
- TNFR2 (1)
- TNM staging (1)
- TRECs (1)
- TSPO (1)
- T\(_H\)17 cells (1)
- Tamm plasmons (1)
- Tanzania (1)
- Targeted therapy (1)
- Task force (1)
- Tellur (1)
- Tellurium (1)
- Temperature rhythms (1)
- Temporal-lobe epilepsy (1)
- Temporomandibular disorders (1)
- Temporomandibular joint disc (1)
- Term follow-up (1)
- Terminology (1)
- TerraSAR-X (1)
- Test accuracy (1)
- Th17 (1)
- Thigmotaxis (1)
- Thin film growth (1)
- Thioredoxin (1)
- Thrombus formation (1)
- TiO\(_2\) (1)
- Time Calibration (1)
- Time-course (1)
- Tissue (1)
- Tissue engineering (1)
- Toll-like receptors (1)
- Tourette syndrome (1)
- TraDIS (1)
- Trans-reservatrol (1)
- Transaction costs (1)
- Transcription (1)
- Transcription initiation (1)
- Transcription start site (1)
- Transferases (1)
- Transgenic mice (1)
- Transovarial transmission (1)
- Transport (1)
- Transposon insertion sequencing (1)
- Transverse Myelitis (1)
- Transverse myelitis (1)
- Tregs (1)
- Trial (1)
- Trinidadian guppy (1)
- Trypanosoma-brucei (1)
- Trypanosomes (1)
- Tumor-necrosis-factor (1)
- Tumorigenicity (1)
- Tumors (1)
- Type II quantum wells (1)
- Type-II quantum well (1)
- Typhimurium (1)
- Tyrosine phosphorylation (1)
- USP9X (1)
- UV/Vis spectroscopy (1)
- Ube2S (1)
- Ubiquitin-conjugating (E2) enzymes (1)
- Ulcerative colitis (1)
- Uterine tumors (1)
- Uveitis (1)
- VACV (1)
- VBM (1)
- VE-cadherin (1)
- VEGF (1)
- VMAT (1)
- Vaccination (1)
- Vaccine (1)
- Vaccinia virus (1)
- Vacuum chambers (1)
- Variants (1)
- Varicella-Zoster-Virus (1)
- Varicella-zoster-virus (1)
- Vascular plasticity (1)
- Venous Thrombosis (1)
- Ventricular-arrhythmias (1)
- Venusfliegenfalle (1)
- Vertical integration (1)
- Viability (1)
- Vibronic contributions (1)
- Vigilance (1)
- Viral (1)
- Virotherapy (1)
- Virtual-reality (1)
- Vivo (1)
- Vortices (1)
- W-boson (1)
- WDR5 (1)
- WIMP (1)
- Wallemia ichthyophaga (1)
- Weight (1)
- West Africa (1)
- Williamsia sp. ARP1 (1)
- Wilms tumor (1)
- Wingerchuk criteria 2006 and 2015 (1)
- Wnt signalling (1)
- Wonderful plants (1)
- X-ray analysis (1)
- X. couchianus (1)
- X. hellerii (1)
- XIAP (1)
- XPS (1)
- Xiphophorus (1)
- Xiphophorus fish (1)
- Yersinia (1)
- Yield (1)
- Zebrafish (1)
- Zenith Angle (1)
- \(^{68}\)Ga-Pentixafor (1)
- accumulation (1)
- acetyltransferases (1)
- achaete-scute homolog 1 (1)
- acquired thermotolerance (1)
- acquisition (1)
- action potential (1)
- active transport (1)
- active zone (1)
- acute Graft versus Host Disease (1)
- acute lymphocytic leukaemia (1)
- adaptation models (1)
- adaptive immune system (1)
- adenocarcinoma of the ampulla of Vater (1)
- adenocarcinoma of the lung (1)
- adenomas (1)
- adenoviruses (1)
- adhesion (1)
- adipose (1)
- adipose tissue (1)
- adipose tissue dysfunction (1)
- adipose-derived stem cells (1)
- adjuvant (1)
- adolescence (1)
- adult attention deficit/hyperactivity disorder (1)
- adults (1)
- aerodynamics (1)
- age factors (1)
- age-related macular degeneration (1)
- aged (1)
- aged 80 and over (1)
- aggressiveness (1)
- agri-environment schemes (1)
- agriculture (1)
- albumin excretion rate (1)
- alfabetización mediática (1)
- algorithm (1)
- aliphatic compounds (1)
- alkenes (1)
- allergy (1)
- allogeneic hematopoietic stem cell transplantation (1)
- allogeneic stem cell transplantation (1)
- allostatic load (1)
- alpha-galactosidase A (1)
- alternative to animal testing (1)
- alternatives (1)
- amber codon suppression (1)
- amino-acids (1)
- aminoquinolinium salts (1)
- amphotericin B (1)
- amplicon sequencing (1)
- analysis of variance (1)
- anaplastic medulloblastoma (1)
- anastomotic leakage (1)
- anatomical landmark (1)
- anchoring (1)
- anemia (1)
- aneurysm surgery (1)
- angiogenesis (1)
- angiogenic cytokines (1)
- angiography (1)
- animal models (1)
- animal movement (1)
- animals (1)
- anionic dimetalloborylene complexes (1)
- anisotropy energy (1)
- annotation (1)
- ant-mimicking spiders (1)
- antennas (1)
- anterior optic tubercle (1)
- antero-posterior axis (1)
- anthropogenic activities (1)
- anti-tumor effects (1)
- antibacterial activity (1)
- anticipation (1)
- anticipatory planning (1)
- anticoagulants (1)
- antidepressants (1)
- antidiabetic agents (1)
- antiferromagnet (1)
- antimicrobial resistance (1)
- antimycotics (1)
- antioxidants (1)
- antiretroviral therapy (1)
- antitumor immune response (1)
- antiviral immunity (1)
- antiviral treatment (1)
- ants (1)
- anxiety disorders (1)
- anxiety-like behavior (1)
- análisis transnacional (1)
- aphasia (1)
- applied physics (1)
- approach (1)
- aquaporin 4 (1)
- aquaporin-4 antibodies (AQP4-IgG) (1)
- aqueous-solution (1)
- arabidopsis (1)
- arabidopsis-thaliana (1)
- arctic (1)
- army ants (1)
- arousal (1)
- artificial diet (1)
- ascites (1)
- aspergillus fumigatus (1)
- assembly (1)
- assembly chaperone (1)
- assistive technology (1)
- association (1)
- associative memory (1)
- asthma (1)
- astrocytes (1)
- atmospheric chemistry (1)
- atopic-dermatitis (1)
- atrial fibrillation (1)
- attentional bias (1)
- attraction (1)
- audio stimulus (1)
- auditory (1)
- auditory stimulation (1)
- autism (1)
- autism spectrum disorder (1)
- autoantibody (1)
- autoimmunity (1)
- autophagy (1)
- autoradiography (1)
- azidothymidine (1)
- azobenzenes (1)
- bacterial genetics (1)
- bacterial infection (1)
- bed bug (1)
- bee community (1)
- bees (1)
- behavior (1)
- benzoquinone (1)
- beta oscillations (1)
- beta-D-glucan (1)
- beta-blockers (1)
- beta2-adrenoceptor knockout (1)
- beta3 CL 316,243 (1)
- biliary-tract cancer (1)
- binding components (1)
- bio-orthogonal chemistry (1)
- biochemistry (1)
- biocompatibility (1)
- biodiversity assessment (1)
- bioenergetics (1)
- biofuels (1)
- biogenic volatile organic compounds (1)
- bioinformatics (1)
- bioinspired materials (1)
- biolog (1)
- biological mechanism (1)
- bioluminescence (1)
- bioluminescence imaging (1)
- biomarkers Myelomas (1)
- biomechanical test (1)
- biophotonic imaging (1)
- biopsy (1)
- biosensors (1)
- birth cohort (1)
- bis-terpyridyl ligands (1)
- black lipid bilayer (1)
- blastemal (1)
- blood (1)
- blood coagulation (1)
- blood flow (1)
- blood plasma (1)
- blood pressure (1)
- blood pressure monitoring (1)
- body mass index (1)
- body weight (1)
- body weight regulation (1)
- bone imaging (1)
- bone metastases (1)
- boron (1)
- botulinum toxin (1)
- brain computer interface (1)
- brain derived neurotrophic factor (1)
- brain response (1)
- brain swelling (1)
- brain tumor (1)
- brain-computer interface (1)
- brain-computer interface (BCI) (1)
- brain-injury (1)
- break-in parties (1)
- breast cancer subtypes (1)
- breast-cancer (1)
- brefeldin-a (1)
- broodtranslocation (1)
- bug riptortus-pedestris (1)
- bull’s eye plot (1)
- cAMP (1)
- caenorhabditis elegans (1)
- cag pathogenicity island (1)
- calcification (1)
- calcineurin signaling cascade (1)
- calcitonin gene-related peptide (1)
- calcium sensitivity (1)
- calcium signaling (1)
- calorie content (1)
- calyx (1)
- camelina-sativa (1)
- camponotus ants (1)
- campylobacter jejuni infection (1)
- campylobacter-jejuni (1)
- cancer biology (1)
- cancer cells (1)
- cancer chemotherapy (1)
- cancer detection and diagnosis (1)
- cancer risk (1)
- cancer stem cells (1)
- canopy spiders (1)
- capacitance (1)
- carbenes (1)
- cardiac (1)
- cardiac arrest documentation (1)
- cardiac pacing (1)
- cardiopulmonary resuscitation (1)
- cardiorespiratory disease (1)
- cardiovascular (1)
- cardiovascular disease (1)
- cardiovascular outcomes (1)
- care (1)
- carotid arteries (1)
- cascade reactions (1)
- cell biology (1)
- cell compartmentation (1)
- cell cycle and cell division (1)
- cell cycle arrest (1)
- cell death (1)
- cell differentiation (1)
- cell labeling (1)
- cell membranes (1)
- cell motility (1)
- cell proliferation (1)
- cell signalling (1)
- cell staining (1)
- cell vaccines (1)
- cellular imaging (1)
- central complex (1)
- central lung (1)
- central nervous system (1)
- cephalosporin-resistant gram-negative bacteria (1)
- cerebral blood flow (1)
- cervical dystonia (1)
- cesioflammea (1)
- cestodes (1)
- chemokine receptor-4 (1)
- chemotaxis (1)
- child development (1)
- child memory (1)
- childhood asthma (1)
- childhood maltreatment (1)
- chip analyses (1)
- chloroquine (1)
- chorioretinal lesions (1)
- chromatin (1)
- chromism (1)
- chronic myelogenous leukemia (1)
- chronic myeloid leukemia (1)
- chronic obstructive (1)
- chronic periodontitis (1)
- chronic respiratory-diseases (1)
- chronobiology (1)
- circularly-polarized light (1)
- classification (1)
- classification and labeling (1)
- claudin 5 (1)
- climate factors (1)
- climate impact (1)
- clinical (1)
- clinical trial (1)
- clinical-practice (1)
- clip control (1)
- cloning (1)
- closed-loop (1)
- cloud gap filling (1)
- cluster-RCT (1)
- co-adaptive (1)
- coagulation factor XIIa (1)
- coatings (1)
- cochlear nucleus neurons (1)
- coconut cocos-nucifera (1)
- coexistence (1)
- cognition (1)
- cognition development (1)
- cognitive functions (1)
- coherence (1)
- coherence analysis (1)
- coherent light (1)
- colony survival (1)
- color vision (1)
- common factors (1)
- common teal (1)
- community ecology (1)
- community-dwelling (1)
- comparative HRM (1)
- competency based teaching (1)
- complexes (1)
- complication (1)
- composites (1)
- compounds (1)
- computer-assisted (1)
- conditioned response (1)
- conductance (1)
- conductive hearing loss (1)
- cone beam CT (1)
- cones (1)
- confocal laser microscopy (1)
- congenital ocular motor apraxia (1)
- consistent partial least squares (1)
- conspicuous consumption (1)
- contact activation system (1)
- contrast (1)
- conversion (1)
- converting enzyme-inhibition (1)
- coping with challenge (1)
- copper (1)
- corneal equivalent (1)
- corporate restructuring (1)
- correlation function (1)
- correlation properties (1)
- correlative light and electron microscopy (1)
- corticosteroids and cyclophosphamide (1)
- costly (1)
- couplers (1)
- critical limits (1)
- crop pollination (1)
- cropland vegetation phenology (1)
- cross-species comparison (1)
- crossnational analysis (1)
- cryptogenic stroke (1)
- crystal-structure (1)
- curricula (1)
- currículo de la educación en medios (1)
- currículum (1)
- cuticular transpiration (1)
- cuticular wax (1)
- cutin (1)
- cyclic perylene bisimide (1)
- cyclic test (1)
- cycloid psychoses (1)
- cytokinins (1)
- cytoplasm (1)
- cytoplasmic staining (1)
- cytoskeleton dynamics (1)
- cytosol (1)
- cytostatic (1)
- dRNA-Seq (1)
- damped-oscillator-model of photoperiodic clock (1)
- daratumumab monotherapy (1)
- dark matter (1)
- dark matter detectors (1)
- dark matter experiments (1)
- data mining/methods (1)
- decision making (1)
- decision support (1)
- deep sea neutrino telescope (1)
- deficient mutant (1)
- dehydration (1)
- delineation (1)
- democracy (1)
- dendric cells (1)
- depreissia decipiens (1)
- depression (1)
- dermal melanocytosis (1)
- desert (1)
- design (1)
- detrusor muscle (1)
- deuterostomes (1)
- development (1)
- developmental biology (1)
- developmental delay (1)
- developmental disorders (1)
- devices for energy harvesting (1)
- diabetes (1)
- diabolical points (1)
- diagnosis (1)
- diapause (1)
- diarrhea (1)
- diborenes (1)
- dichroism (1)
- dichthadiigynes (1)
- dicyclohexyl phthalate (1)
- dietary sodium restriction (1)
- diffuse (1)
- dilaboration (1)
- dimerization (1)
- direct anterior approach (1)
- direct stochasticoptical reconstruction microscopy (1)
- discordance (1)
- disease risk-factors (1)
- disease-activity score (1)
- distance running (1)
- distributed control (1)
- disulfide bonds (1)
- dogs (1)
- dopamine transporters (1)
- dopaminergics (1)
- dorsolateral prefrontal cortex (1)
- dosimetry (1)
- dot probe (1)
- draft genome (1)
- dressed states (1)
- drug (1)
- drug adherence (1)
- drug treatment (1)
- drug-eluting beads (1)
- drug-minded protein (1)
- dsRNA binding protein (1)
- dual function (1)
- dual polarimetry (1)
- dunce (1)
- dyes/pigments (1)
- dyspnea (1)
- early diagnosis (1)
- early literacy (1)
- early secretory pathway (1)
- echocardiography (1)
- economic growth (1)
- ecosystem services (1)
- ectotherms (1)
- edema (1)
- educación en medios (1)
- educational tool (1)
- effectiveness (1)
- electric field distribution (1)
- electrocardiography (1)
- electronic and spintronic devices (1)
- ellipsoid (1)
- elliptic PDE (1)
- embryonic stem cells (1)
- emissions (1)
- emotion (1)
- emotional regulation (1)
- emotions (1)
- empagliflozin (1)
- end-state comfort effect (1)
- endemism (1)
- endocrine therapy (1)
- endoplasmic-reticulum (1)
- endosomes (1)
- endosponge (1)
- endothelial cells (1)
- endovascular treatment (1)
- endurance (1)
- energy density (1)
- energy deprivation (1)
- enhanced green fluorescent protein (1)
- enoyl-ACP reductase inhibitors (1)
- enseñanzapor por competencias (1)
- enteric pathogens (1)
- entropy production (1)
- enzyme (1)
- enzyme purification (1)
- enzyme regulation (1)
- enzyme structure (1)
- enzymes (1)
- epidermis (1)
- epigenetic silencing (1)
- epigenetics (1)
- epilepsy (1)
- epithelial-mesenchymal transition (1)
- erythrocytes (1)
- essential tremor (1)
- ethanol (1)
- euchromatin (1)
- european leukemia net (1)
- eutrino physics (1)
- evaluation (1)
- evolutionary consumer psychology (1)
- evolutionary fixation (1)
- exciton coupling (1)
- exciton transfer (1)
- exciton-polariton (1)
- exciton-polariton condensates (1)
- excitons (1)
- excretory-secretory (1)
- executive function training (1)
- exocrine glands (1)
- expectation (1)
- experience (1)
- experimental cerebral malaria (1)
- experimental design (1)
- expert systems (1)
- export (1)
- eye irritation testing (1)
- eyes (1)
- fMRI (1)
- fabry disease (1)
- factor XII (1)
- familial amyloidotic polyneuropathy (1)
- fatal cardiovascular disease (1)
- fatigue (1)
- fatty liver (1)
- fear generalization (1)
- fear response (1)
- female (1)
- female choice (1)
- females (1)
- fentanyl (1)
- ferromagnet (1)
- ferromagnetism (1)
- fetal brain development (1)
- fetal testis (1)
- fibroblast (1)
- fibromyalgia syndrome (1)
- field (1)
- field boundaries (1)
- fine-needle-aspiration (1)
- fine-scale mapping (1)
- finger protein 11 (1)
- fingers (1)
- fish (1)
- fish model (1)
- flagella (1)
- flavonoid (1)
- fluorescence recovery after photobleaching (1)
- fluorescence spectra (1)
- fluorescent dyes (1)
- fluorescent-probes (1)
- fluorophore (1)
- fluorophores (1)
- focal (1)
- follicular T helper cells (1)
- food consumption (1)
- food-cues (1)
- foraging (1)
- force relationship (1)
- forest edges (1)
- forest fragmentation (1)
- forest hedges (1)
- forest specialists (1)
- formación de profesorado (1)
- formation flight (1)
- frontal cortex (1)
- fruit-flies (1)
- fully automatic (1)
- functional magnetic resonance imaging (1)
- fungal disease (1)
- fungal host response (1)
- fungal infection (1)
- fungicide (1)
- gait analysis (1)
- galactomannan (1)
- gamma radiation (1)
- gap junction (1)
- gastrointestinal dysfunction (1)
- gastrointestinal tract (1)
- gaze independence (1)
- gefitinib (1)
- gels (1)
- gemcitabine (1)
- gender (1)
- gene expression data (1)
- gene regulation in immune cells (1)
- genes (1)
- genetic dissection (1)
- genetic polymorphisms (1)
- genetics memory (1)
- genome integrity (1)
- genome sequencing (1)
- genome-wide association study (1)
- geographic biases (1)
- geographical variation (1)
- geomorphology (1)
- german multicenter (1)
- germinal center (1)
- germline (1)
- giant intracranial aneurysm (1)
- glands (1)
- glioblastoma (1)
- global dataset (1)
- global reporting initiative (1)
- glucocorticoid receptor (1)
- glucocorticoid replacement therapy (1)
- glucose handling (1)
- glucose lowering agent (1)
- glucose metabolism (1)
- glutamate (1)
- glycation end products (1)
- glycemic control (1)
- glycine (1)
- goutallier (1)
- granules (1)
- ground states (1)
- group 3 (1)
- group refractive index (1)
- growth-factor-receptor (1)
- guality-of-life (1)
- guidelines (1)
- gut microbiota (1)
- gynecologic surgical procedures/methods (1)
- hOCT1 (1)
- habitat use (1)
- hadronic colliders (1)
- halophilic fungus (1)
- hands (1)
- happiness (1)
- hazard perception (1)
- health monitoring (1)
- health risk assessment (1)
- health status (1)
- health status instruments (1)
- health-assessment questionnaire (1)
- heart (1)
- heart disease (1)
- heart failure (1)
- hematological disorders (1)
- hematopoietic SCT (1)
- hematopoietic stem cells (1)
- hemoglobin (1)
- hepatic stellate cells (1)
- hepatocellular carcinoma (1)
- heteromorphic sex chromosomes (1)
- heuristics and biases (1)
- high resolution visualisation (1)
- high-altitude training (1)
- high-intensity interval training (1)
- high-intensity training (1)
- high-osmolarity glycerol (HOG) (1)
- high-risk hematology (1)
- high-risk prostate cancer (1)
- high-throughput (1)
- high-throughput screening (1)
- highly-active antiretroviral therapy (1)
- hip (1)
- hip replacement (1)
- hippocampal neurogenesis (1)
- hippocampus (1)
- histologic diversity (1)
- histology (1)
- histone H3 (1)
- histone acetylation (1)
- histone γH2AX (1)
- histopathology (1)
- homeostasisIon channels (1)
- homochirality (1)
- honeybee (1)
- hormona therapy (1)
- hormones (1)
- host cells (1)
- hour-glass (1)
- hourglass clock (1)
- human (1)
- human biomarker (1)
- human cell nucleus (1)
- human cholangiocellular carcinoma (1)
- human ectoparasite (1)
- human hematopoiesis (1)
- human intrahepatic cholangiocarcinoma (1)
- human retinal pigment epithelium (1)
- humoral immunity (1)
- hybrid state (1)
- hydnocarpin (1)
- hydrogen bonding (1)
- hydrogenation (1)
- hydrolysis (1)
- hyperekplexia (1)
- hypermethylated DNA (1)
- hypermethylation (1)
- hypersensitivity (1)
- hyperspectral autofluorescence imaging (1)
- hypertension (1)
- hyperthermia (1)
- hypertonic solution (1)
- hypertrophic cardiomyopathy (1)
- hyponatremia (1)
- hypothalamus (1)
- hypoxia-inducible factor 3A (1)
- iNOS (1)
- iberis amara extract (1)
- image data (1)
- image processing (1)
- image quality (1)
- immersion (1)
- immersive classroom (1)
- immersive classroom management (1)
- immune activation (1)
- immune cell recruitment (1)
- immune cells (1)
- immune escape (1)
- immune response (1)
- immune-responses (1)
- immunoglobulin-e (1)
- immunohistochemistry (1)
- immunological reactivity (1)
- immunoreactive neurons (1)
- impulsivity (1)
- in-vitro (1)
- indirect detection (1)
- induce cyclooxygenase-2 expression (1)
- infant faces (1)
- infection control (1)
- infections (1)
- inflammatory bowel disease (1)
- inflammatory diseases (1)
- influenza virus (1)
- informality (1)
- inherited metabolic disorders (1)
- innexins (1)
- insect flight (1)
- insects (1)
- insertable cardiac monitor (1)
- instructional support (1)
- insulin resistance (1)
- insulin signaling (1)
- insulin tolerance test (1)
- integraed care (1)
- integrins (1)
- intelligent vehicles (1)
- intensification (1)
- intensive glucose control (1)
- interaction partners (1)
- interband cascade laser (1)
- interferon alpha (IFNα) (1)
- interferon alpha signalling (1)
- interferon signaling (1)
- interferon-alpha (1)
- interleukin-1β (1)
- interleukins (1)
- internalization (1)
- interstitial duplications (1)
- intestinal-type adenocarcinoma (1)
- intracellular domain (1)
- intracellular hydrogen-peroxide (1)
- intracellular membranes (1)
- intracellular receptors (1)
- intracellular transport (1)
- intrachromosomal telomeric sequences (1)
- intraoperative (1)
- intraoperative radiotherapy (1)
- intraosseous (1)
- intrasexual competition (1)
- intrathecal application (1)
- invasive aspergillosis (1)
- invasive fungal infections (1)
- invasive meningococcal disease (1)
- invasive vascular interventions (1)
- investigación (1)
- investigación de currículo universitario (1)
- inflammatory response (1)
- iota-toxin (1)
- iron (1)
- irrigated cropland extent (1)
- jasmonates (1)
- jasmonic acid biosynthesis (1)
- judgment (1)
- jump-diffusion processes (1)
- jumping spiders (1)
- junction proteins (1)
- ketogenic dients (1)
- kidney (1)
- kidney disease (1)
- kinematics (1)
- kinetics (1)
- knee rotator cuff (1)
- knees (1)
- knowledge-based systems (1)
- lamivudine (1)
- land and water management (1)
- land-cover change (1)
- land-use change (1)
- landsat central asia (1)
- landscape compositionv (1)
- laparoscopy/methods (1)
- large-scale assessment (1)
- larval drosophila (1)
- lasers (1)
- late gadolinium enhancement (1)
- late-onset (1)
- leaf beetle (1)
- left ventricular hypertrophy (1)
- leg cramps (1)
- legionary ants (1)
- leukemia inhibitory factor (1)
- life history (1)
- light pulses (1)
- light sources (1)
- light-induced gene expression (1)
- light-matter coupling (1)
- light-trapping (1)
- light–matter interaction (1)
- linkage (1)
- lipid desaturation (1)
- lithium (1)
- liver metastasis (1)
- lncRNAs (1)
- localization micoscopy (1)
- locked-in syndrome (1)
- locomotion (1)
- locomotor activity (1)
- long ncRNA (1)
- long-term survivors (1)
- low-threshold fibers (1)
- lower body (1)
- luciferase (1)
- lung and intrathoracic tumors (1)
- lungfish (1)
- lutetium-177 (1)
- lux (1)
- luxury brands (1)
- lymph node dissection (1)
- lymph nodes (1)
- lymphocyte differentiation (1)
- lymphoma (1)
- lysosomal storage disease (1)
- mRNA (1)
- machine leaning (1)
- macroecology (1)
- magnetic dopants (1)
- magnetic fields (1)
- magnetic properties and materials (1)
- magnetic resonance spectroscopy (1)
- magnetic susceptibility (1)
- magnetism (1)
- magnetized sphere/cylinder (1)
- main-group chemistry (1)
- male rats (1)
- mammography (1)
- managing big data (1)
- mandible (1)
- marrow stromal cells (1)
- mass index (1)
- maternal behavior (1)
- mathematical model (1)
- mathematical modeling (1)
- matrix metalloproteinases (1)
- maturation (1)
- mechanical energy (1)
- mechanical thrombectomy (1)
- mechanism (1)
- mechanisms (1)
- media education (1)
- media literacy (1)
- medical collateral ligament (1)
- medical rehabilitation (1)
- meiotic ‘superring’ (1)
- melanoma (1)
- melanoma therapy (1)
- meliponines (1)
- membrane biophysics (1)
- membrane proteins (1)
- memory formation (1)
- men (1)
- meningococcal disease (1)
- merocyanines (1)
- mesenchymal stem-cells (1)
- messenger RNA (1)
- metabolic risk (1)
- metabolic syndrome (1)
- metacognitive prompting (1)
- metal borylene complexes (1)
- metal caponyls (1)
- metal cluster (1)
- metal-cluster hybrid systems (1)
- metal-to-ligand charge transfer (MLCT) (1)
- metallaboranes (1)
- metamorphosis (1)
- methylation (1)
- methylphenidate (1)
- miRNA (1)
- miRNA expression (1)
- miRNAs (1)
- micro-level analysis (1)
- microRNAs (1)
- microbiota (1)
- microcavity exciton polaritons (1)
- microcrystalline zinc hydroxyapatiteimpact (1)
- microglomeruli (1)
- microlaser (1)
- micronuclei (1)
- microprocessor (1)
- microscopy (1)
- microvascular endothelial cells (1)
- microwave radiation (1)
- middle Aged (1)
- middle ear (1)
- middle ear implant (1)
- migration (1)
- minimally conscious state (1)
- minimally important difference (1)
- minimally-invasive (1)
- minimum (1)
- mismatch (1)
- mitogen activated protein kinase (MAPK) (1)
- mitosis (1)
- mixed hearing loss (1)
- model (1)
- model following (1)
- modeling (1)
- modis (1)
- modulated arc therapy (1)
- modulation spectroscopy (1)
- molar tooth sign (1)
- molecular biology (1)
- molecular dynamics (1)
- molecular mechanics (1)
- molecular response in cml (1)
- molecular-structure (1)
- monoclonial gammopathy (1)
- monocyte subset (1)
- moral judgment (1)
- moths (1)
- motion (1)
- motor axonal neuropathy (1)
- motor control (1)
- motor development (1)
- mouse model (1)
- mouse models DNA damage (1)
- mouse-brain (1)
- mucosa (1)
- mucosal inflammation (1)
- multi-drug resistance (1)
- multifaceted approaches (1)
- multifocal choroiditis (1)
- multihit targeting (1)
- multimetallic complexes (1)
- multimodal (1)
- multimorbidity (1)
- multiple myeloma Lesions (1)
- multiple sequence alignments (1)
- multiple sklerosis (1)
- music background (1)
- musical training (1)
- mutation detection (1)
- myeloma cells (1)
- myocardial infarction (1)
- myocardial lipid content (1)
- myocardial fibrosis (1)
- myocarditis (1)
- myocardium (1)
- myocyte (1)
- n-hexyl phthalate (1)
- nab-paclitaxel (1)
- naive T cells (1)
- nano LDH (1)
- nanoagent (1)
- nanographene (1)
- nanoparticle albumin-bound paclitaxel (1)
- nanophysics (1)
- nanotube (1)
- natural genetic variation (1)
- natural language processing (1)
- natural products (1)
- neck circumference (1)
- needle surface waxes (1)
- neoadjuvant (1)
- neovascularization, physiologic (1)
- nerve fibers (1)
- nerve ultrasonography (1)
- nervous-system (1)
- nervous-sytem (1)
- neural circuits (1)
- neural stem-cells (1)
- neuroendocrine tumor (1)
- neuroendocrine tumor (NET) (1)
- neurogenic locus notch homolog (1)
- neuroimaging (1)
- neuroimmunology (1)
- neuromyelitis optica (1)
- neuromyelitis optica spectrum disorders (NMOSD) (1)
- neuropathy (1)
- neuropeptides (1)
- neuroplasticity (1)
- neutralino (1)
- neutralizing antibody (1)
- neutrino detectors (1)
- neutrino emission (1)
- neutrino mass hierarchy (1)
- neutrino telescope (1)
- neutrophil (1)
- neutrophils (1)
- niche dynamics (1)
- nicotinic acetylcholine receptors (1)
- nitric oxide (1)
- nitrites (1)
- no-flow fraction (1)
- nocebo hyperalgesia (1)
- nodes of Ranvier (1)
- noise and multimode dynamics (1)
- non-crop habitats (1)
- non-invasive biomarkers (1)
- non-motor features (1)
- nonadiabatic dynamics (1)
- nonlinear dynamics (1)
- nuclear power (1)
- nuclear staining (1)
- nucleation elongation (1)
- nucleation-elongation model (1)
- nucleoside transporter (1)
- nurses (1)
- obsessive-compulsive disorder (1)
- octopamine (1)
- off-targets (1)
- oil storage (1)
- older people (1)
- olfaction (1)
- olfactory receptor (1)
- oncology (1)
- oncolytic virus therapy (1)
- one-electron oxidation (1)
- online adaption (1)
- online monitoring system (1)
- online tool (1)
- onset craniopharyngioma (1)
- ontologies (1)
- open surgical repair (1)
- opponent processes (1)
- optic neuritis (1)
- optical coherence tomography (1)
- optical response (1)
- optics and photonics (1)
- optimal control (1)
- optimal control theory (1)
- optoelectronics (1)
- ordinal categorical indicators (1)
- organic (1)
- orthotopic xenograft (1)
- osteoporosis (1)
- otitis media (1)
- outer membrane protein (1)
- outer retinal tubulation (1)
- output elasticities (1)
- over-the-counter drugs (1)
- overload (1)
- oxygen-metabolism (1)
- oxytocin (1)
- p27(KIP1) (1)
- pCa (1)
- pICln (1)
- palladium (1)
- pancreatobiliary type (1)
- panobinostat (1)
- parainfluenza virus (1)
- parasite biology (1)
- parasitic cell cycles (1)
- parasitic diseases (1)
- parasitic life cycles (1)
- parasitology (1)
- parental origin (1)
- partial integro-differential Fokker-Planck Equation (1)
- pathogens (1)
- pathway analysis (1)
- patient education (1)
- pedagogy (1)
- pedagogía (1)
- pediatric brain tumor (1)
- pelvic organ prolapse/surgery (1)
- perforator (1)
- performance (1)
- performance monitoring (1)
- performance parameters (1)
- periodontal health (1)
- peripheral artery occlusive disease (1)
- peripheral injury (1)
- peripheral nerve (1)
- peripheral neuropathy (1)
- peripheral vision (1)
- peripheral-blood (1)
- perylene bisimide hydrogels (1)
- phage display (1)
- phakomatosis pigmentovascularis (1)
- pharmacogenetics (1)
- phase transitions and critical phenomena (1)
- phasematching (1)
- phenology (1)
- phenomenology (1)
- phenotype (1)
- phenotypic microarray (1)
- phonological awareness (1)
- phonological training (1)
- phosphocholine (1)
- phosphoproteomics (1)
- photoactivation (1)
- photoinduced electron transfer (1)
- photon bunching (1)
- photon lasing (1)
- photon statistics (1)
- photonics (1)
- photoperiodic time mesurement (1)
- photoreceptors (1)
- phototransduction (1)
- phyllosphere (1)
- phylotypic (1)
- physical therapy modalities (1)
- physicians (1)
- physiological traits (1)
- phytoprostanes (1)
- piRNA (1)
- pig model (1)
- pigment (1)
- pinned orbital moments (1)
- pitcher-plant mosquito (1)
- pituitary adenomas (1)
- pituitary gland (1)
- placebo hypoalgesia (1)
- planarian (1)
- planning variability (1)
- plans (1)
- plant cuticle (1)
- plant symbioses (1)
- plaque (1)
- plaque formation (1)
- plasma extravasation (1)
- plasmid copy number (1)
- plasminogen (1)
- plasticity (1)
- platelet dysfunction (1)
- platyhelminthes (1)
- polarimetric decomposition (1)
- polarition condensate (1)
- polariton laser (1)
- polarity effects (1)
- polarization vision (1)
- pollution functions (1)
- polychoric correlation (1)
- polycyclic aromatic hydrocarbons (1)
- polymer characterization (1)
- polymer synthesis (1)
- polyomavirus (1)
- polypyridyl complexes (1)
- polysensitization (1)
- popliteal aneurysm (1)
- positive lymph node (1)
- positron emission tomography/computed tomography (1)
- post-processing (1)
- post-traumatic stress disorder (1)
- postoperative complications/epidemiology (1)
- postpartum (1)
- posttranslational modifications (1)
- precedes multiple-myeloma (1)
- pregnancy (1)
- pregnancy gingivitis (1)
- preprocessing (1)
- preschool children (1)
- presence (1)
- preservice teacher education (1)
- prevention (1)
- prey selection (1)
- primary sclerosing cholangitis (1)
- probiotic lozenges (1)
- process mining (1)
- progenitors (1)
- prognosis (1)
- proliferating cell nuclear antigen (PCNA) (1)
- promoter affinity (1)
- propensity score matching (1)
- prophage (1)
- prospective study (1)
- prostate-cancer (1)
- protein engineering (1)
- protein phosphorylation (1)
- protein synthesis (1)
- protein translocation (1)
- protein ubiquitination (1)
- proteomes (1)
- proteomic analysis (1)
- proteomics (1)
- protocadherin gamma cluster (1)
- protophormia terraenovae (1)
- proximal method (1)
- proximal methods (1)
- pseudocarcinomatous hyperplasia (1)
- psoriasis (1)
- psychological placebo intervention (1)
- pulmonary aspergillosis (1)
- pulmonary disease (1)
- pulmonary imaging (1)
- pulmonary toxicity (1)
- punishment (1)
- pustular exanthema (1)
- pyramidal neurons (1)
- quadcopter (1)
- quality-control (1)
- quantitative assessments (1)
- quantum billiard (1)
- quantum chemical analysis (1)
- quantum dot laser (1)
- queens (1)
- quinine (1)
- quorum sensing (QS) (1)
- radar (1)
- radiation sensitivity (1)
- radiation-therapy (1)
- radioactive waste (1)
- radiotherapy (1)
- rainforest (1)
- random forest models (1)
- randomized controlled clinical trial (1)
- randomized trial (1)
- ranscription factors (1)
- rare SNP (1)
- rare diseases (1)
- rats (1)
- reaction mechanism (1)
- reaction mechanisms (1)
- reactive electrophilic species (1)
- reactive oxygen species (1)
- real-time PCR (1)
- receptor (1)
- receptor tyrosine kinase (1)
- recombinant proteins (1)
- recombinat-human-erythropoietin (1)
- reconsolidation (1)
- reconstruction (1)
- reconstructive surgical procedures/methods (1)
- recurrence (1)
- reflection (1)
- regressive (1)
- regulatory T cells (1)
- relapsed (1)
- relapsed and refractory (1)
- relaxation (1)
- relief (1)
- renal scintigraphy (1)
- renal system (1)
- renoprotection (1)
- repair and replication (1)
- repeated shuttle sprints (1)
- replication (1)
- reported outcomes (1)
- reporter genes (1)
- reproducible science (1)
- reproductive and developmental toxicity (1)
- reproductive character displacement (1)
- reproductive diapause (1)
- research (1)
- resolution limit (1)
- resource availability (1)
- respiratory syncytial virus (1)
- response inhibition (1)
- retinal dystrophies (1)
- retinal neuro-axonal damage (1)
- retro-cue (1)
- retrospective Studies (1)
- return to work (1)
- reverse transcriptase (1)
- reward (1)
- rheumatology (1)
- rhinitis (1)
- rhythmic components (1)
- ribavirin serum levels (1)
- ribonuclease H (1)
- ribosome (1)
- rice (1)
- right inferior frontalgyrus (1)
- risk factor (1)
- risk-assesment (1)
- robustness (1)
- root growth (1)
- rostral-migratory-stream (1)
- rotator cuff (1)
- rotors (1)
- safety (1)
- salvage radiotherapy (1)
- sampling bias (1)
- sampling method (1)
- sarcoidosis (1)
- sarcopenia (1)
- sarcopterygian fish (1)
- scalable quadcopter (1)
- sclerostin (1)
- second hit (1)
- secondary CNV (1)
- secondary lung tumors (1)
- seedlings (1)
- seeds (1)
- segmentation (1)
- selective accessibility (1)
- self-assembly (1)
- self-management (1)
- self-regulated learning (1)
- self-renewal (1)
- semantic technologies (1)
- semi-natural habitats (1)
- semismooth Newton method (1)
- sensory cues (1)
- sensory perception (1)
- sequencing protocol (1)
- serial RNA interactome capture (1)
- service infrastructure (1)
- settlement expansion (1)
- setup verification (1)
- sex pheromone (1)
- sexual development (1)
- shock response (1)
- short Synacthen test (1)
- short-term memory (1)
- short-term methylphenidate brain (1)
- shoulder surgery (1)
- sialic acids (1)
- side effects (1)
- side-peak emission (1)
- signal peptides (1)
- signal transduction (1)
- signaling pathway (1)
- signalling pathways (1)
- silaboration (1)
- silybin (1)
- simulation system (1)
- single-molecule biophysics (1)
- skeleton (1)
- skin anatomy (1)
- skin blood flow (1)
- skin cancer (1)
- skin conductance (1)
- skin diseases (1)
- skin equivalents (1)
- skin physiology (1)
- skinned fibers (1)
- sky-compass orientation (1)
- sleep (1)
- slope deposits (1)
- small RNA-sequencing (1)
- small cell lung cancer (1)
- small interfering RNAs (1)
- snRNPs (1)
- social experience (1)
- sodium channel (1)
- sodium uptake (1)
- software (1)
- solubility (1)
- soluble guanylate cyclase (1)
- solvents (1)
- somatostatin receptor (1)
- sorafenib (1)
- speciation (1)
- species distribution model (1)
- species diversification (1)
- specific phobia (1)
- speckle tracking imaging (1)
- spectral characterization (1)
- spectral karyotyping (1)
- spectral-domain optical coherence tomography (1)
- spectroscopy (1)
- speed (1)
- spillover (1)
- spin distribution (1)
- spin response (1)
- spine radiosurgery (1)
- spiroborates (1)
- sports technology (1)
- stage renal-disease (1)
- stalking predators (1)
- standard semiconductor laser (1)
- standards (1)
- static mixer (1)
- static test (1)
- statistical data (1)
- stem cell transplantation (1)
- stent implantation (1)
- sterol pathway (1)
- stress markers (1)
- stress signaling cascade (1)
- stressful life events (1)
- stroke (1)
- stroke prevention (1)
- stroke rehabilitation (1)
- structural equation models (1)
- structure (1)
- structured illumination microscopy (1)
- student simulation (1)
- subcutaneous adipose-tissue (1)
- subgingival (1)
- substantia nigra (1)
- subthalamic nucleus (1)
- sun (1)
- super-resolution imaging (1)
- super-resolution microscopy (1)
- superconductors (1)
- supercurrent (1)
- superficial peroneal nerve (1)
- superradiant pulse emission (1)
- supersymmetry (1)
- support vector machines (1)
- suppression (1)
- supramolecular polymerization (1)
- sural nerve (1)
- surgery (1)
- surgical Mesh (1)
- surgical aneurysm treatment (1)
- survival (1)
- susceptibility (1)
- sustainability reporting (1)
- sustained fear (1)
- swim test (1)
- swimming (1)
- synaptic connections (1)
- synaptic inhibition (1)
- synaptic plasticity (1)
- synaptic vesicles (1)
- synapticplasticity (1)
- syndrome (1)
- synthesis process (1)
- systemic immunosuppression (1)
- systemic inflammatory response syndrome (1)
- systemic sclerosis (1)
- targeted re-sequencing (1)
- targets (1)
- taxonomic biases (1)
- taxonomy (1)
- team sport (1)
- teeth (1)
- telomere length (1)
- telomeres (1)
- terminal alkynes (1)
- testosterone (1)
- testosterone production (1)
- tetrametallaborides (1)
- tetraorganoborate salt (1)
- therapy (1)
- thermal adaptation (1)
- thermoregulation (1)
- thermotolerance (1)
- think-aloud data (1)
- thrombopoiesis (1)
- thrombus formation (1)
- thymectomy (1)
- tibial fracture fixation (1)
- tibial head fracture (1)
- time resolved spectroscopy (1)
- time series (1)
- time series analysis (1)
- time-resolved photoelectron spectroscopy (1)
- to-height ratio (1)
- tolerability (1)
- tooth eruption (1)
- torque (1)
- total electric field (1)
- trachea (1)
- tracking (1)
- traffic (1)
- trafficking (1)
- training (1)
- training adaptation (1)
- training load (1)
- trans-splicing (1)
- transarterial chemoembolization (1)
- transcranial direct current stimulation (1)
- transcriptional profiling (1)
- transcriptome (1)
- transcriptome analysis (1)
- transfection (1)
- transferability (1)
- transient absorption (1)
- transition charge (1)
- transition density (1)
- transition dipole moment (1)
- transition temperature (1)
- translation (1)
- translational panic model (1)
- transperineal ultrasound (1)
- transporter protein associated with antigen processing-1 (TAP1) (1)
- transporters (1)
- transposable elements (1)
- treatment (1)
- treatment guidelines (1)
- tremor (1)
- triceps brachii (1)
- triglycerides (1)
- trimetallaborides (1)
- trisomy 21 (1)
- triterpenoids (1)
- tropical ecology (1)
- troponin T (1)
- trypanosoma brucei gambiense (1)
- tryptophan (1)
- tumor associated macrophages (1)
- tumor cell (1)
- tumor growth (1)
- tumor size (1)
- tundra (1)
- two-dimensional materials (1)
- two-dimensional nanostructures (1)
- tympanic membrane (1)
- type 2 diabetes (1)
- types of government (1)
- tyrosine kinase inhibitors (1)
- ubiquitin (1)
- ultimatum game (1)
- ultrasound (1)
- ultrastructure (1)
- ultraviolet light (1)
- undetermined significance (1)
- unfolded protein response (1)
- unmanned aerial vehicle (1)
- unnatural amino acid (1)
- unresponsive wakefulness syndrome (1)
- upper body (1)
- upramolecular polymerization process (1)
- upstream regulator (1)
- urban growth modelling (1)
- urbanization (1)
- urinary incontinence/surgery (1)
- user-centered design (1)
- uterine prolapse/surgery (1)
- uveal melanoma (1)
- vagina/surgery (1)
- valence (1)
- validation (1)
- variant of unknown significance (1)
- vascular permeability (1)
- vascular type (1)
- vascularization (1)
- vasculitis (1)
- vasoconstriction (1)
- vegetation dynamics (1)
- vegetative state (1)
- vehicle dynamics (1)
- velocity (1)
- vertebral metastases (1)
- vertebrates (1)
- vesicles (1)
- vessel patency (1)
- vibration (1)
- vibroplasty (1)
- viral carcinogenesis (1)
- viral load (1)
- viral replication (1)
- viral shedding (1)
- virtual agent interaction (1)
- virtual reality (1)
- virtual reality training (1)
- visceral adiposity (1)
- viscosity (1)
- visual acuity (1)
- visual evoked potentials (1)
- visual orientation (1)
- visual working memory (1)
- vitamin D (1)
- volatile (1)
- wasp-mimicking (1)
- water (1)
- wave functions (1)
- wearable technologies (1)
- weight drop (1)
- weight gain (1)
- weight of evidence (1)
- whole genome duplications (1)
- whole genome sequencing (1)
- whole-body electromyostimulation (1)
- whole-genome shotgun sequencing (1)
- wild plant pollination (1)
- withdrawal (1)
- words (1)
- work ability (1)
- work-related medical rehabilitation (1)
- working memory (1)
- wyeomyia smithii (1)
- xenopus oocytes (1)
- µ-Opioid receptor (1)
- π–π Stacking (1)
Institute
- Theodor-Boveri-Institut für Biowissenschaften (87)
- Medizinische Klinik und Poliklinik II (35)
- Neurologische Klinik und Poliklinik (31)
- Institut für Psychologie (27)
- Physikalisches Institut (27)
- Medizinische Klinik und Poliklinik I (25)
- Julius-von-Sachs-Institut für Biowissenschaften (22)
- Rudolf-Virchow-Zentrum (22)
- Medizinische Fakultät (19)
- Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie (18)
Sonstige beteiligte Institutionen
FANCM is a highly conserved DNA remodeling enzyme that promotes the activation of the Fanconi anemia DNA repair pathway and facilitates replication traverse of DNA interstrand crosslinks. However, how FANCM interacts with the replication machinery to promote traverse remains unclear. Here, we show that FANCM and its archaeal homolog Hef from Thermoplasma acidophilum interact with proliferating cell nuclear antigen (PCNA), an essential co-factor for DNA polymerases in both replication and repair. The interaction is mediated through a conserved PIP-box; and in human FANCM, it is strongly stimulated by replication stress. A FANCM variant carrying a mutation in the PIP-box is defective in promoting replication traverse of interstrand crosslinks and is also inefficient in promoting FANCD2 monoubiquitination, a key step of the Fanconi anemia pathway. Our data reveal a conserved interaction mode between FANCM and PCNA during replication stress, and suggest that this interaction is essential for FANCM to aid replication machines to traverse DNA interstrand crosslinks prior to post-replication repair.
Model enteric bacteria such as Escherichia coli and Salmonella enterica express hundreds of small non-coding RNAs (sRNAs), targets for most of which are yet unknown. Some sRNAs are remarkably well conserved, indicating that they serve cellular functions that go beyond the necessities of a single species. One of these ‘core sRNAs’ of largely unknown function is the abundant ∼100-nucleotide SdsR sRNA which is transcribed by the general stress σ-factor, σ\(^{S}\) and accumulates in stationary phase. In Salmonella, SdsR was known to inhibit the synthesis of the species-specific porin, OmpD. However, sdsR genes are present in almost all enterobacterial genomes, suggesting that additional, conserved targets of this sRNA must exist. Here, we have combined SdsR pulse-expression with whole genome transcriptomics to discover 20 previously unknown candidate targets of SdsR which include mRNAs coding for physiologically important regulators such as the carbon utilization regulator, CRP, the nucleoid-associated chaperone, StpA and the antibiotic resistance transporter, TolC. Processing of SdsR by RNase E results in two cellular SdsR variants with distinct target spectra. While the overall physiological role of this orphan core sRNA remains to be fully understood, the new SdsR targets present valuable leads to determine sRNA functions in resting bacteria.
The Josephson effect describes the generic appearance of a supercurrent in a weak link between two superconductors. Its exact physical nature deeply influences the properties of the supercurrent. In recent years, considerable efforts have focused on the coupling of superconductors to the surface states of a three-dimensional topological insulator. In such a material, an unconventional induced p-wave superconductivity should occur, with a doublet of topologically protected gapless Andreev bound states, whose energies vary 4π-periodically with the superconducting phase difference across the junction. In this article, we report the observation of an anomalous response to rf irradiation in a Josephson junction made of a HgTe weak link. The response is understood as due to a 4π-periodic contribution to the supercurrent, and its amplitude is compatible with the expected contribution of a gapless Andreev doublet. Our work opens the way to more elaborate experiments to investigate the induced superconductivity in a three-dimensional insulator.
Phase coexistence phenomena have been intensively studied in strongly correlated materials where several ordered states simultaneously occur or compete. Material properties critically depend on external parameters and boundary conditions, where tiny changes result in qualitatively different ground states. However, up to date, phase coexistence phenomena have exclusively been reported for complex compounds composed of multiple elements. Here we show that charge- and magnetically ordered states coexist in double-layer Fe/Rh(001). Scanning tunnelling microscopy and spectroscopy measurements reveal periodic charge-order stripes below a temperature of 130 K. Close to liquid helium temperature, they are superimposed by ferromagnetic domains as observed by spin-polarized scanning tunnelling microscopy. Temperature-dependent measurements reveal a pronounced cross-talk between charge and spin order at the ferromagnetic ordering temperature about 70 K, which is successfully modelled within an effective Ginzburg–Landau ansatz including sixth-order terms. Our results show that subtle balance between structural modifications can lead to competing ordering phenomena.
Topological insulators interacting with magnetic impurities have been reported to host several unconventional effects. These phenomena are described within the framework of gapping Dirac quasiparticles due to broken time-reversal symmetry. However, the overwhelming majority of studies demonstrate the presence of a finite density of states near the Dirac point even once topological insulators become magnetic. Here, we map the response of topological states to magnetic impurities at the atomic scale. We demonstrate that magnetic order and gapless states can coexist. We show how this is the result of the delicate balance between two opposite trends, that is, gap opening and emergence of a Dirac node impurity band, both induced by the magnetic dopants. Our results evidence a more intricate and rich scenario with respect to the once generally assumed, showing how different electronic and magnetic states may be generated and controlled in this fascinating class of materials.
The protein density in biological membranes can be extraordinarily high, but the impact of molecular crowding on the diffusion of membrane proteins has not been studied systematically in a natural system. The diversity of the membrane proteome of most cells may preclude systematic studies. African trypanosomes, however, feature a uniform surface coat that is dominated by a single type of variant surface glycoprotein (VSG). Here we study the density-dependence of the diffusion of different glycosylphosphatidylinositol-anchored VSG-types on living cells and in artificial membranes. Our results suggest that a specific molecular crowding threshold (MCT) limits diffusion and hence affects protein function. Obstacles in the form of heterologous proteins compromise the diffusion coefficient and the MCT. The trypanosome VSG-coat operates very close to its MCT. Importantly, our experiments show that N-linked glycans act as molecular insulators that reduce retarding intermolecular interactions allowing membrane proteins to function correctly even when densely packed.
Exciton coupling is of fundamental importance and determines functional properties of organic dyes in (opto-)electronic and photovoltaic devices. Here we show that strong exciton coupling is not limited to the situation of equal chromophores as often assumed. Quadruple dye stacks were obtained from two bis(merocyanine) dyes with same or different chromophores, respectively, which dimerize in less-polar solvents resulting in the respective homo- and heteroaggregates. The structures of the quadruple dye stacks were assigned by NMR techniques and unambiguously confirmed by single-crystal X-ray analysis. The heteroaggregate stack formed from the bis(merocyanine) bearing two different chromophores exhibits remarkably different ultraviolet/vis absorption bands compared with those of the homoaggregate of the bis(merocyanine) comprising two identical chromophores. Quantum chemical analysis based on an extension of Kasha’s exciton theory appropriately describes the absorption properties of both types of stacks revealing strong exciton coupling also between different chromophores within the heteroaggregate.
Solid-state cavity quantum electrodynamics is a rapidly advancing field, which explores the frontiers of light–matter coupling. Metal-based approaches are of particular interest in this field, as they carry the potential to squeeze optical modes to spaces significantly below the diffraction limit. Transition metal dichalcogenides are ideally suited as the active material in cavity quantum electrodynamics, as they interact strongly with light at the ultimate monolayer limit. Here, we implement a Tamm-plasmon-polariton structure and study the coupling to a monolayer of WSe\(_{2}\), hosting highly stable excitons. Exciton-polariton formation at room temperature is manifested in the characteristic energy–momentum dispersion relation studied in photoluminescence, featuring an anti-crossing between the exciton and photon modes with a Rabi-splitting of 23.5 meV. Creating polaritonic quasiparticles in monolithic, compact architectures with atomic monolayers under ambient conditions is a crucial step towards the exploration of nonlinearities, macroscopic coherence and advanced spinor physics with novel, low-mass bosons.
Monolayers of transition metal dichalcogenide materials emerged as a new material class to study excitonic effects in solid state, as they benefit from enormous Coulomb correlations between electrons and holes. Especially in WSe\(_{2}\), sharp emission features have been observed at cryogenic temperatures, which act as single photon sources. Tight exciton localization has been assumed to induce an anharmonic excitation spectrum; however, the evidence of the hypothesis, namely the demonstration of a localized biexciton, is elusive. Here we unambiguously demonstrate the existence of a localized biexciton in a monolayer of WSe\(_{2}\), which triggers an emission cascade of single photons. The biexciton is identified by its time-resolved photoluminescence, superlinearity and distinct polarization in micro-photoluminescence experiments. We evidence the cascaded nature of the emission process in a cross-correlation experiment, which yields a strong bunching behaviour. Our work paves the way to a new generation of quantum optics experiments with two-dimensional semiconductors.
The factors determining gradients of biodiversity are a fundamental yet unresolved topic in ecology. While diversity gradients have been analysed for numerous single taxa, progress towards general explanatory models has been hampered by limitations in the phylogenetic coverage of past studies. By parallel sampling of 25 major plant and animal taxa along a 3.7 km elevational gradient on Mt. Kilimanjaro, we quantify cross-taxon consensus in diversity gradients and evaluate predictors of diversity from single taxa to a multi-taxa community level. While single taxa show complex distribution patterns and respond to different environmental factors, scaling up diversity to the community level leads to an unambiguous support for temperature as the main predictor of species richness in both plants and animals. Our findings illuminate the influence of taxonomic coverage for models of diversity gradients and point to the importance of temperature for diversification and species coexistence in plant and animal communities.
Background
Ovarian cancer is mostly associated with pathologically regulated permeability of peritoneal vessels, leading to ascites. Here, we investigated the molecular regulation of endothelial permeability by the vascular endothelial growth factor (VEGF) and both tight and adherens junction proteins (VE-cadherin and claudin 5) with regards to the tumor biology of different ovarian cancer types.
Methods
Serum and ascites samples before and after surgery, as well as peritoneal biopsies of 68 ovarian cancer patients and 20 healthy controls were collected. In serum and ascites VEGF protein was measured by ELISA. In peritoneal biopsies co-localization of VE-cadherin and claudin 5 was investigated using immunohistochemical dual staining. In addition, the gene expression of VE-cadherin and claudin 5 was quantified by Real-time PCR. Differences in VEGF levels, VE-cadherin and claudin 5 gene expression were analyzed in relation to various tumor characteristics (tumor stage, grading, histological subtypes, resection status after surgery) and then compared to controls. Furthermore, human primary ovarian cancer cells were co-cultured with human umbilical vein endothelial cells (HUVEC) and changes in VE-cadherin and claudin 5 were investigated after VEGF inhibition.
Results
VEGF was significantly increased in tumor patients in comparison to controls and accumulates in ascites. The highest VEGF levels were found in patients diagnosed with advanced tumor stages, with tumors of poor differentiation, or in the group of solid / cystic-solid tumors. Patients with residual tumor after operation showed significantly higher levels of VEGF both before and after surgery as compared to tumor-free resected patients. Results of an immunohistochemical double-staining experiment indicated co-localization of VE-cadherin and claudin 5 in the peritoneal vasculature. Compared to controls, expression of VE-cadherin and claudin 5 was significantly suppressed in peritoneal vessels of tumor patients, but there were no significant differences regarding VE-cadherin and claudin 5 expression in relation to different tumor characteristics. A significant positive correlation was found between VE-cadherin and claudin 5 expression. VEGF inhibition in vitro was associated with significant increase in VE-cadherin and claudin 5.
Conclusions
Our results indicate that increased peritoneal permeability in ovarian cancer is due to down-regulation of adhesion proteins via tumor derived VEGF. Advanced ovarian cancer with aggressive tumor biology may be associated with early dysregulation of vascular permeability leading to ascites. These patients may benefit from therapeutic VEGF inhibition.
Background
The mechanisms by which vaccinia virus (VACV) interacts with the innate immune components are complex and involve different mechanisms. iNOS-mediated NO production by myeloid cells is one of the central antiviral mechanisms and this study aims to investigate specifically whether iNOS-mediated NO production by myeloid cells, is involved in tumor eradication following the virus treatment.
Methods
Human colon adenocarcinoma (HCT-116) xenograft tumors were infected by VACV. Infiltration of iNOS\(^{+}\) myeloid cell population into the tumor, and virus titer was monitored following the treatment. Single-cell suspensions were stained for qualitative and quantitative flow analysis. The effect of different myeloid cell subsets on tumor growth and colonization were investigated by depletion studies. Finally, in vitro culture experiments were carried out to study NO production and tumor cell killing. Student’s t test was used for comparison between groups in all of the experiments.
Results
Infection of human colon adenocarcinoma (HCT-116) xenograft tumors by VACV has led to recruitment of many CD11b\(^{+}\) ly6G\(^{+}\) myeloid-derived suppressor cells (MDSCs), with enhanced iNOS expression in the tumors, and to an increased intratumoral virus titer between days 7 and 10 post-VACV therapy. In parallel, both single and multiple rounds of iNOS-producing cell depletions caused very rapid tumor growth within the same period after virus injection, indicating that VACV-induced iNOS\(^{+}\) MDSCs could be an important antitumor effector component. A continuous blockade of iNOS by its specific inhibitor, L-NIL, showed similar tumor growth enhancement 7–10 days post-infection. Finally, spleen-derived iNOS+ MDSCs isolated from virus-injected tumor bearing mice produced higher amounts of NO and effectively killed HCT-116 cells in in vitro transwell experiments.
Conclusions
We initially hypothesized that NO could be one of the factors that limits active spreading of the virus in the cancerous tissue. In contrast to our initial hypothesis, we observed that PMN-MDSCs were the main producer of NO through iNOS and NO provided a beneficial antitumor effect, The results strongly support an important novel role for VACV infection in the tumor microenvironment. VACV convert tumor-promoting MDSCs into tumor-killing cells by inducing higher NO production.
Objective:
Over the past decade, myocardial triglyceride content has become an accepted biomarker for chronic metabolic and cardiac disease. The purpose of this study was to use proton (hydrogen 1)-magnetic resonance spectroscopy (\(^{1}\)H-MRS) at 3Tesla (3 T) field strength to assess potential gender-related differences in myocardial triglyceride content in healthy individuals.
Methods:
Cardiac MR imaging was performed to enable accurate voxel placement and obtain functional and morphological information. Double triggered (i.e., ECG and respiratory motion gating) \(^{1}\)H-MRS was used to quantify myocardial triglyceride levels for each gender. Two-sample t-test and Mann-Whitney U-test were used for statistical analyses.
Results:
In total, 40 healthy volunteers (22 male, 18 female; aged >18 years and age matched) were included in the study. Median myocardial triglyceride content was 0.28% (interquartile range [IQR] 0.17–0.42%) in male and 0.24% (IQR 0.14–0.45%) in female participants, and no statistically significant difference was observed between the genders. Furthermore, no gender-specific difference in ejection fraction was observed, although on average, male participants presented with a higher mean ± SD left ventricular mass (136.3 ± 25.2 g) than female participants (103.9 ± 16.1 g).
Conclusions:
The study showed that \(^{1}\)H-MRS is a capable, noninvasive tool for acquisition of myocardial triglyceride metabolites. Myocardial triglyceride concentration was shown to be unrelated to gender in this group of healthy volunteers.
Pea Aphids (Hemiptera: Aphididae) Have Diurnal Rhythms When Raised Independently of a Host Plant
(2016)
Seasonal timing is assumed to involve the circadian clock, an endogenous mechanism to track time and measure day length. Some debate persists, however, and aphids were among the first organisms for which circadian clock involvement was questioned. Inferences about links to phenology are problematic, as the clock itself is little investigated in aphids. For instance, it is unknown whether aphids possess diurnal rhythms at all. Possibly, the close interaction with host plants prevents independent measurements of rhythmicity. We reared the pea aphid Acyrthosiphon pisum (Harris) on an artificial diet, and recorded survival, moulting, and honeydew excretion. Despite their plant-dependent life style, aphids were independently rhythmic under light–dark conditions. This first demonstration of diurnal aphid rhythms shows that aphids do not simply track the host plant’s rhythmicity.
The next-to-leading-order electroweak corrections to pp→l\(^{+}\)l\(^{-}\)/ν¯¯¯ν+γ+X production, including all off-shell effects of intermediate Z bosons in the complex-mass scheme, are calculated for LHC energies, revealing the typically expected large corrections of tens of percent in the TeV range. Contributions from quark-photon and photon-photon initial states are taken into account as well, but their impact is found to be moderate or small. Moreover, the known next-to-leading-order QCD corrections are reproduced. In order to separate hard photons from jets, both a quark-to-photon fragmentation function á la Glover/Morgan and Frixione’s cone isolation are employed. The calculation is available in the form of Monte Carlo programs allowing for the evaluation of arbitrary differential cross sections. Predictions for integrated cross sections are presented for the LHC at 7 TeV, 8 TeV, and 14 TeV, and differential distributions are discussed at 14 TeV for bare muons and dressed leptons. Finally, we consider the impact of anomalous ZZγ and Zγγ couplings.
We present a supersymmetric left-right model which predicts gauge coupling unification close to the string scale and extra vector bosons at the TeV scale. The subtleties in constructing a model which is in agreement with the measured quark masses and mixing for such a low left-right breaking scale are discussed. It is shown that in the constrained version of this model radiative breaking of the gauge symmetries is possible and a SM-like Higgs is obtained. Additional CP-even scalars of a similar mass or even much lighter are possible. The expected mass hierarchies for the supersymmetric states differ clearly from those of the constrained MSSM. In particular, the lightest down-type squark, which is a mixture of the sbottom and extra vector-like states, is always lighter than the stop. We also comment on the model’s capability to explain current anomalies observed at the LHC.
Next-to-leading-order electroweak corrections to pp -> W\(^{+}\)W\(^{-}\) -> 4 leptons at the LHC
(2016)
We present results of the first calculation of next-to-leading-order electroweak corrections to W-boson pair production at the LHC that fully takes into account leptonic W-boson decays and off-shell effects. Employing realistic event selections, we discuss the corrections in situations that are typical for the study of W-boson pairs as a signal process or of Higgs-boson decays H → WW∗, to which W-boson pair production represents an irreducible background. In particular, we compare the full off-shell results, obtained treating the W-boson resonances in the complex-mass scheme, to previous results in the so-called double-pole approximation, which is based on an expansion of the loop amplitudes about the W resonance poles. At small and intermediate scales, i.e. in particular in angular and rapidity distributions, the two approaches show the expected agreement at the level of fractions of a percent, but larger differences appear in the TeV range. For transverse-momentum distributions, the differences can even exceed the 10% level in the TeV range where “background diagrams” with one instead of two resonant W bosons gain in importance because of recoil effects.
Most research on human fear conditioning and its generalization has focused on adults whereas only little is known about these processes in children. Direct comparisons between child and adult populations are needed to determine developmental risk markers of fear and anxiety. We compared 267 children and 285 adults in a differential fear conditioning paradigm and generalization test. Skin conductance responses (SCR) and ratings of valence and arousal were obtained to indicate fear learning. Both groups displayed robust and similar differential conditioning on subjective and physiological levels. However, children showed heightened fear generalization compared to adults as indexed by higher arousal ratings and SCR to the generalization stimuli. Results indicate overgeneralization of conditioned fear as a developmental correlate of fear learning. The developmental change from a shallow to a steeper generalization gradient is likely related to the maturation of brain structures that modulate efficient discrimination between danger and (ambiguous) safety cues.
Reconstructing and understanding the Human Physiome virtually is a complex mathematical problem, and a highly demanding computational challenge. Mathematical models spanning from the molecular level through to whole populations of individuals must be integrated, then personalized. This requires interoperability with multiple disparate and geographically separated data sources, and myriad computational software tools. Extracting and producing knowledge from such sources, even when the databases and software are readily available, is a challenging task. Despite the difficulties, researchers must frequently perform these tasks so that available knowledge can be continually integrated into the common framework required to realize the Human Physiome. Software and infrastructures that support the communities that generate these, together with their underlying standards to format, describe and interlink the corresponding data and computer models, are pivotal to the Human Physiome being realized. They provide the foundations for integrating, exchanging and re-using data and models efficiently, and correctly, while also supporting the dissemination of growing knowledge in these forms. In this paper, we explore the standards, software tooling, repositories and infrastructures that support this work, and detail what makes them vital to realizing the Human Physiome.
The transcriptional coactivator Bob1 promotes the development of follicular T helper cells via Bcl6
(2016)
Follicular T helper (Tfh) cells are key regulators of the germinal center reaction and long-term humoral immunity. Tfh cell differentiation requires the sustained expression of the transcriptional repressor Bcl6; however, its regulation in CD4\(^+\) T cells is incompletely understood. Here, we report that the transcriptional coactivator Bob1, encoded by the Pou2af1 gene, promotes Bcl6 expression and Tfh cell development. We found that Bob1 together with the octamer transcription factors Oct1/Oct2 can directly bind to and transactivate the Bcl6 and Btla promoters. Mixed bone marrow chimeras revealed that Bob1 is required for the expression of normal levels of Bcl6 and BTLA, thereby controlling the pool size and composition of the Tfh compartment in a T cell-intrinsic manner. Our data indicate that T cell-expressed Bob1 is directly involved in Tfh cell differentiation and required for mounting normal T cell-dependent B-cell responses.
Background: In the phase III AVAGAST trial, the addition of bevacizumab to chemotherapy improved progression-free survival (PFS) but not overall survival (OS) in patients with advanced gastric cancer. We studied the role of Angiopoietin-2 (Ang-2), a key driver of tumour angiogenesis, metastasis and resistance to antiangiogenic treatment, as a biomarker.
Methods: Previously untreated, advanced gastric cancer patients were randomly assigned to receive bevacizumab (n = 387) or placebo (n = 387) in combination with chemotherapy. Plasma collected at baseline and at progression was analysed by ELISA. The role of Ang-2 as a prognostic and a predictive biomarker of bevacizumab efficacy was studied using a Cox proportional hazards model. Logistic regression analysis was applied for correlations with metastasis. Results: Median baseline plasma Ang-2 levels were lower in Asian (2143 pg ml\(^-\)\(^1\)) vs non-Asian patients (3193 pg ml\(^-\)\(^1\)), P<0.0001. Baseline plasma Ang-2 was identified as an independent prognostic marker for OS but did not predict bevacizumab efficacy alone or in combination with baseline VEGF. Baseline plasma Ang-2 correlated with the frequency of liver metastasis (LM) at any time: Odds ratio per 1000 pg ml\(^-\)\(^1\) increase: 1.19; 95% CI 1.10-1.29; P<0.0001 (non-Asians) and 1.37; 95% CI 1.13-1.64; P = 0.0010 (Asians).
Conclusions: Baseline plasma Ang-2 is a novel prognostic biomarker for OS in advanced gastric cancer strongly associated with LM. Differences in Ang-2 mediated vascular response may, in part, account for outcome differences between Asian and non-Asian patients; however, data have to be further validated. Ang-2 is a promising drug target in gastric cancer.
Animal models point towards a key role of brain-derived neurotrophic factor (BDNF), insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor (VEGF) in mediating exercise-induced structural and functional changes in the hippocampus. Recently, also platelet derived growth factor-C (PDGF-C) has been shown to promote blood vessel growth and neuronal survival. Moreover, reductions of these neurotrophic and angiogenic factors in old age have been related to hippocampal atrophy, decreased vascularization and cognitive decline. In a 3-month aerobic exercise study, forty healthy older humans (60 to 77 years) were pseudo-randomly assigned to either an aerobic exercise group (indoor treadmill, n = 21) or to a control group (indoor progressive-muscle relaxation/stretching, n = 19). As reported recently, we found evidence for fitness-related perfusion changes of the aged human hippocampus that were closely linked to changes in episodic memory function. Here, we test whether peripheral levels of BDNF, IGF-I, VEGF or PDGF-C are related to changes in hippocampal blood flow, volume and memory performance. Growth factor levels were not significantly affected by exercise, and their changes were not related to changes in fitness or perfusion. However, changes in IGF-I levels were positively correlated with hippocampal volume changes (derived by manual volumetry and voxel-based morphometry) and late verbal recall performance, a relationship that seemed to be independent of fitness, perfusion or their changes over time. These preliminary findings link IGF-I levels to hippocampal volume changes and putatively hippocampus-dependent memory changes that seem to occur over time independently of exercise. We discuss methodological shortcomings of our study and potential differences in the temporal dynamics of how IGF-1, VEGF and BDNF may be affected by exercise and to what extent these differences may have led to the negative findings reported here.
In biological tissue, an accumulation of similarly shaped objects with a susceptibility difference to the surrounding tissue generates a local distortion of the external magnetic field in magnetic resonance imaging. It induces stochastic field fluctuations that characteristically influence proton spin dephasing in the vicinity of these magnetic perturbers. The magnetic field correlation that is associated with such local magnetic field inhomogeneities can be expressed in the form of a dynamic frequency autocorrelation function that is related to the time evolution of the measured magnetization. Here, an eigenfunction expansion for two simple magnetic perturber shapes, that of spheres and cylinders, is considered for restricted spin diffusion in a simple model geometry. Then, the concept of generalized moment analysis, an approximation technique that is applied in the study of (non-)reactive processes that involve Brownian motion, allows deriving analytical expressions of the correlation function for different exponential decay forms. Results for the biexponential decay for both spherical and cylindrical magnetized objects are derived and compared with the frequently used (less accurate) monoexponential decay forms. They are in asymptotic agreement with the numerically exact value of the correlation function for long and short times.
A search for Secluded Dark Matter annihilation in the Sun using 2007-2012 data of the ANTARES neutrino telescope is presented. Three different cases are considered: a) detection of dimuons that result from the decay of the mediator, or neutrino detection from: b) mediator that decays into a dimuon and, in turn, into neutrinos, and c) mediator that decays directly into neutrinos. As no significant excess over background is observed, constraints are derived on the dark matter mass and the lifetime of the mediator.
Previous studies of social phobia have reported an increased vigilance to social threat cues but also an avoidance of socially relevant stimuli such as eye gaze. The primary aim of this study was to examine attentional mechanisms relevant for perceiving social cues by means of abnormalities in scanning of facial features in patients with social phobia. In two novel experimental paradigms, patients with social phobia and healthy controls matched on age, gender and education were compared regarding their gazing behavior towards facial cues. The first experiment was an emotion classification paradigm which allowed for differentiating reflexive attentional shifts from sustained attention towards diagnostically relevant facial features. In the second experiment, attentional orienting by gaze direction was assessed in a gaze-cueing paradigm in which non-predictive gaze cues shifted attention towards or away from subsequently presented targets. We found that patients as compared to controls reflexively oriented their attention more frequently towards the eyes of emotional faces in the emotion classification paradigm. This initial hypervigilance for the eye region was observed at very early attentional stages when faces were presented for 150 ms, and persisted when facial stimuli were shown for 3 s. Moreover, a delayed attentional orienting into the direction of eye gaze was observed in individuals with social phobia suggesting a differential time course of eye gaze processing in patients and controls. Our findings suggest that basic mechanisms of early attentional exploration of social cues are biased in social phobia and might contribute to the development and maintenance of the disorder.
Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. CCA is the second most common primary liver tumour and the incidence is increasing worldwide. CCA has high mortality owing to its aggressiveness, late diagnosis and refractory nature. In May 2015, the "European Network for the Study of Cholangiocarcinoma" (ENS-CCA: www.enscca.org or www.cholangiocarcinoma.eu) was created to promote and boost international research collaboration on the study of CCA at basic, translational and clinical level. In this Consensus Statement, we aim to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted.
A newly developed compact measuring system for assessment of transmittance changes in the near-infrared spectral region is described; it allows deconvolution of redox changes due to ferredoxin (Fd), P700, and plastocyanin (PC) in intact leaves. In addition, it can also simultaneously measure chlorophyll fluorescence. The major opto-electronic components as well as the principles of data acquisition and signal deconvolution are outlined. Four original pulse-modulated dual-wavelength difference signals are measured (785-840 nm, 810-870 nm, 870-970 nm, and 795-970 nm). Deconvolution is based on specific spectral information presented graphically in the form of 'Differential Model Plots' (DMP) of Fd, P700, and PC that are derived empirically from selective changes of these three components under appropriately chosen physiological conditions. Whereas information on maximal changes of Fd is obtained upon illumination after dark-acclimation, maximal changes of P700 and PC can be readily induced by saturating light pulses in the presence of far-red light. Using the information of DMP and maximal changes, the new measuring system enables on-line deconvolution of Fd, P700, and PC. The performance of the new device is demonstrated by some examples of practical applications, including fast measurements of flash relaxation kinetics and of the Fd, P700, and PC changes paralleling the polyphasic fluorescence rise upon application of a 300-ms pulse of saturating light.
No abstract available.
Aims: We set out to investigate the antibacterial activity of a new Mn-based photoactivated carbon monoxide-releasing molecule (PhotoCORM, [Mn(CO)\(_3\)(tpa-kappa\(^3\)N)]\(^+\)) against an antibiotic-resistant uropathogenic strain (EC958) of Escherichia coli. Results: Activated PhotoCORM inhibits growth and decreases viability of E. coli EC958, but non-illuminated carbon monoxide-releasing molecule (CORM) is without effect. NADH-supported respiration rates are significantly decreased by activated PhotoCORM, mimicking the effect of dissolved CO gas. CO from the PhotoCORM binds to intracellular targets, namely respiratory oxidases in strain EC958 and a bacterial globin heterologously expressed in strain K-12. However, unlike previously characterized CORMs, the PhotoCORM is not significantly accumulated in cells, as deduced from the cellular manganese content. Activated PhotoCORM reacts avidly with hydrogen peroxide producing hydroxyl radicals; the observed peroxide-enhanced toxicity of the PhotoCORM is ameliorated by thiourea. The PhotoCORM also potentiates the effect of the antibiotic, doxycycline. Innovation: The present work investigates for the first time the antimicrobial activity of a light-activated PhotoCORM against an antibiotic-resistant pathogen. A comprehensive study of the effects of the PhotoCORM and its derivative molecules upon illumination is performed and mechanisms of toxicity of the activated PhotoCORM are investigated. Conclusion: The PhotoCORM allows a site-specific and time-controlled release of CO in bacterial cultures and has the potential to provide much needed information on the generality of CORM activities in biology. Understanding the mechanism(s) of activated PhotoCORM toxicity will be key in exploring the potential of this and similar compounds as antimicrobial agents, perhaps in combinatorial therapies with other agents.
Aims
We previously reported that in the EMPA-REG OUTCOME(R) trial, empagliflozin added to standard of care reduced the risk of 3-point major adverse cardiovascular events, cardiovascular and all-cause death, and hospitalization for heart failure in patients with type 2 diabetes and high cardiovascular risk. We have now further investigated heart failure outcomes in all patients and in subgroups, including patients with or without baseline heart failure.
Methods and results
Patients were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo. Seven thousand and twenty patients were treated; 706 (10.1%) had heart failure at baseline. Heart failure hospitalization or cardiovascular death occurred in a significantly lower percentage of patients treated with empagliflozin 265/4687 patients (5.7%)] than with placebo 198/2333 patients (8.5%)] hazard ratio, HR: 0.66 (95% confidence interval: 0.55-0.79); P < 0.001], corresponding to a number needed to treat to prevent one heart failure hospitalization or cardiovascular death of 35 over 3 years. Consistent effects of empagliflozin were observed across subgroups defined by baseline characteristics, including patients with vs. without heart failure, and across categories of medications to treat diabetes and/or heart failure. Empagliflozin improved other heart failure outcomes, including hospitalization for or death from heart failure 2.8 vs. 4.5%; HR: 0.61 (0.47-0.79); P < 0.001] and was associated with a reduction in all-cause hospitalization 36.8 vs. 39.6%; HR: 0.89 (0.82-0.96); P = 0.003]. Serious adverse events and adverse events leading to discontinuation were reported by a higher proportion of patients with vs. without heart failure at baseline in both treatment groups, but were no more common with empagliflozin than with placebo.
Conclusion
In patients with type 2 diabetes and high cardiovascular risk, empagliflozin reduced heart failure hospitalization and cardiovascular death, with a consistent benefit in patients with and without baseline heart failure.
The main objectives of the KM3NeT Collaboration are (i) the discovery and subsequent observation of high-energy neutrino sources in the Universe and (ii) the determination of the mass hierarchy of neutrinos. These objectives are strongly motivated by two recent important discoveries, namely: (1) the high-energy astrophysical neutrino signal reported by IceCube and (2) the sizable contribution of electron neutrinos to the third neutrino mass eigenstate as reported by Daya Bay, Reno and others. To meet these objectives, the KM3NeT Collaboration plans to build a new Research Infrastructure consisting of a network of deep-sea neutrino telescopes in the Mediterranean Sea. A phased and distributed implementation is pursued which maximises the access to regional funds, the availability of human resources and the synergistic opportunities for the Earth and sea sciences community. Three suitable deep-sea sites are selected, namely off-shore Toulon (France), Capo Passero (Sicily, Italy) and Pylos (Peloponnese, Greece). The infrastructure will consist of three so-called building blocks. A building block comprises 115 strings, each string comprises 18 optical modules and each optical module comprises 31 photo-multiplier tubes. Each building block thus constitutes a three-dimensional array of photo sensors that can be used to detect the Cherenkov light produced by relativistic particles emerging from neutrino interactions. Two building blocks will be sparsely configured to fully explore the IceCube signal with similar instrumented volume, different methodology, improved resolution and
Infections of the central nervous system (CNS) are infrequently diagnosed in immunocompetent patients, but they do occur in a significant proportion of patients with hematological disorders. In particular, patients undergoing allogeneic hematopoietic stem-cell transplantation carry a high risk for CNS infections of up to 15%. Fungi and Toxoplasma gondii are the predominant causative agents. The diagnosis of CNS infections is based on neuroimaging, cerebrospinal fluid examination and biopsy of suspicious lesions in selected patients. However, identification of CNS infections in immunocompromised patients could represent a major challenge since metabolic disturbances, side-effects of antineoplastic or immunosuppressive drugs and CNS involvement of the underlying hematological disorder may mimic symptoms of a CNS infection. The prognosis of CNS infections is generally poor in these patients, albeit the introduction of novel substances (e.g. voriconazole) has improved the outcome in distinct patient subgroups. This guideline has been developed by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) with the contribution of a panel of 14 experts certified in internal medicine, hematology/oncology, infectious diseases, intensive care, neurology and neuroradiology. Grades of recommendation and levels of evidence were categorized by using novel criteria, as recently published by the European Society of Clinical Microbiology and Infectious Diseases.
Tumor models based on cancer cell lines cultured two-dimensionally (2D) on plastic lack histological complexity and functionality compared to the native microenvironment. Xenogenic mouse tumor models display higher complexity but often do not predict human drug responses accurately due to species-specific differences. We present here a three-dimensional (3D) in vitro colon cancer model based on a biological scaffold derived from decellularized porcine jejunum (small intestine submucosa+mucosa, SISmuc). Two different cell lines were used in monoculture or in coculture with primary fibroblasts. After 14 days of culture, we demonstrated a close contact of human Caco2 colon cancer cells with the preserved basement membrane on an ultrastructural level as well as morphological characteristics of a well-differentiated epithelium. To generate a tissue-engineered tumor model, we chose human SW480 colon cancer cells, a reportedly malignant cell line. Malignant characteristics were confirmed in 2D cell culture: SW480 cells showed higher vimentin and lower E-cadherin expression than Caco2 cells. In contrast to Caco2, SW480 cells displayed cancerous characteristics such as delocalized E-cadherin and nuclear location of beta-catenin in a subset of cells. One central drawback of 2D cultures-especially in consideration of drug testing-is their artificially high proliferation. In our 3D tissue-engineered tumor model, both cell lines showed decreased numbers of proliferating cells, thus correlating more precisely with observations of primary colon cancer in all stages (UICC I-IV). Moreover, vimentin decreased in SW480 colon cancer cells, indicating a mesenchymal to epithelial transition process, attributed to metastasis formation. Only SW480 cells cocultured with fibroblasts induced the formation of tumor-like aggregates surrounded by fibroblasts, whereas in Caco2 cocultures, a separate Caco2 cell layer was formed separated from the fibroblast compartment beneath. To foster tissue generation, a bioreactor was constructed for dynamic culture approaches. This induced a close tissue-like association of cultured tumor cells with fibroblasts reflecting tumor biopsies. Therapy with 5-fluorouracil (5-FU) was effective only in 3D coculture. In conclusion, our 3D tumor model reflects human tissue-related tumor characteristics, including lower tumor cell proliferation. It is now available for drug testing in metastatic context-especially for substances targeting tumor-stroma interactions.
Aims:
Patients with Fabry disease (FD) characteristically develop peripheral neuropathy at an early age, with pain being a crucial symptom of underlying pathology. However, the diagnosis of pain is challenging due to the heterogeneous and nonspecific symptoms. Practical guidance on the diagnosis and management of pain in FD is needed.
Methods:
In 2014, experts met to discuss recent advances on this topic and update clinical guidance.
Results:
Emerging disease-specific tools, including FabryScan, Fabry-specific Pediatric Health and Pain Questionnaire, and Wurzburg Fabry Pain Questionnaire, and more general tools like the Total Symptom Score can aid diagnosis, characterization, and monitoring of pain in patients with FD. These tools can be complemented by more objective and quantifiable sensory testing. In male and female patients of any age, pain related to FD can be an early indication to start disease-specific enzyme replacement therapy before potentially irreversible organ damage to the kidneys, heart, or brain occurs.
Conclusion:
To improve treatment outcomes, pain should be diagnosed early in unrecognized or newly identified FD patients. Treatment should include: (a) enzyme replacement therapy controlling the progression of underlying pathology; (b) adjunctive, symptomatic pain management with analgesics for chronic neuropathic and acute nociceptive, and inflammatory or mixed pain; and (c) lifestyle modifications.
Aggressiveness is a behavioral trait that has the potential to be harmful to individuals and society. With an estimated heritability of about 40%, genetics is important in its development. We performed an exploratory genome-wide association (GWA) analysis of childhood aggressiveness in attention deficit hyperactivity disorder (ADHD) to gain insight into the underlying biological processes associated with this trait. Our primary sample consisted of 1,060 adult ADHD patients (aADHD). To further explore the genetic architecture of childhood aggressiveness, we performed enrichment analyses of suggestive genome-wide associations observed in aADHD among GWA signals of dimensions of oppositionality (defiant/vindictive and irritable dimensions) in childhood ADHD (cADHD). No single polymorphism reached genome-wide significance (P<5.00E-08). The strongest signal in aADHD was observed at rs10826548, within a long noncoding RNA gene (beta = -1.66, standard error (SE) = 0.34, P = 1.07E-06), closely followed by rs35974940 in the neurotrimin gene (beta = 3.23, SE = 0.67, P = 1.26E-06). The top GWA SNPs observed in aADHD showed significant enrichment of signals from both the defiant/vindictive dimension (Fisher's P-value = 2.28E-06) and the irritable dimension in cADHD (Fisher's P-value = 0.0061). In sum, our results identify a number of biologically interesting markers possibly underlying childhood aggressiveness and provide targets for further genetic exploration of aggressiveness across psychiatric disorders.
The interleukin (IL)-12-type cytokines IL-12 and IL-23 are involved in T-helper (Th) 1 and Th17 immunity, respectively. They share the IL-12 receptor beta 1 (IL-12R beta 1) as one component of their receptor signaling complexes, with IL-12R beta 2 as second receptor for IL-12 and IL-23R for IL-23 signal transduction. Stimulation with IL-12 and IL-23 results in activation of receptor-associated Janus kinases (Jak) and phosphorylation of STAT proteins in target cells. The Janus kinase tyrosine kinase (Tyk) 2 associates with IL-12R beta 1, whereas Jak2 binds to IL-23R and also to IL-12R beta 2. Receptor association of Jak2 is mediated by Box1 and Box2 motifs located within the intracellular domain of the receptor chains. Here we define the Box1 and Box2 motifs in IL-12R beta 1 and an unusual Jak2-binding site in IL-23R by the use of deletion and site-directed mutagenesis. Our data show that nonfunctional box motifs abolish IL-12- and IL-23-induced STAT3 phosphorylation and cytokine-dependent proliferation of Ba/F3 cells. Coimmunoprecipitation of Tyk2 by IL-12R beta 1 and Jak2 by IL-23R supported these findings. In addition, our data demonstrate that association of Jak2 with IL-23R is mandatory for IL-12 and/or IL-23 signaling, whereas Tyk2 seems to be dispensable.
Patients with genetic cardiomyopathy that involves myocardial hypertrophy often develop clinically relevant arrhythmias that increase the risk of sudden death. Consequently, guidelines for medical device therapy were established for hypertrophic cardiomyopathy, but not for conditions with only anecdotal evidence of arrhythmias, like Fabry cardiomyopathy. Patients with Fabry cardiomyopathy progressively develop myocardial fibrosis, and sudden cardiac death occurs regularly. Because 24-hour Holier electrocardiograms (ECGs) might not detect clinically important arrhythmias, we tested an implanted loop recorder for continuous heart rhythm surveillance and determined its impact on therapy. This prospective study included 16 patients (12 men) with advanced Fabry cardiomyopathy, relevant hypertrophy, and replacement fibrosis in "loco typico." No patients previously exhibited clinically relevant arrhythmias on Holier ECGs. Patients received an implantable loop recorder and were prospectively followed with telemedicine for a median of 1.2 years (range 0.3 to 2.0 years). The primary end point was a clinically meaningful event, which required a therapy change, captured with the loop recorder. Patients submitted data regularly (14 +/- 11 times per month). During follow-up, 21 events were detected (including 4 asystole, i.e., ECG pauses >= 3 seconds) and 7 bradycardia events; 5 episodes of intermittent atrial fibrillation (>3 minutes) and 5 episodes of ventricular tachycardia (3 sustained and 2 nonsustained). Subsequently, as defined in the primary end point, 15 events leaded to a change of therapy. These patients required therapy with a pacemaker or cardioverter defibrillator implantation and/or anticoagulation therapy for atrial fibrillation. In conclusion, clinically relevant arrhythmias that require further device and/or medical therapy are often missed with Holier ECGs in patients with advanced stage Fabry cardiomyopathy, but they can be detected by telemonitoring with an implantable loop recorder.
Objective:
Adrenal masses are incidentally discovered in 5% of CT scans. In 2013/2014, 81 million CT examinations were undertaken in the USA and 5 million in the UK. However, uncertainty remains around the optimal imaging approach for diagnosing malignancy. We aimed to review the evidence on the accuracy of imaging tests for differentiating malignant from benign adrenal masses. Design: A systematic review and meta-analysis was conducted.
Methods:
We searched MEDLINE, EMBASE, Cochrane CENTRAL Register of Controlled Trials, Science Citation Index, Conference Proceedings Citation Index, and ZETOC (January 1990 to August 2015). We included studies evaluating the accuracy of CT, MRI, or F-18-fluoro-deoxyglucose (FDG)-PET compared with an adequate histological or imaging-based follow-up reference standard.
Results:
We identified 37 studies suitable for inclusion, after screening 5469 references and 525 full-text articles. Studies evaluated the accuracy of CT (n = 16), MRI (n = 15), and FDG-PET (n = 9) and were generally small and at high or unclear risk of bias. Only 19 studies were eligible for meta-analysis. Limited data suggest that CT density >10 HU has high sensitivity for detection of adrenal malignancy in participants with no prior indication for adrenal imaging, that is, masses with <= 10 HU are unlikely to be malignant. All other estimates of test performance are based on too small numbers.
Conclusions:
Despite their widespread use in routine assessment, there is insufficient evidence for the diagnostic value of individual imaging tests in distinguishing benign from malignant adrenal masses. Future research is urgently needed and should include prospective test validation studies for imaging and novel diagnostic approaches alongside detailed health economics analysis.
The standard property rights approach is focused on ex ante investment incentives, while there are no transaction costs that might restrain ex post negotiations. We explore the implications of such transaction costs. Prominent conclusions of the property rights theory may be overturned: A party may have stronger investment incentives when a non investing party is the owner, and joint ownership can be the uniquely optimal ownership structure. Intuitively, an ownership structure that is unattractive in the standard model may now be desirable, because it implies large gains from trade, such that the parties are more inclined to incur the transaction costs.
Chronobiological studies of individual activity rhythms in social insects can be constrained by the artificial isolation of individuals from their social context. We present a new experimental set-up that simultaneously measures the temperature rhythm in a queen-less but brood raising mini colony and the walking activity rhythms of singly kept honey bees that have indirect social contact with it. Our approach enables monitoring of individual bees in the social context of a mini colony under controlled laboratory conditions. In a pilot experiment, we show that social contact with the mini colony improves the survival of monitored young individuals and affects locomotor activity patterns of young and old bees. When exposed to conflicting Zeitgebers consisting of a light-dark (LD) cycle that is phase-delayed with respect to the mini colony rhythm, rhythms of young and old bees are socially synchronized with the mini colony rhythm, whereas isolated bees synchronize to the LD cycle. We conclude that the social environment is a stronger Zeitgeber than the LD cycle and that our new experimental set-up is well suited for studying the mechanisms of social entrainment in honey bees.
The genomes of kinetoplastids are organized into polycistronic gene clusters that are flanked by the modified DNA base J. Previous work has established a role of base J in promoting RNA polymerase II termination in Leishmania spp. where the loss of J leads to termination defects and transcription into adjacent gene clusters. It remains unclear whether these termination defects affect gene expression and whether read through transcription is detrimental to cell growth, thus explaining the essential nature of J. We now demonstrate that reduction of base J at specific sites within polycistronic gene clusters in L. major leads to read through transcription and increased expression of downstream genes in the cluster. Interestingly, subsequent transcription into the opposing polycistronic gene cluster does not lead to downregulation of sense mRNAs. These findings indicate a conserved role for J regulating transcription termination and expression of genes within polycistronic gene clusters in trypanosomatids. In contrast to the expectations often attributed to opposing transcription, the essential nature of J in Leishmania spp. is related to its role in gene repression rather than preventing transcriptional interference resulting from read through and dual strand transcription.
Introduction
A novel neurostimulation system allows steering current in horizontal directions by combining segmented leads and multiple independent current control. The aim of this study was to evaluate directional DBS effects on parkinsonian motor features and adverse effects of subthalamic neurostimulation.
Methods
Seven PD patients implanted with the novel directional DBS system for bilateral subthalamic DBS underwent an extended monopolar review session during the first postoperative week, in which current thresholds were determined for rigidity control and stimulation-induced adverse effects using either directional or ring-mode settings.
Results
Effect or adverse effect thresholds were modified by directional settings for each of the 14 STN leads. Magnitude of change varied markedly between leads, as did orientation of optimal horizontal current steering.
Conclusion
Directional current steering through chronically implanted segmented electrodes is feasible, alters adverse effect and efficacy thresholds in a highly individual manner, and expands the therapeutic window in a monopolar review as compared to ring-mode DBS.
Fluorescence enhancement of a high-mobility polymer semiconductor is achieved via energy transfer to a higher fluorescence quantum yield squaraine dye molecule on 50 ps timescales. In organic light-emitting diodes, an order of magnitude enhancement of the external quantum efficiency is observed without reduction in the charge-carrier mobility resulting in radiances of up to 5 W str\(^{-1}\) m\(^{-2}\) at 800 nm.
Donor CD4\(^+\)Foxp3\(^+\) regulatory T cells (T reg cells) suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HCT allo-HCT]). Current clinical study protocols rely on the ex vivo expansion of donor T reg cells and their infusion in high numbers. In this study, we present a novel strategy for inhibiting GvHD that is based on the in vivo expansion of recipient T reg cells before allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in T reg cell biology. Expanding radiation-resistant host T reg cells in recipient mice using a mouse TNFR2-selective agonist before allo-HCT significantly prolonged survival and reduced GvHD severity in a TNFR2-and T reg cell-dependent manner. The beneficial effects of transplanted T cells against leukemia cells and infectious pathogens remained unaffected. A corresponding human TNFR2-specific agonist expanded human T reg cells in vitro. These observations indicate the potential of our strategy to protect allo-HCT patients from acute GvHD by expanding T reg cells via selective TNFR2 activation in vivo.
The EANM 2015 Annual Congress, held from October 10th to 14th in Hamburg, Germany, was outstanding in many respects. With 5550 participants, this was by far the largest European congress concerning nuclear medicine. More than 1750 scientific presentations were submitted, with more than 250 abstracts from young scientists, indicating that the future success of our discipline is fuelled by a high number of young individuals becoming involved in a multitude of scientific activities. Significant improvements have been made in molecular imaging of cancer, particularly in prostate cancer. PSMA-directed PET/CT appears to become a new gold standard for staging and restaging purposes. Novel tumour specific compounds have shown their potential for target identification also in other solid neoplasms and further our understanding of tumour biology and heterogeneity. In addition, a variety of nuclear imaging techniques guiding surgical interventions have been introduced. A particular focus of the congress was put on targeted, radionuclide based therapies. Novel theranostic concepts addressing also tumour entities with high incidence rates such as prostate cancer, melanoma, and lymphoma, have shown effective anti-tumour activity. Strategies have been presented to improve further already established therapeutic regimens such as somatostatin receptor based radio receptor therapy for treating advanced neuroendocrine tumours. Significant contributions were presented also in the neurosciences track. An increasing number of target structures of high interest in neurology and psychiatry are now available for PET and SPECT imaging, facilitating specific imaging of different subtypes of dementia and movement disorders as well as neuroinflammation. Major contributions in the cardiovascular track focused on further optimization of cardiac perfusion imaging by reducing radiation exposure, reducing scanning time, and improving motion correction. Besides coronary artery disease, many contributions focused on cardiac inflammation, cardiac sarcoidosis, and specific imaging of large vessel vasculitis. The physics and instrumentation track included many highlights such as novel, high resolution scanners. The most noteworthy news and developments of this meeting were summarized in the highlights lecture. Only 55 scientific contributions were mentioned, and hence they represent only a brief summary, which is outlined in this article. For a more detailed view, all presentations can be accessed by the online version of the European Journal of Nuclear Medicine and Molecular Imaging (Volume 42, Supplement 1).
BACKGROUND:
Thigmotaxis refers to a specific behavior of animals (i.e., to stay close to walls when exploring an open space). Such behavior can be assessed with the open field test (OFT), which is a well-established indicator of animal fear. The detection of similar open field behavior in humans may verify the translational validity of this paradigm. Enhanced thigmotaxis related to anxiety may suggest the relevance of such behavior for anxiety disorders, especially agoraphobia.
METHODS:
A global positioning system was used to analyze the behavior of 16 patients with agoraphobia and 18 healthy individuals with a risk for agoraphobia (i.e., high anxiety sensitivity) during a human OFT and compare it with appropriate control groups (n = 16 and n = 19). We also tracked 17 patients with agoraphobia and 17 control participants during a city walk that involved walking through an open market square. RESULTS: Our human OFT triggered thigmotaxis in participants; patients with agoraphobia and participants with high anxiety sensitivity exhibited enhanced thigmotaxis. This behavior was evident in increased movement lengths along the wall of the natural open field and fewer entries into the center of the field despite normal movement speed and length. Furthermore, participants avoided passing through the market square during the city walk, indicating again that thigmotaxis is related to agoraphobia.
CONCLUSIONS:
This study is the first to our knowledge to verify the translational validity of the OFT and to reveal that thigmotaxis, an evolutionarily adaptive behavior shown by most species, is related to agoraphobia, a pathologic fear of open spaces, and anxiety sensitivity, a risk factor for agoraphobia.
Infectious complications after allogeneic haematopoietic stem cell transplantation (allo-HCT) remain a clinical challenge. This is a guideline provided by the AGIHO (Infectious Diseases Working Group) of the DGHO (German Society for Hematology and Medical Oncology). A core group of experts prepared a preliminary guideline, which was discussed, reviewed, and approved by the entire working group. The guideline provides clinical recommendations for the preventive management including prophylactic treatment of viral, bacterial, parasitic, and fungal diseases. The guideline focuses on antimicrobial agents but includes recommendations on the use of vaccinations. This is the updated version of the AGHIO guideline in the field of allogeneic haematopoietic stem cell transplantation utilizing methods according to evidence-based medicine criteria.
Background
Tumour resistance to a wide range of drugs (multiple drug resistant, MDR) acquired after intensive chemotherapy is considered to be the main obstacle of the curative treatment of cancer patients. Recent work has shown that oncolytic viruses demonstrated prominent potential for effective treatment of diverse cancers. Here, we evaluated whether genetically modified vaccinia virus (LIVP-GFP) may be effective in treatment of cancers displaying MDR phenotype.
Methods
LIVP-GFP replication, transgene expression and cytopathic effects were analysed in human cervical carcinomas KB-3-1 (MDR−), KB-8-5 (MDR+) and in murine melanoma B-16 (MDR−), murine lymphosarcomas RLS and RLS-40 (MDR+). To investigate the efficacy of this therapy in vivo, we treated immunocompetent mice bearing murine lymphosarcoma RLS-40 (MDR+) (6- to 8-week-old female CBA mice; n = 10/group) or melanoma B-16 (MDR−) (6- to 8-week-old female C57Bl mice; n = 6/group) with LIVP-GFP (5 × 107 PFU of virus in 0.1 mL of IMDM immediately and 4 days after tumour implantation).
Results
We demonstrated that LIVP-GFP replication was effective in human cervical carcinomas KB-3-1 (MDR−) and KB-8-5 (MDR+) and in murine melanoma B-16 (MDR−), whereas active viral production was not detected in murine lymphosarcomas RLS and RLS-40 (MDR+). Additionally, it was found that in tumour models in immunocompetent mice under the optimized regimen intratumoural injections of LIVP-GFP significantly inhibited melanoma B16 (33 % of mice were with complete response after 90 days) and RLS-40 tumour growth (fourfold increase in tumour doubling time) as well as metastasis.
Conclusion
The anti-tumour activity of LIVP-GFP is a result of direct oncolysis of tumour cells in case of melanoma B-16 because the virus effectively replicates and destroys these cells, and virus-mediated activation of the host immune system followed by immunologically mediated destruction of of tumour cells in case of lymphosarcoma RLS-40. Thus, the recombinant vaccinia virus LIVP-GFP is able to inhibit the growth of malignant cells with the MDR phenotype and tumour metastasis when administered in the early stages of tumour development.
Neurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling
(2016)
In neurons, microtubules form a dense array within axons, and the stability and function of this microtubule network is modulated by neurofilaments. Accumulation of neurofilaments has been observed in several forms of neurodegenerative diseases, but the mechanisms how elevated neurofilament levels destabilize axons are unknown so far. Here, we show that increased neurofilament expression in motor nerves of pmn mutant mice, a model of motoneuron disease, causes disturbed microtubule dynamics. The disease is caused by a point mutation in the tubulin-specific chaperone E (Tbce) gene, leading to an exchange of the most C-terminal amino acid tryptophan to glycine. As a consequence, the TBCE protein becomes instable which then results in destabilization of axonal microtubules and defects in axonal transport, in particular in motoneurons. Depletion of neurofilament increases the number and regrowth of microtubules in pmn mutant motoneurons and restores axon elongation. This effect is mediated by interaction of neurofilament with the stathmin complex. Accumulating neurofilaments associate with stathmin in axons of pmn mutant motoneurons. Depletion of neurofilament by Nefl knockout increases Stat3-stathmin interaction and stabilizes the microtubules in pmn mutant motoneurons. Consequently, counteracting enhanced neurofilament expression improves axonal maintenance and prolongs survival of pmn mutant mice. We propose that this mechanism could also be relevant for other neurodegenerative diseases in which neurofilament accumulation and loss of microtubules are prominent features.
Background
Agalsidase beta is a form of enzyme replacement therapy for Fabry disease, a genetic disorder characterised by low alpha-galactosidase A activity, accumulation of glycosphingolipids and life-threatening cardiovascular, renal and cerebrovascular events. In clinical trials, agalsidase beta cleared glycolipid deposits from endothelial cells within 6 months; clearance from other cell types required sustained treatment. We hypothesised that there might be a 'lag time' to clinical benefit after initiating agalsidase beta treatment, and analysed the incidence of severe clinical events over time in patients receiving agalsidase beta.
Methods
The incidence of severe clinical events (renal failure, cardiac events, stroke, death) was studied in 1044 adult patients (641 men, 403 women) enrolled in the Fabry Registry who received agalsidase beta (average dose 1 mg/kg every 2 weeks) for up to 5 years.
Results
The incidence of all severe clinical events was 111 per 1000 person-years (95% CI 84 to 145) during the first 6 months. After 6 months, the incidence decreased and remained stable within the range of 40-58 events per 1000 patient-years. The largest decrease in incidence rates was among male patients and those aged >= 40 years when agalsidase beta was initiated.
Conclusions
Contrary to the expected increased incidence of severe clinical events with time, adult patients with Fabry disease had decreased incidence of severe clinical events after 6 months treatment with agalsidase beta 1 mg/kg every 2 weeks.
Although the concept of botanical carnivory has been known since Darwin's time, the molecular mechanisms that allow animal feeding remain unknown, primarily due to a complete lack of genomic information. Here, we show that the transcriptomic landscape of the Dionaea trap is dramatically shifted toward signal transduction and nutrient transport upon insect feeding, with touch hormone signaling and protein secretion prevailing. At the same time, a massive induction of general defense responses is accompanied by the repression of cell death-related genes/processes. We hypothesize that the carnivory syndrome of Dionaea evolved by exaptation of ancient defense pathways, replacing cell death with nutrient acquisition.
Objective
To analyse the role of multibiomarker disease activity (MBDA) score in predicting disease relapses in patients with rheumatoid arthritis (RA) in sustained remission who tapered disease modifying antirheumatic drug (DMARD) therapy in RETRO, a prospective randomised controlled trial.
Methods
MBDA scores (scale 1-100) were determined based on 12 inflammation markers in baseline serum samples from 94 patients of the RETRO study. MBDA scores were compared between patients relapsing or remaining in remission when tapering DMARDs. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining predictors of relapse.
Results
Moderate-to-high MBDA scores were found in 33% of patients with RA overall. Twice as many patients who relapsed (58%) had moderate/high MBDA compared with patients who remained in remission (21%). Baseline MBDA scores were significantly higher in patients with RA who were relapsing than those remaining in stable remission (N=94; p=0.0001) and those tapering/stopping (N=59; p=0.0001). Multivariate regression analysis identified MBDA scores as independent predictor for relapses in addition to anticitrullinated protein antibody (ACPA) status. Relapse rates were low (13%) in patients who were MBDA-/ACPA-, moderate in patients who were MBDA+/ACPA- (33.3%) and MBDA-ACPA+ (31.8%) and high in patients who were MBDA+/ACPA+ (76.4%).
Conclusions
MBDA improved the prediction of relapses in patients with RA in stable remission undergoing DMARD tapering. If combined with ACPA testing, MBDA allowed prediction of relapse in more than 80% of the patients.
Trial registration number EudraCT
2009-015740-42.
Synaptopathies: synaptic dysfunction in neurological disorders - a review from students to students
(2016)
Synapses are essential components of neurons and allow information to travel coordinately throughout the nervous system to adjust behavior to environmental stimuli and to control body functions, memories, and emotions. Thus, optimal synaptic communication is required for proper brain physiology, and slight perturbations of synapse function can lead to brain disorders. In fact, increasing evidence has demonstrated the relevance of synapse dysfunction as a major determinant of many neurological diseases. This notion has led to the concept of synaptopathies as brain diseases with synapse defects as shared pathogenic features. In this review, which was initiated at the 13th International Society for Neurochemistry Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental disorders (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer and Parkinson disease). We finally discuss the appropriateness and potential implications of gathering synapse diseases under a single term. Understanding common causes and intrinsic differences in disease-associated synaptic dysfunction could offer novel clues toward synapse-based therapeutic intervention for neurological and neuropsychiatric disorders. In this Review, which was initiated at the 13th International Society for Neurochemistry (ISN) Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer's and Parkinson's diseases), gathered together under the term of synaptopathies. Read the Editorial Highlight for this article on page .
The HIT-SIOP-PNET4 randomised trial for standard risk medulloblastoma (MB) (2001-2006) included 338 patients and compared hyperfractionated and conventional radiotherapy. We here report the long-term outcome after a median follow up of 7.8 years, including detailed information on relapse and the treatment of relapse. Data were extracted from the HIT Group Relapsed MB database and by way of a specific case report form. The event-free and overall (OS) survival at 10 years were 76 +/- 2 % and 78 +/- 2 % respectively with no significant difference between the treatment arms. Seventy-two relapses and three second malignant neoplasms were reported. Thirteen relapses (18 %) were isolated local relapses in the posterior fossa (PF) and 59 (82 %) were craniospinal, metastatic relapses (isolated or multiple) with or without concurrent PF disease. Isolated PF relapse vs all other relapses occurred at mean/median of 38/35 and 28/26 months respectively (p = 0.24). Late relapse, i.e. > 5 years from diagnosis, occurred in six patients (8 %). Relapse treatment consisted of combinations of surgery (25 %), focal radiotherapy (RT 22 %), high dose chemotherapy with stem cell rescue (HDSCR 21 %) and conventional chemotherapy (90 %). OS at 5 years after relapse was 6.0 +/- 4 %. In multivariate analysis; isolated relapse in PF, and surgery were significantly associated with prolonged survival whereas RT and HDSCR were not. Survival after relapse was not related to biological factors and was very poor despite several patients receiving intensive treatments. Exploration of new drugs is warranted, preferably based on tumour biology from biopsy of the relapsed tumour.
The bacterial endosymbiont Blochmannia floridanus of the carpenter ant Camponotus floridanus contributes to its hosts' ontogeny via nutritional upgrading during metamorphosis. This primary endosymbiosis is essential for both partners and vertical transmission of the endosymbionts is guaranteed by bacterial infestation of oocytes. Here we present a detailed analysis of the presence and localisation of B. floridanus in the ants' ovaries obtained by FISH and TEM analyses. The most apical part of the germarium harbouring germ-line stem cells (GSCs) is not infected by the bacteria. The bacteria are detectable for the first time in lower parts of the germarium when cystocytes undergo the 4th and 5th division and B. floridanus infects somatic cells lying under the basal lamina surrounding the ovarioles. With the beginning of cystocyte differentiation, the endosymbionts are exclusively transported from follicle cells into the growing oocytes. This infestation of the oocytes by bacteria very likely involves exocytosis endocytosis processes between follicle cells and the oocytes. Nurse cells were never found to harbour the endosymbionts. Furthermore we present first gene expression data in C floridanus ovaries. These data indicate a modulation of immune gene expression which may facilitate tolerance towards the endosymbionts and thus may contribute to their transovarial transmission.
Purpose
Wilms tumor (WT) is the most common pediatric renal tumor. Treatment planning under International Society of Paediatric Oncology (SIOP) protocols is based on staging and histologic assessment of response to preoperative chemotherapy. Despite high overall survival (OS), many relapses occur in patients without specific risk factors, and many successfully treated patients are exposed to treatments with significant risks of late effects. To investigate whether molecular biomarkers could improve risk stratification, we assessed 1q status and other potential copy number biomarkers in a large WT series.
Materials and Methods
WT nephrectomy samples from 586 SIOP WT 2001 patients were analyzed using a multiplex ligation-dependent probe amplification (MLPA) assay that measured the copy number of 1q and other regions of interest.
Results
One hundred sixty-seven (28%) of 586 WTs had 1q gain. Five-year event-free survival (EFS) was 75.0% in patients with 1q gain (95% CI, 68.5% to 82.0%) and 88.2% in patients without gain (95% CI, 85.0% to 91.4%). OS was 88.4% with gain (95% CI, 83.5% to 93.6%) and 94.4% without gain (95% CI, 92.1% to 96.7%). In univariable analysis, 1q gain was associated with poorer EFS (P<.001; hazard ratio, 2.33) and OS (P=.01; hazard ratio, 2.16). The association of 1q gain with poorer EFS retained significance in multivariable analysis adjusted for 1p and 16q loss, sex, stage, age, and histologic risk group. Gain of 1q remained associated with poorer EFS in tumor subsets limited to either intermediate-risk localized disease or nonanaplastic localized disease. Other notable aberrations associated with poorer EFS included MYCN gain and TP53 loss.
Conclusion
Gain of 1q is a potentially valuable prognostic biomarker in WT, in addition to histologic response to preoperative chemotherapy and tumor stage.
It has been proposed that the observed diphoton excess at 750 GeV could be explained within the constrained minimal supersymmetric standard model via resonantly produced stop bound states. We reanalyze this scenario critically and extend previous work to include the constraints from the stability of the electroweak vacuum and from the decays of the stoponium into a pair of Higgs bosons. It is shown that the interesting regions of parameter space with a light stop and Higgs of the desired mass are ruled out by these constraints. This conclusion is not affected by the presence of the bound states because the binding energy is usually very small in the regions of parameter space which can explain the Higgs mass. Thus, this also leads to strong constraints on the diphoton production cross section which is in general too small.
Over the last 20 years, there has been increasing focus on the development of novel stem cell based therapies for the treatment of disorders and diseases affecting the enteric nervous system (ENS) of the gastrointestinal tract (so-called enteric neuropathies). Here, the idea is that ENS progenitor/stem cells could be transplanted into the gut wall to replace the damaged or absent neurons and glia of the ENS. This White Paper sets out experts' views on the commonly used methods and approaches to identify, isolate, purify, expand and optimize ENS stem cells, transplant them into the bowel, and assess transplant success, including restoration of gut function. We also highlight obstacles that must be overcome in order to progress from successful preclinical studies in animal models to ENS stem cell therapies in the clinic.
The maximum magnetisation (saturation magnetisation) obtainable for iron oxide nanoparticles can be increased by doping the nanocrystals with non-magnetic elements such as zinc. Herein, we closely study how only slightly different synthesis approaches towards such doped nanoparticles strongly influence the resulting sub-nano/atomic structure. We compare two co-precipitation approaches, where we only vary the base (NaOH versus NH\(_3\)), and a thermal decomposition route. These methods are the most commonly applied ones for synthesising doped iron oxide nanoparticles. The measurable magnetisation change upon zinc doping is about the same for all systems. However, the sub-nano structure, which we studied with Mossbauer and X-ray absorption near edge spectroscopy, differs tremendously. We found evidence that a much more complex picture has to be drawn regarding what happens upon Zn doping compared to what textbooks tell us about the mechanism. Our work demonstrates that it is crucial to study the obtained structures very precisely when "playing'' with the atomic order in iron oxide nanocrystals.
The quantum efficiency of light emission is a crucial parameter of supramolecular aggregates that can be tuned by the molecular design of the monomeric species. Here, we report on a strong variation of the fluorescence quantum yield due to different phases of aggregation for the case of a perylene bisimide dye. In particular, a change of the dominant aggregation character from H- to J-type within the first aggregation steps is found, explaining the observed dramatic change in quantum yield. This behaviour is rationalised by means of a systematic study of the intermolecular potential energy surfaces using the time-dependent density functional based tight-binding (TD-DFTB) method. This provides a correlation between structural changes and a coupling strength and supports the notion of H- type stacked dimers and J-type stack-slipped dimers. The exciton-vibrational level structure is modelled by means of an excitonic dimer model including two effective vibrational modes per monomer. Calculated absorption and fluorescence spectra are found to be in reasonable agreement with experimental ones, thus supporting the conclusion on the aggregation behaviour.
Fear is elicited by imminent threat and leads to phasic fear responses with selective attention, whereas anxiety is characterized by a sustained state of heightened vigilance due to uncertain danger. In the present study, we investigated attention mechanisms in fear and anxiety by adapting the NPU-threat test to measure steady-state visual evoked potentials (ssVEPs). We investigated ssVEPs across no aversive events (N), predictable aversive events (P), and unpredictable aversive events (U), signaled by four-object arrays (30 s). In addition, central cues were presented during all conditions but predictably signaled imminent threat only during the P condition. Importantly, cues and context events were flickered at different frequencies (15 Hz vs. 20 Hz) in order to disentangle respective electrocortical responses. The onset of the context elicited larger electrocortical responses for U compared to P context. Conversely, P cues elicited larger electrocortical responses compared to N cues. Interestingly, during the presence of the P cue, visuocortical processing of the concurrent context was also enhanced. The results support the notion of enhanced initial hypervigilance to unpredictable compared to predictable threat contexts, while predictable cues show electrocortical enhancement of the cues themselves but additionally a boost of context processing.
Mass-flowering crops (MFCs) are increasingly cultivated and might influence pollinator communities in MFC fields and nearby semi-natural habitats (SNHs). Across six European regions and 2 years, we assessed how landscape-scale cover of MFCs affected pollinator densities in 408 MFC fields and adjacent SNHs. In MFC fields, densities of bumblebees, solitary bees, managed honeybees and hoverflies were negatively related to the cover of MFCs in the landscape. In SNHs, densities of bumblebees declined with increasing cover of MFCs but densities of honeybees increased. The densities of all pollinators were generally unrelated to the cover of SNHs in the landscape. Although MFC fields apparently attracted pollinators from SNHs, in landscapes with large areas of MFCs they became diluted. The resulting lower densities might negatively affect yields of pollinator- dependent crops and the reproductive success of wild plants. An expansion of MFCs needs to be accompanied by pollinator-supporting practices in agricultural landscapes.
Synapse-associated protein 1 (Syap1/BSTA) is the mammalian homologue of Sap47 (synapse-associated protein of 47 kDa) in Drosophila. Sap47 null mutant larvae show reduced short-term synaptic plasticity and a defect in associative behavioral plasticity. In cultured adipocytes, Syap1 functions as part of a complex that phosphorylates protein kinase B alpha/Akt1 (Akt1) at Ser\(^{473}\) and promotes differentiation. The role of Syap1 in the vertebrate nervous system is unknown. Here, we generated a Syap1 knock-out mouse and show that lack of Syap1 is compatible with viability and fertility. Adult knock-out mice show no overt defects in brain morphology. In wild-type brain, Syap1 is found widely distributed in synaptic neuropil, notably in regions rich in glutamatergic synapses, but also in perinuclear structures associated with the Golgi apparatus of specific groups of neuronal cell bodies. In cultured motoneurons, Syap1 is located in axons and growth cones and is enriched in a perinuclear region partially overlapping with Golgi markers. We studied in detail the influence of Syap1 knockdown and knockout on structure and development of these cells. Importantly, Syap1 knockout does not affect motoneuron survival or axon growth. Unexpectedly, neither knockdown nor knockout of Syap1 in cultured motoneurons is associated with reduced Ser\(^{473}\) or Thr\(^{308}\) phosphorylation of Akt. Our findings demonstrate a widespread expression of Syap1 in the mouse central nervous system with regionally specific distribution patterns as illustrated in particular for olfactory bulb, hippocampus, and cerebellum.
For all sensory organs, the establishment of spatial and temporal cortical resolution is assumed to be initiated by the first sensory experience and a BDNF-dependent increase in intracortical inhibition. To address the potential of cortical BDNF for sound processing, we used mice with a conditional deletion of BDNF in which Cre expression was under the control of the Pax2 or TrkC promoter. BDNF deletion profiles between these mice differ in the organ of Corti (BDNF \(^{Pax2}\) -KO) versus the auditory cortex and hippocampus (BDNF \(^{TrkC}\) -KO). We demonstrate that BDNF \(^{Pax2}\) -KO but not BDNF \(^{TrkC}\) -KO mice exhibit reduced sound-evoked suprathreshold ABR waves at the level of the auditory nerve (wave I) and inferior colliculus (IC) (wave IV), indicating that BDNF in lower brain regions but not in the auditory cortex improves sound sensitivity during hearing onset. Extracellular recording of IC neurons of BDNF \(^{Pax2}\) mutant mice revealed that the reduced sensitivity of auditory fibers in these mice went hand in hand with elevated thresholds, reduced dynamic range, prolonged latency, and increased inhibitory strength in IC neurons. Reduced parvalbumin-positive contacts were found in the ascending auditory circuit, including the auditory cortex and hippocampus of BDNF \(^{Pax2}\) -KO, but not of BDNF \(^{TrkC}\) -KO mice. Also, BDNF \(^{Pax2}\) -WT but not BDNF \(^{Pax2}\) -KO mice did lose basal inhibitory strength in IC neurons after acoustic trauma. These findings suggest that BDNF in the lower parts of the auditory system drives auditory fidelity along the entire ascending pathway up to the cortex by increasing inhibitory strength in behaviorally relevant frequency regions. Fidelity and inhibitory strength can be lost following auditory nerve injury leading to diminished sensory outcome and increased central noise.
To replace the Draize skin irritation assay (OECD guideline 404) several test methods based on reconstructed human epidermis (RHE) have been developed and were adopted in the OECD test guideline 439. However, all validated test methods in the guideline are linked to RHE provided by only three companies. Thus,the availability of these test models is dependent on the commercial interest of the producer. To overcome this limitation and thus to increase the accessibility of in vitro skin irritation testing, an open source reconstructed epidermis (OS-REp) was introduced. To demonstrate the capacity of the OS-REp in regulatory risk assessment, a catch-up-validation study was performed. The participating laboratories used in-house generated OS-REp to assess the set of 20 reference substances according to the performance standards amending the OECD test guideline 439. Testing was performed under blinded conditions. The within-laboratory reproducibility of 87% and the inter-laboratory reproducibility of 85% prove a high reliability of irritancy testing using the OS-REp protocol. In addition, the prediction capacity was with an accuracy of 80% comparable to previous published RHE based test protocols. Taken together the results indicate that the OS-REp test method can be used as a standalone alternative skin irritation test replacing the OECD test guideline 404.
Correlating molecular labeling at the ultrastructural level with high confidence remains challenging. Array tomography (AT) allows for a combination of fluorescence and electron microscopy (EM) to visualize subcellular protein localization on serial EM sections. Here, we describe an application for AT that combines near-native tissue preservation via high-pressure freezing and freeze substitution with super-resolution light microscopy and high-resolution scanning electron microscopy (SEM) analysis on the same section. We established protocols that combine SEM with structured illumination microscopy (SIM) and direct stochastic optical reconstruction microscopy (dSTORM). We devised a method for easy, precise, and unbiased correlation of EM images and super-resolution imaging data using endogenous cellular landmarks and freely available image processing software. We demonstrate that these methods allow us to identify and label gap junctions in Caenorhabditis elegans with precision and confidence, and imaging of even smaller structures is feasible. With the emergence of connectomics, these methods will allow us to fill in the gap-acquiring the correlated ultrastructural and molecular identity of electrical synapses.
Stimulation of cells with epidermal growth factor (EGF) induces internalization and partial degradation of the EGF receptor (EGFR) by the endo-lysosomal pathway. For continuous cell functioning, EGFR plasma membrane levels are maintained by transporting newly synthesized EGFRs to the cell surface. The regulation of this process is largely unknown. In this study, we find that EGF stimulation specifically increases the transport efficiency of newly synthesized EGFRs from the endoplasmic reticulum to the plasma membrane. This coincides with an up-regulation of the inner coat protein complex II (COP II) components SEC23B, SEC24B, and SEC24D, which we show to be specifically required for EGFR transport. Up-regulation of these COP II components requires the transcriptional regulator RNF11, which localizes to early endosomes and appears additionally in the cell nucleus upon continuous EGF stimulation. Collectively, our work identifies a new regulatory mechanism that integrates the degradation and transport of EGFR in order to maintain its physiological levels at the plasma membrane.
High-Sensitivity Troponin: A Clinical Blood Biomarker for Staging Cardiomyopathy in Fabry Disease
(2016)
Background
High‐sensitivity troponin (hs‐TNT), a biomarker of myocardial damage, might be useful for assessing fibrosis in Fabry cardiomyopathy. We performed a prospective analysis of hs‐TNT as a biomarker for myocardial changes in Fabry patients and a retrospective longitudinal follow‐up study to assess longitudinal hs‐TNT changes relative to fibrosis and cardiomyopathy progression.
Methods and Results
For the prospective analysis, hs‐TNT from 75 consecutive patients with genetically confirmed Fabry disease was analyzed relative to typical Fabry‐associated echocardiographic findings and total myocardial fibrosis as measured by late gadolinium enhancement (LE) on magnetic resonance imaging. Longitudinal data (3.9±2.0 years), including hs‐TNT, LE, and echocardiographic findings from 58 Fabry patients, were retrospectively collected. Hs‐TNT level positively correlated with LE (linear correlation coefficient, 0.72; odds ratio, 32.81 [95% CI, 3.56–302.59]; P=0.002); patients with elevated baseline hs‐TNT (>14 ng/L) showed significantly increased LE (median: baseline, 1.9 [1.1–3.3] %; follow‐up, 3.2 [2.3–4.9] %; P<0.001) and slightly elevated hs‐TNT (baseline, 44.7 [30.1–65.3] ng/L; follow‐up, 49.1 [27.6–69.5] ng/L; P=0.116) during follow‐up. Left ventricular wall thickness and EF of patients with elevated hs‐TNT were decreased during follow‐up, indicating potential cardiomyopathy progression.
Conclusions
hs‐TNT is an accurate, easily accessible clinical blood biomarker for detecting replacement fibrosis in patients with Fabry disease and a qualified predictor of cardiomyopathy progression. Thus, hs‐TNT could be helpful for staging and follow‐up of Fabry patients.
Background
Aggression, hyperactivity, impulsivity, helplessness and anhedonia are all signs of depressive-like disorders in humans and are often reported to be present in animal models of depression induced by stress or by inflammatory challenges. However, chronic mild stress (CMS) and clinically silent inflammation, during the recovery period after an infection, for example, are often coincident, but comparison of the behavioural and molecular changes that underpin CMS vs a mild inflammatory challenge and impact of the combined challenge is largely unexplored. Here, we examined whether stress-induced behavioural and molecular responses are analogous to lipopolysaccharide (LPS)-induced behavioural and molecular effects and whether their combination is adaptive or maladaptive.
Methods
Changes in measures of hedonic sensitivity, helplessness, aggression, impulsivity and CNS and systemic cytokine and 5-HT-system-related gene expression were investigated in C57BL/6J male mice exposed to chronic stress alone, low-dose LPS alone or a combination of LPS and stress.
Results
When combined with a low dose of LPS, chronic stress resulted in an enhanced depressive-like phenotype but significantly reduced manifestations of aggression and hyperactivity. At the molecular level, LPS was a strong inducer of TNFα, IL-1β and region-specific 5-HT2A mRNA expression in the brain. There was also increased serum corticosterone as well as increased TNFα expression in the liver. Stress did not induce comparable levels of cytokine expression to an LPS challenge, but the combination of stress with LPS reduced the stress-induced changes in 5-HT genes and the LPS-induced elevated IL-1β levels.
Conclusions
It is evident that when administered independently, both stress and LPS challenges induced distinct molecular and behavioural changes. However, at a time when LPS alone does not induce any overt behavioural changes per se, the combination with stress exacerbates depressive and inhibits aggressive behaviours.
Background
Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been suggested to play a role in a subset of patients with neuromyelitis optica and related disorders.
Objective
To assess (i) the frequency of MOG-IgG in a large and predominantly Caucasian cohort of patients with optic neuritis (ON) and/or myelitis; (ii) the frequency of MOG-IgG among AQP4-IgG-positive patients and vice versa; (iii) the origin and frequency of MOG-IgG in the cerebrospinal fluid (CSF); (iv) the presence of MOG-IgG at disease onset; and (v) the influence of disease activity and treatment status on MOG-IgG titers.
Methods
614 serum samples from patients with ON and/or myelitis and from controls, including 92 follow-up samples from 55 subjects, and 18 CSF samples were tested for MOG-IgG using a live cell-based assay (CBA) employing full-length human MOG-transfected HEK293A cells.
Results
MOG-IgG was detected in 95 sera from 50 patients with ON and/or myelitis, including 22/54 (40.7%) patients with a history of both ON and myelitis, 22/103 (21.4%) with a history of ON but no myelitis and 6/45 (13.3%) with a history of longitudinally extensive transverse myelitis but no ON, and in 1 control patient with encephalitis and a connective tissue disorder, all of whom were negative for AQP4-IgG. MOG-IgG was absent in 221 further controls, including 83 patients with AQP4-IgG-seropositive neuromyelitis optica spectrum disorders and 85 with multiple sclerosis (MS). MOG-IgG was found in 12/18 (67%) CSF samples from MOG-IgG-seropositive patients; the MOG-IgG-specific antibody index was negative in all cases, indicating a predominantly peripheral origin of CSF MOG-IgG. Serum and CSF MOG-IgG belonged to the complement-activating IgG1 subclass. MOG-IgG was present already at disease onset. The antibodies remained detectable in 40/45 (89%) follow-up samples obtained over a median period of 16.5 months (range 0–123). Serum titers were higher during attacks than during remission (p < 0.0001), highest during attacks of simultaneous myelitis and ON, lowest during acute isolated ON, and declined following treatment.
Conclusions
To date, this is the largest cohort studied for IgG to human full-length MOG by means of an up-to-date CBA. MOG-IgG is present in a substantial subset of patients with ON and/or myelitis, but not in classical MS. Co-existence of MOG-IgG and AQP4-IgG is highly uncommon. CSF MOG-IgG is of extrathecal origin. Serum MOG-IgG is present already at disease onset and remains detectable in the long-term course. Serum titers depend on disease activity and treatment status.
Background:
T\(_H\)17 cells have so far been considered to be crucial mediators of autoimmune inflammation. Two distinct types of T\(_H\)17 cells have been described recently, which differed in their polarization requirement for IL-1b and in their cytokine repertoire. Whether these distinct T\(_H\)17 phenotypes translate into distinct T\(_H\)17 cell functions with implications for human health or disease has not been addressed yet.
Objective:
We hypothesized the existence of proinflammatory and anti-inflammatory human T\(_H\)17 cell functions based on the differential expression of IL-10, which is regulated by IL-1 beta. Considering the crucial role of IL-1 beta in the pathogenesis of autoinflammatory syndromes, we hypothesized that IL-1 beta mediates the loss of anti-inflammatory T\(_H\)17 cell functionalities in patients with Schnitzler syndrome, an autoinflammatory disease.
Methods:
To assess proinflammatory versus anti-inflammatory T\(_H\)17 cell functions, we performed suppression assays and tested the effects of IL-1 beta dependent and independent T\(_H\)17 subsets on modulating proinflammatory cytokine secretion by monocytes. Patients with Schnitzler syndrome were analyzed for changes in T\(_H\)17 cell functions before and during therapy with IL-1 beta-blocking drugs.
Results:
Both T\(_H\)17 cell subsets differ in their ability to suppress T-cell proliferation and their ability to modulate proinflammatory cytokine production by antigen-presenting cells because of their differential IL-10 expression properties. In patients with Schnitzler syndrome, systemic overproduction of IL-1 beta translates into a profound loss of anti-inflammatory T\(_H\)17 cell functionalities, which can be reversed by anti-IL-1b treatment.
Conclusion:
IL-1 beta signaling determines the differential expression pattern of IL-10, which is necessary and sufficient to induce proinflammatory versus anti-inflammatory T\(_H\)17 cell functions. Our data introduce T\(_H\)17 cell subsets as novel players in autoinflammation and thus novel therapeutic targets in autoinflammatory syndromes including other IL-1 beta mediated diseases. This demonstrates for the first time alterations in the adaptive immune system in patients with autoinflammatory syndromes.
MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy-related diseases. To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda.
Electrophilic oxylipins trigger a heat-shock-like response in the absence of heat through the canonical heat-shock transcription factor A1, thereby helping to cope with stresses associated with protein damage.Abiotic and biotic stresses are often characterized by an induction of reactive electrophile species (RES) such as the jasmonate 12-oxo-phytodienoic acid (OPDA) or the structurally related phytoprostanes. Previously, RES oxylipins have been shown massively to induce heat-shock-response (HSR) genes including HSP101 chaperones. Moreover, jasmonates have been reported to play a role in basal thermotolerance. We show that representative HSR marker genes are strongly induced by RES oxylipins through the four master regulator transcription factors HSFA1a, b, d, and e essential for short-term adaptation to heat stress in Arabidopsis. When compared with Arabidopsis seedlings treated at the optimal acclimation temperature of 37 A degrees C, the exogenous application of RES oxylipins at 20 A degrees C induced a much weaker induction of HSP101 at both the gene and protein expression levels which, however, was not sufficient to confer short-term acquired thermotolerance. Moreover, jasmonate-deficient mutant lines displayed a wild-type-like HSR and were not compromised in acquiring thermotolerance. Hence, the OPDA- and RES oxylipin-induced HSR is not sufficient to protect seedlings from severe heat stress but may help plants to cope better with stresses associated with protein unfolding by inducing a battery of chaperones in the absence of heat.
This study aimed to evaluate the tumorigenic potential of functionalising poly(LLA-co-CL) scaffolds. The copolymer scaffolds were functionalised with nanodiamonds (nDP) or with nDP and physisorbed BMP-2 (nDP-PHY) to enhance osteoinductivity. Culturing early neoplastic dysplastic keratinocytes (DOK\(^{Luc}\)) on nDP modified scaffolds reduced significantly their subsequent sphere formation ability and decreased significantly the cells' proliferation in the supra-basal layers of in vitro 3D oral neoplastic mucosa (3D-OT) when compared to DOK\(^{Luc}\) previously cultured on nDP-PHY scaffolds. Using an in vivo non-invasive environmentally-induced oral carcinogenesis model, nDP scaffolds were observed to reduce bioluminescence intensity of tumours formed by DOK\(^{Luc}\) + carcinoma associated fibroblasts (CAF). nDP modification was also found to promote differentiation of DOK\(^{Luc}\) both in vitro in 3D-OT and in vivo in xenografts formed by DOKLuc alone. The nDP-PHY scaffold had the highest number of invasive tumours formed by DOK\(^{Luc}\) + CAF outside the scaffold area compared to the nDP and control scaffolds. In conclusion, in vitro and in vivo results presented here demonstrate that nDP modified copolymer scaffolds are able to decrease the tumorigenic potential of DOK\(^{Luc}\), while confirming concerns for the therapeutic use of BMP-2 for reconstruction of bone defects in oral cancer patients due to its tumour promoting capabilities.
The linear and nonlinear optical properties of a series of oligomeric squaraine dyes were investigated by one-photon absorption spectroscopy (1PA) and two-photon absorption (2PA) induced fluorescence spectroscopy. The superchromophores are based on two indolenine squaraine dyes with transoid (SQA) and cisoid configuration (SQB). Using these monomers, linear dimers and trimers as well as star-shaped trimers and hexamers with benzene or triphenylamine cores were synthesised and investigated. The red-shifted and intensified 1PA spectra of all superchromophores could well be explained by exciton coupling theory. In the linear chromophore arrangements we also found superradiance of fluorescence but not in the branched systems. Furthermore, the 2PA showed enhanced cross sections for the linear oligomers but only additivity for the branched systems. This emphasizes that the enhancement of the 2PA cross section in the linear arrangements is probably caused by orbital interactions of higher excited configurations.
Objective:
To assess the therapy-related risk of malignancies in mitoxantrone-treated patients with multiple sclerosis.
Methods:
This retrospective observational cohort study included all mitoxantrone-treated patients with multiple sclerosis seen at our department between 1994 and 2007. We collected follow-up information on medically confirmed malignancies, life status, and cause of death, as of 2010. Malignancy rates were compared to the German national cancer registry matched for sex, age, and year of occurrence.
Results:
Follow-up was completed in 676 of 677 identified patients. Median follow-up time was 8.7 years (interquartile range 6.8-11.2), corresponding to 6,220 person-years. Median cumulative mitoxantrone dose was 79.0 mg/m(2) (interquartile range 50.8-102.4). Thirty-seven patients (5.5%) were diagnosed with a malignancy after mitoxantrone initiation, revealing a standardized incidence ratio of 1.50 (95% confidence interval CI] 1.05-2.08). Entities included breast cancer (n = 9), colorectal cancer (n = 7), acute myeloid leukemia (n = 4, 0.6%), and others (each entity n = 1 or 2). The standardized incidence ratio of colorectal cancer was 2.98 (95% CI 1.20-6.14) and of acute myeloid leukemia 10.44 (95% CI 3.39-24.36). It was not increased for other entities including breast cancer. Multivariate Cox regression identified higher age at treatment initiation but neither cumulative mitoxantrone dose (>75 vs 75 mg/m(2)) nor treatment with other immunosuppressive drugs or sex as a risk factor. Fifty-five patients had died, among them 12 of a malignancy and 43 reportedly of other causes.
Conclusions:
While the overall incidence of malignancies was only mildly increased, the risk of leukemia and colorectal cancer was heightened. If confirmed, posttherapy colonoscopy could become advisable.
Objective:
Traumatic brain injury is a major global public health problem for which specific therapeutic interventions are lacking. There is, therefore, a pressing need to identify innovative pathomechanism-based effective therapies for this condition. Thrombus formation in the cerebral microcirculation has been proposed to contribute to secondary brain damage by causing pericontusional ischemia, but previous studies have failed to harness this finding for therapeutic use. The aim of this study was to obtain preclinical evidence supporting the hypothesis that targeting factor XII prevents thrombus formation and has a beneficial effect on outcome after traumatic brain injury.
Methods:
We investigated the impact of genetic deficiency of factor XII and acute inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused infestin-4 (rHA-Infestin-4) on trauma-induced microvascular thrombus formation and the subsequent outcome in 2 mouse models of traumatic brain injury.
Results:
Our study showed that both genetic deficiency of factor XII and an inhibition of activated factor XII in mice minimize trauma-induced microvascular thrombus formation and improve outcome, as reflected by better motor function, reduced brain lesion volume, and diminished neurodegeneration. Administration of human factor XII in factor XII-deficient mice fully restored injury-induced microvascular thrombus formation and brain damage.
Interpretation:
The robust protective effect of rHA-Infestin-4 points to a novel treatment option that can decrease ischemic injury after traumatic brain injury without increasing bleeding tendencies.
Herein, we report the one-pot synthesis of an electron-poor nanographene containing dicarboximide groups at the corners. We efficiently combined palladium-catalyzed Suzuki-Miyaura cross-coupling and dehydrohalogenation to synthesize an extended two-dimensional pi-scaffold of defined size in a single chemical operation starting from N-(2,6-diisopropylphenyl)-4,5-dibromo-1,8-naphthalimide and a tetrasubstituted pyrene boronic acid ester as readily accessible starting materials. The reaction of these precursors under the conditions commonly used for Suzuki-Miyaura cross-coupling afforded a C\(_{64}\) nanographene through the formation of ten C-C bonds in a one-pot process. Single-crystal X-ray analysis unequivocally confirmed the structure of this unique extended aromatic molecule with a planar geometry. The optical and electrochemical properties of this largest ever synthesized planar electron-poor nanographene skeleton were also analyzed.
The Berezinskii-Kosterlitz-Thouless (BKT) theorem predicts that two-dimensional bosonic condensates exhibit quasi-long-range order which is characterized by a slow decay of the spatial coherence. However previous measurements on exciton-polariton condensates revealed that their spatial coherence can decay faster than allowed under the BKT theory, and different theoretical explanations have already been proposed. Through theoretical and experimental study of exciton-polariton condensates, we show that the fast decay of the coherence can be explained through the simultaneous presence of multiple modes in the condensate.
Optical properties of AlSb/InAs/GaInSb/InAs/AlSb quantum wells (QWs) grown on an InAs substrate were investigated from the point of view of room temperature emission in the mid- and long-wavelength infrared ranges. By means of two independent techniques of optical spectroscopy, photoreflectance and temperature-dependent photoluminescence, it was proven that the main process limiting the performance of such InAs substrate-based type II structures is related to the escape of carriers from the hole ground state of the QW. Two nonradiative recombination channels were identified. The main process was attributed to holes tunneling to the valence band of the GaAsSb spacing layer and the second one with trapping of holes by native defects located in the same layer.
Hormetic shifting of redox environment by pro-oxidative resveratrol protects cells against stress
(2016)
Resveratrol has gained tremendous interest owing to multiple reported health-beneficial effects. However, the underlying key mechanism of action of this natural product remained largely controversial. Here, we demonstrate that under physiologically relevant conditions major biological effects of resveratrol can be attributed to its generation of oxidation products such as reactive oxygen species (ROS). At low nontoxic concentrations (in general < 50 mu M), treatment with resveratrol increased viability in a set of representative cell models, whereas application of quenchers of ROS completely truncated these beneficial effects. Notably, resveratrol treatment led to mild, Nrf2-specific gene expression reprogramming. For example, in primary epidermal keratinocytes derived from human skin this coordinated process resulted in a 1.3-fold increase of endogenously generated glutathione (GSH) and subsequently in a quantitative reduction of the cellular redox environment by 2.61 mV mmol GSH per g protein. After induction of oxidative stress by using 0.78% (v/v) ethanol, endogenous generation of ROS was consequently reduced by 24% in resveratrol pre-treated cells. In contrast to the common perception that resveratrol acts mainly as a chemical antioxidant or as a target protein-specific ligand, we propose that the cellular response to resveratrol treatment is essentially based on oxidative triggering. In physiological microenvironments this molecular training can lead to hormetic shifting of cellular defense towards a more reductive state to improve physiological resilience to oxidative stress.
Peptidase inhibitor 16 is a membrane-tethered regulator of chemerin processing in the myocardium
(2016)
A key response of the myocardium to stress is the secretion of factors with paracrine or endocrine function. Intriguing in this respect is peptidase inhibitor 16 (PI16), a member of the CAP family of proteins which we found to be highly upregulated in cardiac disease. Up to this point, the mechanism of action and physiological function of PI16 remained elusive. Here, we show that PI16 is predominantly expressed by cardiac fibroblasts, which expose PI16 to the interstitium via a glycophosphatidylinositol (-GPI) membrane anchor. Based on a reported genetic association of PI16 and plasma levels of the chemokine chemerin, we investigated whether PI16 regulates post-translational processing of its precursor pro-chemerin. PI16-deficient mice were engineered and found to generate higher levels of processed chemerin than wildtype mice. Purified recombinant PI16 efficiently inhibited cathepsin K, a chemerin-activating protease, in vitro. Moreover, we show that conditioned medium from PI16-overexpressing cells impaired the activation of pro-chemerin. Together, our data indicate that PI16 suppresses chemerin activation in the myocardium and suggest that this circuit may be part of the cardiac stress response.
We investigate the dispersion properties of ridge Bragg-reflection waveguides to deduce their phasematching characteristics. These are crucial for exploiting them as sources of parametric down-conversion (PDC). In order to estimate the phasematching bandwidth we first determine the group refractive indices of the interacting modes via Fabry-Perot experiments in two distant wavelength regions. Second, by measuring the spectra of the emitted PDC photons, we gain access to their group index dispersion. Our results offer a simple approach for determining the PDC process parameters in the spectral domain, and provide important feedback for designing such sources, especially in the broadband case.
Normal human brain development is dependent on highly dynamic epigenetic processes for spatial and temporal gene regulation. Recent work identified wide-spread changes in DNA methylation during fetal brain development. We profiled CpG methylation in frontal cortex of 27 fetuses from gestational weeks 12-42, using Illumina 450K methylation arrays. Sites showing genome-wide significant correlation with gestational age were compared to a publicly available data set from gestational weeks 3-26. Altogether, we identified 2016 matching developmentally regulated differentially methylated positions (m-dDMPs): 1767 m-dDMPs were hypermethylated and 1149 hypomethylated during fetal development. M-dDMPs are underrepresented in CpG islands and gene promoters, and enriched in gene bodies. They appear to cluster in certain chromosome regions. M-dDMPs are significantly enriched in autism-associated genes and CpGs. Our results promote the idea that reduced methylation dynamics during fetal brain development may predispose to autism. In addition, m-dDMPs are enriched in genes with human-specific brain expression patterns and/or histone modifications. Collectively, we defined a subset of dDMPs exhibiting constant methylation changes from early to late pregnancy. The same epigenetic mechanisms involving methylation changes in cis-regulatory regions may have been adopted for human brain evolution and ontogeny.
Panobinostat is an oral pan-histone deacetylase inhibitor developed by Novartis. Panobinostat acts via epigenetic modification and inhibition of the aggresome pathway. In August 2015, the European Commission authorized panobinostat for use in combination with bortezomib and dexamethasone for the treatment of relapsed or relapsed and refractory multiple myeloma (MM) in patients who have received aeyen2 prior regimens including bortezomib and an immunomodulatory drug. In January 2016, the National Institute for Health and Care Excellence recommended panobinostat for use in the same combination and patient population. The authorization and recommendation were based on results from the pivotal phase 3 PANORAMA 1 (NCT01023308) clinical trial, which demonstrated an improvement in median progression-free survival of 7.8 months for the three-drug combination compared with placebo plus bortezomib and dexamethasone in this patient population. This review will discuss the current treatment landscape for relapsed/refractory MM, the mechanism of action of panobinostat, clinical data supporting the European authorization, concerns about safety and strategies for mitigating toxicity, and how panobinostat fits into the current MM landscape in Europe.
Anisotropy of dose contributions-an instrument to upgrade real time IMRT and VMAT adaptation?
(2016)
Purpose:
To suggest a definition of dose deposition anisotropy for the purpose of ad hoc adaptation of intensity modulated arc therapy (IMRT) and volumetric arc therapy (VMAT), particularly in the vicinity of important organs at risk (OAR), also for large deformations.
Methods:
Beam's-eye-view (BEV) based fluence warping is a standard adaptation method with disadvantages for strongly varying OAR shapes. 2-Step-adaptation overcomes these difficulties by a deeper analysis of the 3D properties of adaptation processes, but requires separate arcs for every OAR to spare, which makes it impractical for cases with multiple OARs. The authors aim to extend the 2-Step method to arbitrary intensity modulated plan by analyzing the anisotropy of dose contributions. Anisotropy was defined as a second term of Fourier transformation of gantry angle dependent dose contributions. For a cylindrical planning target volume (PTV) surrounding an OAR of varying diameter, the anisotropy and the dose-normalized anisotropy were analyzed for several scenarios of optimized fluence distributions. 2-Step adaptation to decreasing and increasing OAR diameter was performed, and compared to a usual fluence based adaptation method. For two clinical cases, prostate and neck, the VMAT was generated and the behavior of anisotropy was qualitatively explored for deformed organs at risk. #
Results:
Dose contribution anisotropy in the PTV peaks around nearby OARs. The thickness of the "anisotropy wall" around OAR increases for increasing OAR radius, as also does the width of 2-Step dose saturating fluence peak adjacent to the OAR K. Bratengeier et al., "A comparison between 2-Step IMRT and conventional IMRT planning," Radiother. Oncol. 84, 298-306 (2007)]. Different optimized beam fluence profiles resulted in comparable radial dependence of normalized anisotropy. As predicted, even for patient cases, anisotropy was inflated even more than increasing diameters of OAR.
Conclusions:
For cylindrically symmetric cases, the dose distribution anisotropy defined in the present work implicitly contains adaptation-relevant information about 3D relationships between PTV and OAR and degree of OAR sparing. For more complex realistic cases, it shows the predicted behavior qualitatively. The authors claim to have found a first component for advancing a 2-Step adaptation to a universal adaptation algorithm based on the BEV projection of the dose anisotropy. Further planning studies to explore the potential of anisotropy for adaptation algorithms using phantoms and clinical cases of differing complexity will follow.
Nuclear Magnetic Resonance (NMR) provides a highly flexible platform for non invasive analysis and imaging biological samples, since the manipulation of nuclear spin allows the tailoring of experiments to maximize the informativeness of the data. MRI is capable of visualizing a holistic picture of the lipid storage in living plant/seed. This review has sought to explain how the technology can be used to acquire functional and physiological data from plant samples, and how to exploit it to characterize lipid deposition in vivo. At the same time, we have referred to the current limitations of NMR technology as applied to plants, and in particular of the difficulty of transferring methodologies optimized for animal/medical subjects to plant ones. A forward look into likely developments in the field is included, anticipating its key future role in the study of living plant.
Objective
To use statistical methods to establish a threshold for individual response in patient-reported outcomes (PROs) in patients with rheumatoid arthritis.
Methods
We used an analysis of variance model in patients on stable therapy (discovery cohort) to establish critical differences (d(crit)) for the minimum change associated with a significant individual patient response (beyond normal variation) in the PRO measures of pain (0-10), fatigue (0-10), and function (Funktionsfragebogen Hannover questionnaire; 0-100). We then evaluated PRO responses in patients initiating adalimumab in a noninterventional study (treatment cohort).
Results
In the discovery cohort (n=700), PROs showed excellent long-term retest reliability. The minimum change that exceeded random fluctuation was conservatively determined to be 3 points for pain, 4 points for fatigue, and 16 points for function. In the treatment cohort (n=2,788), 1,483 patients (53.2%) achieved a significant individual therapeutic response as assessed by Disease Activity Score in 28 joints (DAS28)-d(crit) (1.8 points) after 12 months of adalimumab treatment; 68.5% of patients with a DAS28-d(crit) response achieved a significant improvement in pain, whereas approximately 40% achieved significant improvements in fatigue or function. Significant improvements in all 3 PROs occurred in 22.7% of patients; 22.8% did not have any significant PRO responses. In contrast, significant improvements in all 3 PROs occurred in only 4.4% of 1,305 patients who did not achieve a DAS28-d(crit) response at month 12, and 59.1% did not achieve any significant PRO responses.
Conclusion
The establishment of critical differences in PROs distinguishes true responses from random variation and provides insights into appropriate patient management.
Aim:
This randomized controlled trial assessed the impact of Lactobacillus reuteri on pregnancy gingivitis in healthy women.
Materials and Methods:
Forty-five healthy women (24 test/21 placebo) with pregnancy gingivitis in the third trimester of pregnancy were enrolled. At baseline Gingival Index (GI) and Plaque Index (PlI) were assessed at the Ramfjord teeth and venous blood taken for TNF-alpha analysis. Subsequently participants were randomly provided with lozenges to be consumed 2 9 daily until birth (approx. 7 weeks) containing >= 10(8) CFU L. reuteri ATCC PTA 5289 and >= 10(8) CFU L. reuteri DSM 17938 (test) or being devoid of L. reuteri (placebo). Within 2 days after birth recording of GI, PlI and blood sampling were repeated.
Results:
At baseline, mean GI and mean PlI did not differ significantly between both groups. In the test group mean TNF-alpha serum level was significantly (p < 0.02) lower than in the placebo group. At reevaluation, mean GI and mean PlI of the test group were both significantly (p < 0.0001) lower than in the placebo group. Mean TNF-alpha serum level did no longer differ significantly between the groups.
Conclusions:
The consumption of L. reuteri lozenges may be a useful adjunct in the control of pregnancy gingivitis.
Quantitative weight of evidence (QWoE) methodology utilizes detailed scoring sheets to assess the quality/reliability of each publication on toxicity of a chemical and gives numerical scores for quality and observed toxicity. This QWoE-methodology was applied to the reproductive toxicity data on diisononylphthalate (DINP), di-n-hexylphthalate (DnHP), and dicyclohexylphthalate (DCHP) to determine if the scientific evidence for adverse effects meets the requirements for classification as reproductive toxicants. The scores for DINP were compared to those when applying the methodology DCHP and DnHP that have harmonized classifications. Based on the quality/reliability scores, application of the QWoE shows that the three databases are of similar quality; but effect scores differ widely. Application of QWoE to DINP studies resulted in an overall score well below the benchmark required to trigger classification. For DCHP, the QWoE also results in low scores. The high scores from the application of the QWoE methodology to the toxicological data for DnHP represent clear evidence for adverse effects and justify a classification of DnHP as category 1B for both development and fertility. The conclusions on classification based on the QWoE are well supported using a narrative assessment of consistency and biological plausibility.
Physical interaction of skeletal precursors with multiple myeloma cells has been shown to suppress their osteogenic potential while favoring their tumor-promoting features. Although several transcriptome analyses of myeloma patient-derived mesenchymal stem cells have displayed differences compared to their healthy counterparts, these analyses insufficiently reflect the signatures mediated by tumor cell contact, vary due to different methodologies, and lack results in lineage-committed precursors. To determine tumor cell contact-mediated changes on skeletal precursors, we performed transcriptome analyses of mesenchymal stem cells and osteogenic precursor cells cultured in contact with the myeloma cell line INA-6. Comparative analyses confirmed dysregulation of genes which code for known disease-relevant factors and additionally revealed upregulation of genes that are associated with plasma cell homing, adhesion, osteoclastogenesis, and angiogenesis. Osteoclast-derived coupling factors, a dysregulated adipogenic potential, and an imbalance in favor of anti-anabolic factors may play a role in the hampered osteoblast differentiation potential of mesenchymal stem cells. Angiopoietin-Like 4 (ANGPTL4) was selected from a list of differentially expressed genes as a myeloma cell contact-dependent target in skeletal precursor cells which warranted further functional analyses. Adhesion assays with full-length ANGPTL4-coated plates revealed a potential role of this protein in INA6 cell attachment. This study expands knowledge of the myeloma cell contact-induced signature in the stromal compartment of myelomatous bones and thus offers potential targets that may allow detection and treatment of myeloma bone disease at an early stage.
Recombinant human erythropoietin (EPO) improves cognitive performance in neuropsychiatric diseases ranging from schizophrenia and multiple sclerosis to major depression and bipolar disease. This consistent EPO effect on cognition is independent of its role in hematopoiesis. The cellular mechanisms of action in brain, however, have remained unclear. Here we studied healthy young mice and observed that 3-week EPO administration was associated with an increased number of pyramidal neurons and oligodendrocytes in the hippocampus of similar to 20%. Under constant cognitive challenge, neuron numbers remained elevated until >6 months of age. Surprisingly, this increase occurred in absence of altered cell proliferation or apoptosis. After feeding a \(^{15}\)N-leucine diet, we used nanoscopic secondary ion mass spectrometry, and found that in EPO-treated mice, an equivalent number of neurons was defined by elevated \(^{15}\)N-leucine incorporation. In EPO-treated NG2-Cre-ERT2 mice, we confirmed enhanced differentiation of preexisting oligodendrocyte precursors in the absence of elevated DNA synthesis. A corresponding analysis of the neuronal lineage awaits the identification of suitable neuronal markers. In cultured neurospheres, EPO reduced Sox9 and stimulated miR124, associated with advanced neuronal differentiation. We are discussing a resulting working model in which EPO drives the differentiation of non-dividing precursors in both (NG2+) oligodendroglial and neuronal lineages. As endogenous EPO expression is induced by brain injury, such a mechanism of adult neurogenesis may be relevant for central nervous system regeneration.
The majority of patients presenting with a first clinical symptom suggestive of multiple sclerosis (MS) do not fulfill the MRI criteria for dissemination in space and time according to the 2010 revision of the McDonald diagnostic criteria for MS and are thus classified as clinically isolated syndrome (CIS). To re-evaluate the utility of cerebrospinal fluid (CSF) analysis in the context of the revised McDonald criteria from 2010, we conducted a retrospective multicenter study aimed at determining the prevalence and predictive value of oligoclonal IgG bands (OCBs) in patients with CIS. Patients were recruited from ten specialized MS centers in Germany and Austria. We collected data from 406 patients; at disease onset, 44/406 (11 %) fulfilled the McDonald 2010 criteria for MS. Intrathecal IgG OCBs were detected in 310/362 (86 %) of CIS patients. Those patients were twice as likely to convert to MS according to McDonald 2010 criteria as OCB-negative individuals (hazard ratio = 2.1, p = 0.0014) and in a shorter time period of 25 months (95 % CI 21-34) compared to 47 months in OCB-negative individuals (95 % CI 36-85). In patients without brain lesions at first attack and presence of intrathecal OCBs (30/44), conversion rate to MS was 60 % (18/30), whereas it was only 21 % (3/14) in those without OCBs. Our data confirm that in patients with CIS the risk of conversion to MS substantially increases if OCBs are present at onset. CSF analysis definitely helps to evaluate the prognosis in patients who do not have MS according to the revised McDonald criteria.
The prevalence of diabetes around the world has reached epidemic proportions and is projected to increase to 642 million people by 2040. Diabetes is already the leading cause of end-stage kidney disease (ESKD) in most developed countries, and the growth in the number of people with ESKD around the world parallels the increase in diabetes. The presence of kidney disease is associated with a markedly elevated risk of cardiovascular disease and death in people with diabetes. Several new therapies and novel investigational agents targeting chronic kidney disease patients with diabetes are now under development. This conference was convened to assess our current state of knowledge regarding optimal glycemic control, current antidiabetic agents and their safety, and new therapies being developed to improve kidney function and cardiovascular outcomes for this vulnerable population.
The bis(N-heterocyclic carbene)(diphenylacetylene)palladium complex Pd(ITMe)\(_2\)(PhCCPh)] (ITMe=1,3,4,5-tetramethylimidazol-2-ylidene) acts as a highly active pre-catalyst in the diboration and silaboration of azobenzenes to synthesize a series of novel functionalized hydrazines. The reactions proceed using commercially available diboranes and silaboranes under mild reaction conditions.