Refine
Year of publication
Document Type
- Preprint (719)
- Article (581)
- Conference Proceeding (5)
- Report (1)
- Working Paper (1)
Has Fulltext
- yes (1307)
Is part of the Bibliography
- no (1307)
Keywords
- Heavy Ion Experiments (21)
- Hadron-Hadron Scattering (11)
- Hadron-Hadron scattering (experiments) (11)
- LHC (9)
- Heavy-ion collision (6)
- SARS-CoV-2 (6)
- ALICE experiment (4)
- COVID-19 (4)
- COVID19-NMR (4)
- Collective Flow (4)
- Jets (4)
- Quark-Gluon Plasma (4)
- Solution NMR spectroscopy (4)
- 5′-UTR (3)
- ALICE (3)
- Heavy Ions (3)
- Heavy Quark Production (3)
- Jets and Jet Substructure (3)
- anal cancer (3)
- chemoradiotherapy (3)
- p53 (3)
- pp collisions (3)
- risk factors (3)
- Beauty production (2)
- Biochemistry (2)
- C-reactive protein (2)
- Charm physics (2)
- Collectivity (2)
- Correlation (2)
- Diffraction (2)
- Elastic scattering (2)
- Elliptic flow (2)
- Experimental nuclear physics (2)
- Experimental particle physics (2)
- HIV (2)
- Head and neck cancer (2)
- Heavy-ion collisions (2)
- Lepton-Nucleon Scattering (experiments) (2)
- Particle Correlations and Fluctuations (2)
- Particle and resonance production (2)
- Particle correlations and fluctuations (2)
- Patterns of care (2)
- Pb–Pb collisions (2)
- Postoperative radiochemotherapy (2)
- Precipitation inhibition (2)
- QCD (2)
- Quarkonium (2)
- RNA (2)
- Radiotherapy (2)
- Relativistic heavy-ion collisions (2)
- Shear viscosity (2)
- Single electrons (2)
- Supersaturation (2)
- Target validation (2)
- Treatment (2)
- albumin (2)
- biomarker (2)
- cervical cancer (2)
- chemotherapy (2)
- clinically important restrictions and symptoms (2)
- drug resistance (2)
- inflammation (2)
- local control (2)
- nutlin-3 (2)
- observational study (2)
- portal hypertension (2)
- rare disease (2)
- supersaturation (2)
- 19F (1)
- 5'-UTR (1)
- 5_SL4 (1)
- 900 GeV (1)
- ACLF (1)
- ADHD (1)
- AIDS (1)
- ALICE detector (1)
- Adolescents (1)
- Advanced stage (1)
- Anal cancer (1)
- Anti-kaon–nucleon physics (1)
- Anti-nuclei (1)
- Archaeogeophysics (1)
- Atomic and molecular interactions with photons (1)
- Attention-Deficit/Hyperactivity Disorder (ADHD) (1)
- Azores Archipelago (1)
- B-slope (1)
- Biochemistry and chemical biology (1)
- Biodiversity (1)
- Bioenabling formulations (1)
- Biomarker (1)
- Blood sample handling (1)
- Boosted Jets (1)
- CAR (1)
- CD8 (1)
- CD8+ tumor infiltrating lymphocytes (1)
- CNS toxicity (1)
- COVID (1)
- COVID‐19 (1)
- CRT (1)
- CXCR4 (1)
- Cancer genomics (1)
- Centrality Class (1)
- Centrality Selection (1)
- Charge fluctuations (1)
- Charged-particle multiplicity (1)
- Charm quark spatial diffusion coefficient (1)
- Chemical composition (1)
- Chemical physics (1)
- Chemoradiotherapy (1)
- Coalescence (1)
- Cold nuclear matter effects (1)
- Collective Flow, (1)
- Comparative genomics (1)
- Comparison with QCD (1)
- Complicated stage (1)
- Conduct disorder (1)
- Conformational trapping (1)
- Contingent Negative Variation, CNV (1)
- Continuous Performance Test, CPT (1)
- Costs (1)
- Covid19-nmr (1)
- Critical point (1)
- Cue-P3 (1)
- DKTK-ROG (1)
- DNA-PAINT (1)
- Data management (1)
- Data sharing (1)
- Demolition emissions (1)
- Depression (1)
- Deuteron production (1)
- Di-hadron correlations (1)
- Direct oral anticoagulation (1)
- Direct reactions (1)
- Disease Activity (1)
- E. colo (1)
- EP300 (1)
- EWSR1 (1)
- Early Rheumatoid Arthritis (1)
- Ecosystems (1)
- Electron-pion identification (1)
- Electronic structure of atoms and molecules (1)
- Electroweak interaction (1)
- Emotion regulation (1)
- Endocannabinoids (1)
- Enthalpy (1)
- Environment (1)
- Epilepsy (1)
- Ethics Committees/Consultation (1)
- European distribution (1)
- Event related potentials (1)
- Evolution (1)
- FBS (1)
- FOXO1 (1)
- Family Physician (1)
- Females (1)
- Femtoscopy (1)
- Fibre/foam sandwich radiator (1)
- First-line regimen (1)
- Forschung (1)
- Full waveform (1)
- Fungi (1)
- G protein-coupled receptor (GPCR) (1)
- Gene expression profiling (1)
- Gene fusion (1)
- Glioblastoma survival (1)
- Groomed jet radius (1)
- HBT (1)
- HNO (1)
- HNSCC (1)
- HPV (1)
- Hadron production (1)
- Hadron-Hadron Scattering Heavy (1)
- Hadron-hadron interactions (1)
- Hals-Nasen-Ohren-Heilkunde (1)
- Hard Scattering (1)
- Health information (1)
- Health-seeking behaviour (1)
- Heavy Ion Experiment (1)
- Heavy flavor production (1)
- Heavy flavour production (1)
- Heavy ions (1)
- Heavy-Ion Collision (1)
- Heavy-flavor decay electron (1)
- Heavy-flavour decay muons (1)
- Heavy-flavour production (1)
- Helpline (1)
- High-throughput screening (1)
- Higher moments (1)
- HoLEP (1)
- Holmium laser enucleation (1)
- Hsp70 (1)
- ICON model (1)
- IHC (1)
- Imrt (1)
- In vitro selection (1)
- Incidental prostate cancer (1)
- Inclusive spectra (1)
- Intensity interferometry (1)
- Interference fragmentation function (1)
- Interpretation (1)
- Invariant Mass Distribution (1)
- Inversion (1)
- Ionisation energy loss (1)
- J/ψ suppression (1)
- Jet Physics (1)
- Jet Substructure (1)
- Jet substructure (1)
- KCGS (1)
- Kaonic nuclei (1)
- Ki-67/MIB1 (1)
- LEOSS (1)
- Lehre (1)
- Loimia (1)
- Low energy QCD (1)
- Low-molecular-weight heparin (1)
- Lymphocytes (1)
- Lymphoid tissues (1)
- MDM2 (1)
- MRI (1)
- Machine learning (1)
- Massive Online Open Course (1)
- Material budget (1)
- Mechanistic (1)
- Medication Appropriateness Index (1)
- Medicinal chemistry (1)
- Membrane protein (1)
- Mesoporous silica (1)
- Mid-rapidity (1)
- Minimum Bias (1)
- Molecular diagnostics (1)
- Molecular modelling (1)
- Monte Carlo (1)
- Multi-Parton Interactions (1)
- Multi-strange baryons (1)
- Multi-wire proportional drift chamber (1)
- Multiple parton interactions (1)
- Myocarditis (1)
- NK cells (1)
- NMR spectroscopy (1)
- NSCLC (1)
- Nanobody (1)
- Nek1 (1)
- Neural network (1)
- Neuroepithelial tumor (1)
- Neurofeedback (1)
- Nuclear modification factor (1)
- Nuclear reactions (1)
- Nuclear structure & decays (1)
- Nucleon induced nuclear reactions (1)
- ORL (1)
- Observation (1)
- Oncology (1)
- Oppositional defiant disorder (1)
- Otorhinolaryngology (1)
- Outcomes research (1)
- PCV (1)
- PD-L1 (1)
- PLAGL1 (1)
- PM10 (1)
- PYTHIA (1)
- Partial wave analysis (1)
- Particle and Resonance Production (1)
- Pb–Pb (1)
- Phage display (1)
- Pharmacology (1)
- Plant symbiosis (1)
- Plasma (1)
- Pneumocystis jirovecii (1)
- Pneumonia (1)
- Point of care (1)
- Polo-like kinase 3 (1)
- Pre-analytics (1)
- Predictive model (1)
- Primary Care Health Centre (1)
- Production Cross Section (1)
- Prognostic (1)
- Properties of Hadrons (1)
- Prostate cancer (1)
- Proteins (1)
- Proton-proton collisions (1)
- Proton–proton (1)
- Proton–proton collisions (1)
- Pulmonary embolism (1)
- QGP (1)
- Quality of life (1)
- Quark Deconfinement (1)
- Quark Gluon Plasma (1)
- Quark Production (1)
- Quark gluon plasma (1)
- RHIC (1)
- RITA (1)
- RNA Biology (1)
- RNA genome (1)
- RNASolution-state NMR (1)
- Randomised controlled trial (1)
- Randomized Controlled Trial (1)
- Rapidity Range (1)
- Rare diseases (1)
- Relativistic heavy ion physics (1)
- Research (1)
- Research Ethics (1)
- Residency (1)
- Residential care (1)
- Resolution Parameter (1)
- Response control (1)
- Rheumatoid Arthritis (1)
- Ribosome display (1)
- SARS-CoV‑2 pandemic (1)
- SARS-CoV‑2-Pandemie (1)
- SCCHN (1)
- SDF-1 (1)
- SEDDS (1)
- SL1 (1)
- SL5a (1)
- SL5b (1)
- SL5b + c (1)
- SL5c (1)
- SMAD (1)
- SMEDDS (1)
- SNEDDS (1)
- SPSS (1)
- Salivary gland cancer (1)
- Salivary gland carcinoma (1)
- Scientific Research (1)
- Screening (1)
- Seizure (1)
- Serum (1)
- Shell model (1)
- Single muons (1)
- Size distribution (1)
- Skills training (1)
- Slow Cortical Potentials, SCP (1)
- Small molecules (1)
- Social Control of Human Experimentation (1)
- Social Control of Science/Technology (1)
- Socio-ecology (1)
- SoftDrop (1)
- Solid dispersion (1)
- Sonography (1)
- Spanish National Health System (1)
- Specialist training (1)
- Spectroscopic factors & electromagnetic moments (1)
- Splitting function (1)
- Ste2p (1)
- Stereotactic ablative body radiotherapy (1)
- Structural biology and molecular biophysics (1)
- Supratentorial (1)
- Surgery (1)
- Survey (1)
- Sustained attention (1)
- Systematic Uncertainty (1)
- Systemic therapy (1)
- TGFβ (1)
- TR (1)
- TTFields (1)
- TUR-P (1)
- Teaching (1)
- Techniques and instrumentation (1)
- Telemedicine (1)
- Therapeutic anticoagulation (1)
- Thermal model (1)
- Time Projection Chamber (1)
- Tomography (1)
- Tools and ressources (1)
- Topology (1)
- Tracking (1)
- Transition radiation detector (1)
- Transurethral resection of the prostate (1)
- Transverse momentum (1)
- Transversity (1)
- Treatment modification (1)
- Trigger (1)
- Ultrafine particles (1)
- University hospitals (1)
- Universitätskliniken (1)
- Urban aerosol (1)
- Vaccination (1)
- Vector Boson Production (1)
- Weiterbildung (1)
- X-rays (1)
- Xenon-based gas mixture (1)
- accident (1)
- acoustic radiation force impulse (1)
- acute decompensation (1)
- acute-on-chronic liver failure (1)
- aggression (1)
- aging (1)
- algal evolution (1)
- amorphous stability (1)
- anal carcinoma (1)
- antiviral therapy (1)
- archeological modeling (1)
- artifacts (1)
- attention-deficit/hyperactivity disorder (ADHD) (1)
- biogeographic legaciese (1)
- brain cancer (1)
- cART (1)
- cBioPortal (1)
- cancer (1)
- cancer-specific survival (1)
- caspase 8 (1)
- caspase-8 (1)
- chemogenomic set (1)
- chemoresistance (1)
- chromalveolate (1)
- chronic hepatitis C (1)
- cirrhosis (1)
- clinical (1)
- clinical practice (1)
- colorectal cancer (1)
- comorbidities (1)
- complex plastid (1)
- computational biology (1)
- computed tomography (1)
- computer-assisted (1)
- congenital duodenal obstruction (1)
- consensus (1)
- corneas (1)
- corticosteroids (1)
- critically ill patients (1)
- crystal structure determination (1)
- dE/dx (1)
- data quality (1)
- decision making (1)
- decision support systems (1)
- deep neural network models (1)
- deswelling (1)
- detector (1)
- dexamethasone (1)
- diffuse low-grade glioma (1)
- diffusion-weighted magnetic resonance imaging (1)
- direct-acting antiviral (DAA) treatment (1)
- disease-free survival (1)
- drug discovery (1)
- druggable genome (1)
- ectosomes (1)
- electroencephalography (EEG) (1)
- eltrombopag (1)
- emiliania huxleyi (1)
- epilepsy (1)
- excitation (1)
- exosomes (1)
- experimental results (1)
- extracellular vesicles (1)
- fMRI (1)
- fMRI/EEG (1)
- fluorine (1)
- forest classification (1)
- forest functional similarity (1)
- fractionation (1)
- fragment screening (1)
- fragment-based screening (1)
- freshwater ecosystems (1)
- gastrointestinal stromal tumours (1)
- gene signature (1)
- glass forming ability (1)
- glioblastoma survival (1)
- glioma (1)
- global change (1)
- guidelines (1)
- habitat destruction (1)
- head and neck squamous cell carcinoma (1)
- health-related quality of life (1)
- health-relatedquality of life (1)
- heavy ion experiments (1)
- hepatic encephalopathy (1)
- highly-charged ions (1)
- hotmelt extrusion (1)
- hotspot loci (1)
- human (1)
- human cytomegalovirus (1)
- human–environment interaction (1)
- hydrate (1)
- hypothesis (1)
- immune microenvironment (1)
- immunotherapy (1)
- in silico tools (1)
- injury (1)
- insect abundance (1)
- interscalene brachial plexus block (1)
- intraspecific morphological variability (1)
- iron chelation (1)
- keratoplasty (1)
- kinase inhibitor (1)
- land use (1)
- lasso regression (1)
- leukocytosis (1)
- leukopenia (1)
- lipid based formulation (1)
- lipid suspension (1)
- liver (1)
- liver cirrhosis (1)
- local anesthetic (1)
- lockdown (1)
- logistic models (1)
- long-term research (1)
- lung cancer (1)
- mRNA and protein expression (1)
- machine learning (1)
- maternal care (1)
- membrane protein (1)
- merkel cell carcinoma (1)
- mesoporous silica (1)
- metabolic syndromes (1)
- microdeletions (1)
- microkeratome (1)
- microparticles (1)
- microvesicles (1)
- minimal information requirements (1)
- molecular tumor board (1)
- multicenter study (1)
- multiplexed immunofluorescence (1)
- multivariate pattern analysis (1)
- myeloperoxidase (1)
- neoadjuvant chemoradiotherapy (1)
- neoplasms (1)
- neurodegeneration (1)
- neurodevelopmental (1)
- neurological outcome (1)
- neuroscience (1)
- neutrophils (1)
- nomogram (1)
- nuclear magnetic resonance (NMR) (1)
- open science (1)
- oral cavity cancer (1)
- organic pigment (1)
- organic thin films (1)
- outcome (1)
- ovarian cancer (1)
- overall survival (1)
- p+p collisions (1)
- p16 (1)
- p53 activator (1)
- paleoclimate modeling (1)
- paleoenvironment modeling (1)
- paleoenvironment reconstruction (1)
- parameterization development (1)
- pediatric intensive care (1)
- pediatric surgery (1)
- peri-implantitis (1)
- phenotypic screening (1)
- phylogenetic community distance (1)
- plastid protein import (1)
- polo-like kinase 1 (1)
- polo-like kinase 3 (1)
- polymers (1)
- polyomavirus (MCPyV) (1)
- portosystemic shunt (1)
- postnatal care (1)
- postoperative radiochemotherapy (1)
- postoperative radiotherapy (1)
- ppK − (1)
- precipitation inhibitor (1)
- precision medicine (1)
- predictive (1)
- predictive biomarker (1)
- prenatal diagnostic (1)
- prognosis (1)
- prognostic (1)
- prognostic biomarker (1)
- prognostic marker (1)
- propensity score matching (1)
- protein folding (1)
- protein kinase (1)
- proteins (1)
- pulmonary embolism (1)
- quark gluon plasma (1)
- radiation (1)
- radioimmunotherpay (1)
- radiosensitization (1)
- real-world structure (1)
- recurrence pattern (1)
- relativistic collisions (1)
- reproducibility (1)
- requirements analysis (1)
- resilience (1)
- retrospective trial (1)
- rigor (1)
- sarcoma (1)
- sarcopenia (1)
- scene representation (1)
- secondary endosymbiosis (1)
- selenolates (1)
- self-assembled monolayers (1)
- short molecular distance (1)
- single-column mode (1)
- small molecules (1)
- solvate (1)
- spectra (1)
- spontaneous portosystemic shunt (1)
- standardization (1)
- storage rings (1)
- structural biology (1)
- super-SMEDDS (1)
- super-SNEDDS (1)
- supersaturating drug delivery systems (1)
- survival (1)
- temozolomide (1)
- therapeutic anticoagulation (1)
- thiolates (1)
- threats (1)
- thrombopenia (1)
- thrombopietin receptor agonist (1)
- toxic hemisphere syndrome (1)
- toxicity (1)
- transient elastography (1)
- translational investigation (1)
- trauma (1)
- triptycene (1)
- tropical forests (1)
- tumor microenvironment (1)
- tumor-infiltrating-lymphocytes (1)
- tyrosine kinase inhibitors (1)
- understudied kinase (1)
- validation (1)
- venetoclax (1)
- ventral striatum (1)
- visual perception (1)
- xenograft (1)
- √sN N = 2.76 TeV (1)
Institute
- Physik (1129)
- Frankfurt Institute for Advanced Studies (FIAS) (992)
- Informatik (921)
- Medizin (88)
- Geowissenschaften (16)
- Biochemie, Chemie und Pharmazie (14)
- Biowissenschaften (11)
- Zentrum für Biomolekulare Magnetische Resonanz (BMRZ) (8)
- Biochemie und Chemie (7)
- Institut für Ökologie, Evolution und Diversität (5)
Introduction: Merkel cell carcinoma (MCC) is linked to the presence of clonally integrated Merkel cell polyomavirus (MCPyV) in up to 80% of the cases. The aim of the study was to determine the prognostic value of baseline MCPyV viral load and lymphocytic infiltration.
Methods: MCPyV DNA prevalence, integration status and viral load were determined by specific quantitative real-time PCR in surgical specimens obtained from 49 patients with MCC treated with (n = 22, 45%) or without postoperative radiotherapy (RT). CD8+ tumor infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) status were assessed using immunohistochemistry. MCPyV characteristics and immune marker expression were correlated with clinicopathological factors and overall survival (OS).
Results: Median age at diagnosis was 74 (range, 42–100); 51% of the patients were female. One-, three, and five-year OS rates were 83.8, 58.6, and 47.1%, respectively. A positive MCPyV status was associated with female gender (p = 0.042). Tumor localization (head/arms vs. trunk) positively correlated with PD-L1 status (p = 0.011) and combined CD8/PD-L1 expression (p = 0.038). Overall CD8+ infiltration was inversely associated with N-stage (p = 0.048). Stromal TILs correlated significantly with both PD-L1 expression (p = 0.010) and N-stage (p = 0.037). A high viral load (>median) was significantly associated with worse OS (p = 0.029) and high intratumoral CD8+ infiltration with improved OS for the entire cohort (p = 0.045).
Conclusion: These data provide important insight on the role of MCPy DNA viral load and TILs in the context of PD-L1 in patients with Merkel cell carcinoma. Future clinical studies should aim to explore the effect of PD-1/PD-L1 immune-checkpoint inhibitors in combination with existing radiotherapy approaches.
SARS-CoV-2 and stroke characteristics: a report from the Multinational COVID-19 Stroke Study Group
(2020)
Background: Stroke is reported as a consequence of SARS-CoV-2 infection. However, there is a lack of regarding comprehensive stroke phenotype and characteristics
Methods: We conducted a multinational observational study on features of consecutive acute ischemic stroke (AIS), intracranial hemorrhage (ICH), and cerebral venous or sinus thrombosis (CVST) among SARS-CoV-2 infected patients. We further investigated the association of demographics, clinical data, geographical regions, and countries’ health expenditure among AIS patients with the risk of large vessel occlusion (LVO), stroke severity as measured by National Institute of Health stroke scale (NIHSS), and stroke subtype as measured by the TOAST criteria. Additionally, we applied unsupervised machine learning algorithms to uncover possible similarities among stroke patients.
Results: Among the 136 tertiary centers of 32 countries who participated in this study, 71 centers from 17 countries had at least one eligible stroke patient. Out of 432 patients included, 323(74.8%) had AIS, 91(21.1%) ICH, and 18(4.2%) CVST. Among 23 patients with subarachnoid hemorrhage, 16(69.5%) had no evidence of aneurysm. A total of 183(42.4%) patients were women, 104(24.1%) patients were younger than 55 years, and 105(24.4%) patients had no identifiable vascular risk factors. Among 380 patients who had known interval onset of the SARS-CoV-2 and stroke, 144(37.8%) presented to the hospital with chief complaints of stroke-related symptoms, with asymptomatic or undiagnosed SARS-CoV-2 infection. Among AIS patients 44.5% had LVO; 10% had small artery occlusion according to the TOAST criteria. We observed a lower median NIHSS (8[3-17], versus 11 [5-17]; p=0.02) and higher rate of mechanical thrombectomy (12.4% versus 2%; p<0.001) in countries with middle to high-health expenditure when compared to countries with lower health expenditure. The unsupervised machine learning identified 4 subgroups, with a relatively large group with no or limited comorbidities.
Conclusions: We observed a relatively high number of young, and asymptomatic SARS-CoV-2 infections among stroke patients. Traditional vascular risk factors were absent among a relatively large cohort of patients. Among hospitalized patients, the stroke severity was lower and rate of mechanical thrombectomy was higher among countries with middle to high-health expenditure.
The concept of using precipitation inhibitors (PIs) to sustain supersaturation is well established for amorphous formulations but less in the case of lipid-based formulations (LBF). This study applied a systematic in silico–in vitro–in vivo approach to assess the merits of incorporating PIs in supersaturated LBFs (sLBF) using the model drug venetoclax. sLBFs containing hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP), PVP-co-vinyl acetate (PVP/VA), Pluronic F108, and Eudragit EPO were assessed in silico calculating a drug–excipient mixing enthalpy, in vitro using a PI solvent shift test, and finally, bioavailability was assessed in vivo in landrace pigs. The estimation of pure interaction enthalpies of the drug and the excipient was deemed useful in determining the most promising PIs for venetoclax. The sLBF alone (i.e., no PI present) displayed a high initial drug concentration in the aqueous phase during in vitro screening. sLBF with Pluronic F108 displayed the highest venetoclax concentration in the aqueous phase and sLBF with Eudragit EPO the lowest. In vivo, the sLBF alone showed the highest bioavailability of 26.3 ± 14.2%. Interestingly, a trend toward a decreasing bioavailability was observed for sLBF containing PIs, with PVP/VA being significantly lower compared to sLBF alone. In conclusion, the ability of a sLBF to generate supersaturated concentrations of venetoclax in vitro was translated into increased absorption in vivo. While in silico and in vitro PI screening suggested benefits in terms of prolonged supersaturation, the addition of a PI did not increase in vivo bioavailability. The findings of this study are of particular relevance to pre-clinical drug development, where the high in vivo exposure of venetoclax was achieved using a sLBF approach, and despite the perceived risk of drug precipitation from a sLBF, including a PI may not be merited in all cases.
Long-term effects on cirrhosis and portal hypertension of direct antiviral agent (DAA)-based eradication of hepatitis C virus (HCV) are still under debate. We analysed dynamics of liver and spleen elastography to assess potential regression of cirrhosis and portal hypertension 3 years post-treatment. Fifty-four patients with HCV-associated cirrhosis and DAA-induced SVR were included. Liver and spleen stiffness were measured at baseline (BL), end of treatment (EOT), 24 weeks after EOT (FU24) and 1, 2 and 3 (FU144) years post-treatment by transient liver elastography (L-TE) and point shear wave elastography (pSWE) using acoustic radiation force impulse (ARFI) of the liver (L-ARFI) and spleen (S-ARFI). Biochemical, virological and clinical data were also obtained. Liver stiffness assessed by L-TE decreased between BL [median (range), 32.5(9.1–75) kPa] and EOT [21.3(6.7–73.5) kPa; p < .0001] and EOT and FU144 [16(4.1–75) kPa; p = .006]. L-ARFI values improved between EOT [2.5(1.2–4.1) m/s] and FU144 [1.7(0.9–4.1) m/s; p = .001], while spleen stiffness remained unchanged. Overall, L-TE improved in 38 of 54 (70.4%) patients at EOT and 29 of 38 (76.3%) declined further until FU144, whereas L-ARFI values decreased in 30/54 (55.6%) patients at EOT and continued to decrease in 28/30 (93.3%) patients at FU144. Low bilirubin and high albumin levels at BL were associated with improved L-ARFI values (p = .048) at EOT or regression of cirrhosis (<12.5 kPa) by L-TE at FU144 (p = .005), respectively. Liver stiffness, but not spleen stiffness, continued to decline in a considerable proportion of patients with advanced liver disease after HCV eradication.
Abstract: Neurophysiological measures of preparation and attention are often atypical in ADHD. Still, replicated findings that these measures predict which patients improve after Neurofeedback (NF), reveal neurophysiological specificity, and reflect ADHD-severity are limited. Methods: We analyzed children’s preparatory (CNV) and attentional (Cue-P3) brain activity and behavioral performance during a cued Continuous Performance Task (CPT) before and after slow cortical potential (SCP)-NF or semi-active control treatment (electromyogram biofeedback). Mixed-effects models were performed with 103 participants at baseline and 77 were assessed for pre-post comparisons focusing on clinical outcome prediction, specific neurophysiological effects of NF, and associations with ADHD-severity. Results: Attentional and preparatory brain activity and performance were non-specifically reduced after treatment. Preparatory activity in the SCP-NF group increased with clinical improvement. Several performance and brain activity measures predicted non-specific treatment outcome. Conclusion: Specific neurophysiological effects after SCP-NF were limited to increased neural preparation associated with improvement on ADHD-subscales, but several performance and neurophysiological measures of attention predicted treatment outcome and reflected symptom severity in ADHD. The results may help to optimize treatment.
System size and centrality dependence of the balance function in A + A collisions at √sNN = 17.2 GeV
(2004)
Electric charge correlations were studied for p+p, C+C, Si+Si and centrality selected Pb+Pb collisions at sqrt s_NN = 17.2$ GeV with the NA49 large acceptance detector at the CERN-SPS. In particular, long range pseudo-rapidity correlations of oppositely charged particles were measured using the Balance Function method. The width of the Balance Function decreases with increasing system size and centrality of the reactions. This decrease could be related to an increasing delay of hadronization in central Pb+Pb collisions.
System size dependence of multiplicity fluctuations of charged particles produced in nuclear collisions at 158 A GeV was studied in the NA49 CERN experiment. Results indicate a non-monotonic dependence of the scaled variance of the multiplicity distribution with a maximum for semi-peripheral Pb+Pb interactions with number of projectile participants of about 35. This effect is not observed in a string-hadronic model of nuclear collision HIJING.
Vaccination represents one of the fundamentals in the fight against SARS-CoV-2. Myocarditis has been reported as a rare but possible adverse consequence of different vaccines, and its clinical presentation can range from mild symptoms to acute heart failure. We report a case of a 29-year-old man who presented with fever and retrosternal pain after receiving SARS-CoV-2 vaccine. Cardiac magnetic resonance imaging and laboratory data revealed typical findings of acute myocarditis.
Despite the implementation of consolidative immune checkpoint inhibition after definitive chemoradiotherapy (CRT), the prognosis for locally advanced non-small-cell lung cancer (NSCLC) remains poor. We assessed the impact of the C-reactive protein (CRP) to albumin ratio (CAR) as an inflammation-based prognostic score in patients with locally advanced NSCLC treated with CRT. We retrospectively identified and analyzed 52 patients with primary unresectable NSCLC (UICC Stage III) treated with definitive/neoadjuvant CRT between 2014 and 2019. CAR was calculated by dividing baseline CRP by baseline albumin levels and correlated with clinicopathologic parameters to evaluate prognostic impact. After dichotomizing patients by the median, univariate and multivariate Cox regression analyses were performed. An increased CAR was associated with advanced T-stage (p = 0.018) and poor performance status (p = 0.004). Patients with pre-therapeutic elevated CAR had significantly lower hemoglobin and higher leukocyte levels (hemoglobin p = 0.001, leukocytes p = 0.018). High baseline CAR was shown to be associated with worse local control (LPFS, p = 0.006), shorter progression-free survival (PFS, p = 0.038) and overall survival (OS, p = 0.022), but not distant metastasis-free survival (DMFS). Multivariate analysis confirmed an impaired outcome in patients with high CAR (LPFS: HR 3.562, 95% CI 1.294–9.802, p = 0.011). CAR is an easily available and independent prognostic marker after CRT in locally advanced NSCLC. CAR may be a useful biomarker for patient stratification to individualize treatment concepts.
The design, construction, and commissioning of the ALICE Time-Projection Chamber (TPC) is described. It is the main device for pattern recognition, tracking, and identification of charged particles in the ALICE experiment at the CERN LHC. The TPC is cylindrical in shape with a volume close to 90 m3 and is operated in a 0.5 T solenoidal magnetic field parallel to its axis.
In this paper we describe in detail the design considerations for this detector for operation in the extreme multiplicity environment of central Pb–Pb collisions at LHC energy. The implementation of the resulting requirements into hardware (field cage, read-out chambers, electronics), infrastructure (gas and cooling system, laser-calibration system), and software led to many technical innovations which are described along with a presentation of all the major components of the detector, as currently realized. We also report on the performance achieved after completion of the first round of stand-alone calibration runs and demonstrate results close to those specified in the TPC Technical Design Report.
SR proteins function in nuclear pre-mRNA processing, mRNA export, and translation. To investigate their cellular dynamics, we developed a quantitative assay, which detects differences in nucleocytoplasmic shuttling among seven canonical SR protein family members. As expected, SRSF2 and SRSF5 shuttle poorly in HeLa cells but surprisingly display considerable shuttling in pluripotent murine P19 cells. Combining individual-resolution cross-linking and immunoprecipitation (iCLIP) and mass spectrometry, we show that elevated arginine methylation of SRSF5 and lower phosphorylation levels of cobound SRSF2 enhance shuttling of SRSF5 in P19 cells by modulating protein-protein and protein-RNA interactions. Moreover, SRSF5 is bound to pluripotency-specific transcripts such as Lin28a and Pou5f1/Oct4 in the cytoplasm. SRSF5 depletion reduces and overexpression increases their cytoplasmic mRNA levels, suggesting that enhanced mRNA export by SRSF5 is required for the expression of pluripotency factors. Remarkably, neural differentiation of P19 cells leads to dramatically reduced SRSF5 shuttling. Our findings indicate that posttranslational modification of SR proteins underlies the regulation of their mRNA export activities and distinguishes pluripotent from differentiated cells.
Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2α‐mediated stress signaling
(2016)
Phosphorylation of translation initiation factor 2α (eIF2α) attenuates global protein synthesis but enhances translation of activating transcription factor 4 (ATF4) and is a crucial evolutionarily conserved adaptive pathway during cellular stresses. The serine–threonine protein phosphatase 1 (PP1) deactivates this pathway whereas prolonging eIF2α phosphorylation enhances cell survival. Here, we show that the reactive oxygen species‐generating NADPH oxidase‐4 (Nox4) is induced downstream of ATF4, binds to a PP1‐targeting subunit GADD34 at the endoplasmic reticulum, and inhibits PP1 activity to increase eIF2α phosphorylation and ATF4 levels. Other PP1 targets distant from the endoplasmic reticulum are unaffected, indicating a spatially confined inhibition of the phosphatase. PP1 inhibition involves metal center oxidation rather than the thiol oxidation that underlies redox inhibition of protein tyrosine phosphatases. We show that this Nox4‐regulated pathway robustly enhances cell survival and has a physiologic role in heart ischemia–reperfusion and acute kidney injury. This work uncovers a novel redox signaling pathway, involving Nox4–GADD34 interaction and a targeted oxidative inactivation of the PP1 metal center, that sustains eIF2α phosphorylation to protect tissues under stress.
Immersion freezing is the most relevant heterogeneous ice nucleation mechanism through which ice crystals are formed in mixed-phase clouds. In recent years, an increasing number of laboratory experiments utilizing a variety of instruments have examined immersion freezing activity of atmospherically relevant ice nucleating particles (INPs). However, an inter-comparison of these laboratory results is a difficult task because investigators have used different ice nucleation (IN) measurement methods to produce these results. A remaining challenge is to explore the sensitivity and accuracy of these techniques and to understand how the IN results are potentially influenced or biased by experimental parameters associated with these techniques.
Within the framework of INUIT (Ice Nucleation research UnIT), we distributed an illite rich sample (illite NX) as a representative surrogate for atmospheric mineral dust particles to investigators to perform immersion freezing experiments using different IN measurement methods and to obtain IN data as a function of particle concentration, temperature (T), cooling rate and nucleation time. Seventeen measurement methods were involved in the data inter-comparison. Experiments with seven instruments started with the test sample pre-suspended in water before cooling, while ten other instruments employed water vapor condensation onto dry-dispersed particles followed by immersion freezing. The resulting comprehensive immersion freezing dataset was evaluated using the ice nucleation active surface-site density (ns) to develop a representative ns(T) spectrum that spans a wide temperature range (−37 °C < T < −11 °C) and covers nine orders of magnitude in ns.
Our inter-comparison results revealed a discrepancy between suspension and dry-dispersed particle measurements for this mineral dust. While the agreement was good below ~ −26 °C, the ice nucleation activity, expressed in ns, was smaller for the wet suspended samples and higher for the dry-dispersed aerosol samples between about −26 and −18 °C. Only instruments making measurement techniques with wet suspended samples were able to measure ice nucleation above −18 °C. A possible explanation for the deviation between −26 and −18 °C is discussed. In general, the seventeen immersion freezing measurement techniques deviate, within the range of about 7 °C in terms of temperature, by three orders of magnitude with respect to ns. In addition, we show evidence that the immersion freezing efficiency (i.e., ns) of illite NX particles is relatively independent on droplet size, particle mass in suspension, particle size and cooling rate during freezing. A strong temperature-dependence and weak time- and size-dependence of immersion freezing efficiency of illite-rich clay mineral particles enabled the ns parameterization solely as a function of temperature. We also characterized the ns (T) spectra, and identified a section with a steep slope between −20 and −27 °C, where a large fraction of active sites of our test dust may trigger immersion freezing. This slope was followed by a region with a gentler slope at temperatures below −27 °C. A multiple exponential distribution fit is expressed as ns(T) = exp(23.82 × exp(−exp(0.16 × (T + 17.49))) + 1.39) based on the specific surface area and ns(T) = exp(25.75 × exp(−exp(0.13 × (T + 17.17))) + 3.34) based on the geometric area (ns and T in m−2 and °C, respectively). These new fits, constrained by using an identical reference samples, will help to compare IN measurement methods that are not included in the present study and, thereby, IN data from future IN instruments.
Immersion freezing is the most relevant heterogeneous ice nucleation mechanism through which ice crystals are formed in mixed-phase clouds. In recent years, an increasing number of laboratory experiments utilizing a variety of instruments have examined immersion freezing activity of atmospherically relevant ice-nucleating particles. However, an intercomparison of these laboratory results is a difficult task because investigators have used different ice nucleation (IN) measurement methods to produce these results. A remaining challenge is to explore the sensitivity and accuracy of these techniques and to understand how the IN results are potentially influenced or biased by experimental parameters associated with these techniques.
Within the framework of INUIT (Ice Nuclei Research Unit), we distributed an illite-rich sample (illite NX) as a representative surrogate for atmospheric mineral dust particles to investigators to perform immersion freezing experiments using different IN measurement methods and to obtain IN data as a function of particle concentration, temperature (T), cooling rate and nucleation time. A total of 17 measurement methods were involved in the data intercomparison. Experiments with seven instruments started with the test sample pre-suspended in water before cooling, while 10 other instruments employed water vapor condensation onto dry-dispersed particles followed by immersion freezing. The resulting comprehensive immersion freezing data set was evaluated using the ice nucleation active surface-site density, ns, to develop a representative ns(T) spectrum that spans a wide temperature range (−37 °C < T < −11 °C) and covers 9 orders of magnitude in ns.
In general, the 17 immersion freezing measurement techniques deviate, within a range of about 8 °C in terms of temperature, by 3 orders of magnitude with respect to ns. In addition, we show evidence that the immersion freezing efficiency expressed in ns of illite NX particles is relatively independent of droplet size, particle mass in suspension, particle size and cooling rate during freezing. A strong temperature dependence and weak time and size dependence of the immersion freezing efficiency of illite-rich clay mineral particles enabled the ns parameterization solely as a function of temperature. We also characterized the ns(T) spectra and identified a section with a steep slope between −20 and −27 °C, where a large fraction of active sites of our test dust may trigger immersion freezing. This slope was followed by a region with a gentler slope at temperatures below −27 °C. While the agreement between different instruments was reasonable below ~ −27 °C, there seemed to be a different trend in the temperature-dependent ice nucleation activity from the suspension and dry-dispersed particle measurements for this mineral dust, in particular at higher temperatures. For instance, the ice nucleation activity expressed in ns was smaller for the average of the wet suspended samples and higher for the average of the dry-dispersed aerosol samples between about −27 and −18 °C. Only instruments making measurements with wet suspended samples were able to measure ice nucleation above −18 °C. A possible explanation for the deviation between −27 and −18 °C is discussed. Multiple exponential distribution fits in both linear and log space for both specific surface area-based ns(T) and geometric surface area-based ns(T) are provided. These new fits, constrained by using identical reference samples, will help to compare IN measurement methods that are not included in the present study and IN data from future IN instruments.
Recently significant advances have been made in the collection, detection, and characterization of ice nucleating particles (INP). Ice nuclei are particles that facilitate the heterogeneous formation of ice within the atmospheric aerosol by lowering the free energy barrier to spontaneous nucleation and growth of ice from atmospheric water and/or vapor. The Frankfurt isostatic diiffusion chamber (FRIDGE) is an INP collection and offline detection system that has become widely deployed and shows additional potential for ambient measurements. Since its initial development FRIDGE has gone through several iterations and improvements. Here we describe improvements that have been made in the collection and analysis techniques. We detail the uncertainties inherent in the measurement method, and suggest a systematic method of error analysis for FRIDGE measurements. Thus what is presented herein should serve as a foundation for the dissemination of all current and future measurements using FRIDGE instrumentation.
Ice nucleating particles over the eastern mediterranean measured by unmanned aircraft systems
(2017)
During an intensive field campaign on aerosol, clouds, and ice nucleation in the Eastern Mediterranean in April 2016, we measured the abundance of ice nucleating particles (INPs) in the lower troposphere from unmanned aircraft systems (UASs). Aerosol samples were collected by miniaturized electrostatic precipitators onboard the UASs at altitudes up to 2.5 km. The number of INPs in these samples, which are active in the deposition and condensation modes at temperatures from −20 to −30 °C, were analyzed immediately after collection on site using the ice nucleus counter FRIDGE (FRankfurt Ice nucleation Deposition freezinG Experiment). During the 1-month campaign, we encountered a series of Saharan dust plumes that traveled at several kilometers' altitude. Here we present INP data from 42 individual flights, together with aerosol number concentrations, observations of lidar backscattering, dust concentrations derived by the dust transport model DREAM (Dust Regional Atmospheric Model), and results from scanning electron microscopy. The effect of the dust plumes is reflected by the coincidence of INPs with the particulate matter (PM), the lidar signal, and the predicted dust mass of the model. This suggests that mineral dust or a constituent related to dust was a major contributor to the ice nucleating properties of the aerosol. Peak concentrations of above 100 INPs std L−1 were measured at −30 °C. The INP concentration in elevated plumes was on average a factor of 10 higher than at ground level. Since desert dust is transported for long distances over wide areas of the globe predominantly at several kilometers' altitude, we conclude that INP measurements at ground level may be of limited significance for the situation at the level of cloud formation.
Ice nucleating particles over the Eastern Mediterranean measured by unmanned aircraft systems
(2016)
During an intensive field campaign on aerosol, clouds and ice nucleation in the Eastern Mediterranean in April 2016, we have measured the abundance of ice nucleating particles (INP) in the lower troposphere from unmanned aircraft systems (UAS). Aerosol samples were collected by miniaturized electrostatic precipitators onboard the UAS at altitudes up to 2.5 km. The number of INP in these samples, which are active in the deposition and condensation modes at temperatures from −20 to −30 ◦C, were analyzed immediately after collection on site using the ice nucleus counter FRIDGE. During the one month campaign we encountered a series of Saharan dust plumes that traveled at several kilometers altitude. Here we present INP data from 42 individual flights, together with aerosol number concentrations, observations of lidar backscattering, dust concentrations derived by the dust transport model DREAM (Dust Regional Atmospheric Model), and results from scanning electron microscopy. The effect of the dust plumes is reflected by the coincidence of INP with the particulate mass (PM), the lidar signal and with the predicted dust mass of the model. This suggests that mineral dust or a constituent related to dust was a major contributor to the ice nucleating properties of the aerosol. Peak concentrations of above 100 INP std.l -1 were measured at −30 ◦C. The INP concentration in elevated plumes was on average a factor of 10 higher than at ground level. Since desert dust is transported for long distances over wide areas of the globe predominantly at several km altitude we conclude that INP measurements at ground level may be of limited significance for the situation at the level of cloud formation.
Recently significant advances have been made in the collection, detection and characterization of ice nucleating particles (INPs). Ice nuclei are particles that facilitate the heterogeneous formation of ice within the atmospheric aerosol by lowering the free energy barrier to spontaneous nucleation and growth of ice from atmospheric water and/or vapor. The Frankfurt isostatic diffusion chamber (FRankfurt Ice nucleation Deposition freezinG Experiment: FRIDGE) is an INP collection and offline detection system that has become widely deployed and shows additional potential for ambient measurements. Since its initial development FRIDGE has gone through several iterations and improvements. Here we describe improvements that have been made in the collection and analysis techniques. We detail the uncertainties inherent in the measurement method and suggest a systematic method of error analysis for FRIDGE measurements. Thus what is presented herein should serve as a foundation for the dissemination of all current and future measurements using FRIDGE instrumentation.
In this report, we present the contributions, outcomes, ideas, discussions and conclusions obtained at the PaleoMaps Workshop 2019, that took place at the Institute of Geography of the University of Cologne on 23 and 24 September 2019. The twofold aim of the workshop was: (1) to provide an overview of approaches and methods that are presently used to incorporate paleoenvironmental information in human–environment interaction modeling applications, and building thereon; (2) to devise new approaches and solutions that might be used to enhance the reconstruction of past human–environmental interconnections. This report first outlines the presented papers, and then provides a joint protocol of the often extensive discussions that came up following the presentations or else during the refreshment intervals. It concludes by adressing the open points to be resolved in future research avenues, e.g., implementation of open science practices, new procedures for reviewing of publications, and future concepts for quality assurance of the often complex paleoenvironmental data. This report may serve as an overview of the state of the art in paleoenvironment mapping and modeling. It includes an extensive compilation of the basic literature, as provided by the workshop attendants, which will itself facilitate the necessary future research.
We describe Loimia davidi sp. nov. (Annelida, Terebellidae) from São Miguel Island (Azores). It resembles Loimia gigantea (Montagu, 1819) (English Channel) in having very large adults, the ventral shield shape and the types of capillary notochaetae (three), while differing in shape and colour of the lateral lappets, branchiae length, the arrangement of segments, ventral shields, uncini and pygidial papillae. Large (> 30 cm long) and small (≈ 5 cm long) specimens of L. davidi sp. nov. show typically interspecific morphological differences while clustering in a single entity after species delimitation analyses of a cytochrome c oxidase I fragment. Therefore, we consider them to belong to a single species and discuss the taxonomic implications of size-dependent morphological differences. Within Loimia, we (1) suggest that large specimens may have been scarcely reported due to their rarity and collecting difficulty, while small specimens may have been reported either as ‘sp.’ or as the ‘cosmopolitan’ Loimia medusa (Savigny, 1822), (2) evaluate the size-related morphological disparity in all described species using a hypervolume analysis, (3) identify possible similar size-dependency in previously described species, (4) summarise the morphological information of all known species of Loimia; and (5) discuss on the four species reported in Europe.
A recent global meta‐analysis reported a decrease in terrestrial but increase in freshwater insect abundance and biomass (van Klink et al., Science 368, p. 417). The authors suggested that water quality has been improving, thereby challenging recent reports documenting drastic global declines in freshwater biodiversity. We raise two major concerns with the meta‐analysis and suggest that these account for the discrepancy with the declines reported elsewhere. First, total abundance and biomass alone are poor indicators of the status of freshwater insect assemblages, and the observed differences may well have been driven by the replacement of sensitive species with tolerant ones. Second, many of the datasets poorly represent global trends and reflect responses to local conditions or nonrandom site selection. We conclude that the results of the meta‐analysis should not be considered indicative of an overall improvement in the condition of freshwater ecosystems.
Since type and duration of an appropriate adjuvant chemotherapy in early-stage ovarian cancer (OC) are still being debated, novel markers for a better stratification of these patients are of utmost importance for the design of an improved chemotherapeutical strategy. In contrast to numerous cancer studies on cellular proliferation based on the immunohistochemistry-driven evaluation of protein expression, we compared mRNA and protein expression of two independent markers of cellular proliferation, Ki-67 and Plk1, in a large cohort of 243 early-stage OC and their relationship with clinicopathological features and survival. Based on marker expression we demonstrate that early-stage OC patients (stages I/II, low-grade, serous) with high expression (Ki-67, Plk1) had a significantly shorter progression-free survival (PFS) and overall survival (OS) compared to patients with low expression (Ki-67, Plk1). Remarkably, based on mRNA expression this significant difference got lost in advanced stages (III/IV): At least for PFS, high levels of Ki-67 and Plk1 correlate with moderately better survival compared to patients with low expressing tumors. Our data suggest that in addition to Ki-67, Plk1 is a novel marker for the stratification of early-stage OC patients to maximize therapeutic efforts. Both, Ki-67 and Plk1, seem to be better suited in early-stages (I/II) as therapeutical targets compared to advanced-stages (III/IV) OC.
We have recently shown that caspase-8 is a new substrate of Polo-like kinase 3 (Plk3) that phosphorylates the protein on residue T273 thereby promoting its pro-apoptotic function. In the present study we aimed to investigate the clinical relevance of Plk3 expression and phosphorylation of caspase-8 at T273 in patients with anal squamous cell carcinoma (SSC) treated with 5-fluorouracil and mitomycin C-based chemoradiotherapy (CRT). Immunohistochemical detection of the markers was performed in pretreatment biopsy specimens of 95 patients and was correlated with clinical/histopathologic characteristics including HPV-16 virus load/p16INK4a expression and cumulative incidence of local and distant failure, cancer specific survival (CSS), and overall survival (OS). We observed significant positive correlations between Plk3 expression, pT273 caspase-8 signal, and levels of HPV-16 virus DNA load/p16INK4a detection. Patients with high scores of Plk3 and pT273 caspase-8 showed increased local control (p = 0.011; p = 0.001), increased CSS (p = 0.011; p = 0.013) and OS (p = 0.024; p = 0.001), while the levels of pT273 caspase-8 were significantly associated (p = 0.033) with distant metastases. In multivariate analyses Plk3 expression remained significant for local failure (p = 0.018), CSS (p = 0.016) and OS (p = 0.023). Moreover, a combined HPV16 DNA load and Plk3 or pT273 caspase-8 variable revealed a significant correlation to decreased local failure (p = 0.001; p = 0.009), increased CSS (p = 0.016; p = 0.023) and OS (p = 0.003; p = 0.003). In conclusion these data indicate that elevated levels of Plk3 and pT273 caspase-8 are correlated with favorable clinical outcome in patients with anal SCC treated with concomitant CRT.
NIMA (never-in-mitosis gene A)-related kinase 1 (Nek1) is shown to impact on different cellular pathways such as DNA repair, checkpoint activation, and apoptosis. Its role as a molecular target for radiation sensitization of malignant cells, however, remains elusive. Stably transduced doxycycline (Dox)-inducible Nek1 shRNA HeLa cervix and siRNA-transfected HCT-15 colorectal carcinoma cells were irradiated in vitro and 3D clonogenic radiation survival, residual DNA damage, cell cycle distribution, and apoptosis were analyzed. Nek1 knockdown (KD) sensitized both cell lines to ionizing radiation following a single dose irradiation and more pronounced in combination with a 6 h fractionation (3 × 2 Gy) regime. For preclinical analyses we focused on cervical cancer. Nek1 shRNA HeLa cells were grafted into NOD/SCID/IL-2Rγc−/− (NSG) mice and Nek1 KD was induced by Dox-infused drinking water resulting in a significant cytostatic effect if combined with a 6 h fractionation (3 × 2 Gy) regime. In addition, we correlated Nek1 expression in biopsies of patients with cervical cancer with histopathological parameters and clinical follow-up. Our results indicate that elevated levels of Nek1 were associated with an increased rate of local or distant failure, as well as with impaired cancer-specific and overall survival in univariate analyses and for most endpoints in multivariable analyses. Finally, findings from The Cancer Genome Atlas (TCGA) validation cohort confirmed a significant association of high Nek1 expression with a reduced disease-free survival. In conclusion, we consider Nek1 to represent a novel biomarker and potential therapeutic target for drug development in the context of optimized fractionation intervals.
The aim of this study is to investigate the incidental prostate cancer (iPCa) detection rates of different embedding methods in a large, contemporary cohort of patients with bladder outlet obstruction (BOO) treated with transurethral surgery. We relied on an institutional tertiary-care database to identify BOO patients who underwent either transurethral loop resection or laser (Holmium:yttrium–aluminium garnet) enucleation of the prostate (HoLEP) between 01/2012 and 12/2019. Embedding methods differed with regard to the extent of the additional prostate tissue submitted following the first ten cassettes of primary embedding (cohort A: one [additional] cassette/10 g residual tissue vs. cohort B: complete embedding of the residual tissue). Detection rates of iPCa among the different embedding methods were compared. Subsequently, subgroup analyses by embedding protocol were repeated in HoLEP-treated patients only. In the overall cohort, the iPCa detection rate was 11% (46/420). In cohort A (n = 299), tissue embedding resulted in a median of 8 cassettes/patient (range 1–38) vs. a median of 15 (range 2–74) in cohort B (n = 121) (p < .001). The iPCa detection rate was 8% (23/299) and 19% (23/121) in cohort A vs. cohort B, respectively (p < .001). Virtual reduction of the number of tissue cassettes to ten cassettes resulted in a iPCa detection rate of 96% in both cohorts, missing one stage T1a/ISUP grade 1 carcinoma. Increasing the number of cassettes by two and eight cassettes, respectively, resulted in a detection rate of 100% in both cohorts without revealing high-grade carcinomas. Subgroup analyses in HoLEP patients confirmed these findings, demonstrated by a 100 vs. 96% iPCa detection rate following examination of the first ten cassettes, missing one case of T1a/ISUP 1. Examination of 8 additional cassettes resulted in a 100% detection rate. The extent of embedding of material obtained from transurethral prostate resection correlates with the iPCa detection rate. However, the submission of 10 cassettes appears to be a reasonable threshold to reduce resource utilization while maintaining secure cancer detection.
Background: With the aging population and a rising incidence of squamous cell carcinoma of the head and neck (SCCHN), there is an emerging need for developing strategies to treat elderly patients.
Patients and Methods: We retrospectively analyzed 158 patients treated with definitive, concurrent chemoradiotherapy (CRT) for SCCHN. Clinicopathological characteristics, acute toxicities, and oncological outcomes were compared between patients younger and older than (or of age equal to) 65, 70, and 75 years.
Results: RT dose, chemotherapy regimen, and total chemotherapy dose were balanced between the groups. After a median follow-up of 29 months, overall survival (OS), progression-free survival (PFS), local control rate, and distant metastasis-free survival stratified by age of ≥65, ≥70, or ≥75 years revealed no differences. The rate of acute toxicities was also not higher for older patients. Worse ECOG performance score (ECOG 2-3) was associated with impaired OS () and PFS ().
Conclusion: Definitive treatment with CRT for SCCHN is feasible and effective; even in advanced age treatment decisions should be made according to general condition and comorbidity, rather than calendar age alone.
Mesoporous silica has emerged as an enabling formulation for poorly soluble active pharmaceutical ingredients (APIs). Unlike other formulations, mesoporous silica typically does not inhibit precipitation of supersaturated API therefore, a suitable precipitation inhibitor (PI) should be added to increase absorption from the gastrointestinal (GI) tract. However, there is limited research about optimal processes for combining PIs with silica formulations. Typically, the PI is added by simply blending the API-loaded silica mechanically with the selected PI. This has the drawback of an additional blending step and may also not be optimal with regard to release of drug and PI. By contrast, loading PI simultaneously with the API onto mesoporous silica, i.e. co-incorporation, is attractive from both a performance and practical perspective. The aim of this study was to demonstrate the utility of a co-incorporation approach for combining PIs with silica formulations, and to develop a mechanistic rationale for improvement of the performance of silica formulations using the co-incorporation approach. The results indicate that co-incorporating HPMCAS with glibenclamide onto silica significantly improved the extent and duration of drug supersaturation in single-medium and transfer dissolution experiments. Extensive spectroscopic characterization of the formulation revealed that the improved performance was related to the formation of drug-polymer interactions already in the solid state; the immobilization of API-loaded silica on HPMCAS plates, which prevents premature release and precipitation of API; and drug-polymer proximity on disintegration of the formulation, allowing for rapid onset of precipitation inhibition. The data suggests that co-incorporating the PI with the API is appealing for silica formulations from both a practical and formulation performance perspective.
Amorphous formulation technologies to improve oral absorption of poorly soluble active pharmaceutical ingredients (APIs) have become increasingly prevalent. Currently, polymer-based amorphous formulations manufactured by spray drying, hot melt extrusion (HME), or co-precipitation are most common. However, these technologies have challenges in terms of the successful stabilization of poor glass former compounds in the amorphous form. An alternative approach is mesoporous silica, which stabilizes APIs in non-crystalline form via molecular adsorption inside nano-scale pores. In line with these considerations, two poor glass formers, haloperidol and carbamazepine, were formulated as polymer-based solid dispersion via HME and with mesoporous silica, and their stability was compared under accelerated conditions. Changes were monitored over three months with respect to solid-state form and dissolution. The results were supported by solid-state nuclear magnetic resonance spectroscopy (SS-NMR) and scanning electron microscopy (SEM). It was demonstrated that mesoporous silica was more successful than HME in the stabilization of the selected poor glass formers. While both drugs remained non-crystalline during the study using mesoporous silica, polymer-based HME formulations showed recrystallization after one week. Thus, mesoporous silica represents an attractive technology to extend the formulation toolbox to poorly soluble poor glass formers.
Background: Duodenal obstruction is a rare cause of congenital bowel obstruction. Prenatal ultrasound could be suggestive of duodenal atresia if polyhydramnios and the double bubble sign are visible. Prenatal diagnosis should prompt respective prenatal care, including surgery. The aim of this study was to investigate the rate and importance of prenatally diagnosed duodenal obstruction, comparing incomplete and complete duodenal obstruction. Methods: A retrospective, single-center study was performed using data from patients operated on for duodenal obstruction between 2004 and 2019. Prenatal ultrasound findings were obtained from maternal logbooks and directly from the investigating obstetricians. Postnatal data were obtained from electronic charts, including imaging, operative notes and follow-up. Results: A total of 33/64 parents of respective patients agreed to provide information on prenatal diagnostics. In total, 11/15 patients with complete duodenal obstruction and 0/18 patients with incomplete duodenal obstruction showed typical prenatal features. Prenatal diagnosis prompted immediate surgical treatment after birth. Conclusion: Prenatal diagnosis of congenital duodenal obstruction is only achievable in cases of complete congenital duodenal obstruction by sonographic detection of the pathognomonic double bubble sign. Patients with incomplete duodenal obstruction showed no sign of duodenal obstruction on prenatal scans and thus were diagnosed and treated later.
The transverse mass mt distributions for deuterons and protons are measured in Pb+Pb reactions near midrapidity and in the range 0<mt–m<1.0 (1.5) GeV/c2 for minimum bias collisions at 158A GeV and for central collisions at 40 and 80 A GeV beam energies. The rapidity density dn/dy, inverse slope parameter T and mean transverse mass <mt> derived from mt distributions as well as the coalescence parameter B2 are studied as a function of the incident energy and the collision centrality. The deuteron mt spectra are significantly harder than those of protons, especially in central collisions. The coalescence factor B2 shows three systematic trends. First, it decreases strongly with increasing centrality reflecting an enlargement of the deuteron coalescence volume in central Pb+Pb collisions. Second, it increases with mt. Finally, B2 shows an increase with decreasing incident beam energy even within the SPS energy range. The results are discussed and compared to the predictions of models that include the collective expansion of the source created in Pb+Pb collisions.
Introduction: Definitive chemoradiation (CRT) followed by high-dose-rate (HDR) brachytherapy (BT) represents state-of-the-art treatment for locally-advanced cervical cancer. Despite use of this treatment paradigm, disease-related outcomes have stagnated in recent years, indicating the need for biomarker development and improved patient stratification. Here, we report the association of Polo-like kinase (PLK) 3 expression and Caspase 8 T273 phosphorylation levels with survival among patients with cervical squamous cell carcinoma (CSCC) treated with CRT plus BT.
Methods: We identified 74 patients with FIGO Stage Ib to IVb cervix squamous cell carcinoma. Baseline immunohistochemical scoring of PLK3 and pT273 Caspase 8 levels was performed on pre-treatment samples. Correlation was then assessed between marker expression and clinical endpoints, including cumulative incidences of local and distant failure, cancer-specific survival (CSS) and overall survival (OS). Data were then validated using The Cancer Genome Atlas (TCGA) dataset.
Results: PLK3 expression levels were associated with pT273 Caspase 8 levels (p = 0.009), as well as N stage (p = 0.046), M stage (p = 0.026), and FIGO stage (p = 0.001). By the same token, pT273 Caspase 8 levels were associated with T stage (p = 0.031). Increased PLK3 levels corresponded to a lower risk of distant relapse (p = 0.009), improved CSS (p = 0.001), and OS (p = 0.003). Phospho T273 Caspase 8 similarly corresponded to decreased risk of distant failure (p = 0.021), and increased CSS (p < 0.001) and OS (p < 0.001) and remained a significant predictor for OS on multivariate analysis. TCGA data confirmed the association of low PLK3 expression with resistance to radiotherapy and BT (p < 0.05), as well as increased propensity for metastasis (p = 0.019). Finally, a combined PLK3 and pT273 Caspase 8 score predicted for decreased distant relapse (p = 0.005), and both improved CSS (p < 0.001) and OS (p < 0.001); this combined score independently predicted distant failure (p = 0.041) and CSS (p = 0.003) on multivariate analyses.
Conclusion: Increased pre-treatment tumor levels of PLK3 and pT273 Caspase 8 correspond to improved disease-related outcomes among cervical cancer patients treated with CRT plus BT, representing a potential biomarker in this context.
Endocannabinoids (ECs) are potent lipid mediators with high physiological relevance. They are involved in a wide variety of diseases like depression or multiple sclerosis and are closely connected to metabolic parameters in humans. Therefore, their suitability as a biomarker in different (patho-)physiological conditions is discussed intensively and predominantly investigated by analyzing systemic concentrations in easily accessible matrices like blood. Carefully designed pre-analytical sample handling is of major importance for high-quality data, but harmonization is not achieved yet. Whole blood is either processed to serum or plasma before the onset of analytical workflows and while knowledge about pre-analytical challenges in plasma handling is thorough they were not systematically investigated for serum.
Therefore, the ECs AEA and 2-AG, and closely related EC-like substances 1-AG, DHEA, and PEA were examined by LC-MS/MS in serum samples of nine healthy volunteers employing different pre-analytical sample handling protocols, including prolonged coagulation, and storage after centrifugation at room temperature (RT) or on ice. Furthermore, all analytes were also assessed in plasma samples obtained from the same individuals at the same time points to investigate the comparability between those two blood-based matrices regarding obtained concentrations and their 2-AG/1-AG ratio.
This study shows that ECs and EC-like substances in serum samples were significantly higher than in plasma and are especially prone to ex vivo changes during initial and prolonged storage for coagulation at RT. Storage on ice after centrifugation is less critical. However, storage at RT further increases 1-AG and 2-AG concentrations, while also lowering the already reduced 2-AG/1-AG ratio due to isomerization. Thus, avoidance of prolonged processing at RT can increase data quality if serum as the matrix of choice is unavoidable. However, serum preparation in itself is expected to initiate changes of physiological concentrations as standard precautionary measures like fast and cooled processing can only be utilized by using plasma, which should be the preferred matrix for analyses of ECs and EC-like substances.
The SARS-CoV-2 pandemic has challenged researchers at a global scale. The scientific community’s massive response has resulted in a flood of experiments, analyses, hypotheses, and publications, especially in the field of drug repurposing. However, many of the proposed therapeutic compounds obtained from SARS-CoV-2 specific assays are not in agreement and thus demonstrate the need for a singular source of COVID-19 related information from which a rational selection of drug repurposing candidates can be made. In this paper, we present the COVID-19 PHARMACOME, a comprehensive drug-target-mechanism graph generated from a compilation of 10 separate disease maps and sources of experimental data focused on SARS-CoV-2 / COVID-19 pathophysiology. By applying our systematic approach, we were able to predict the synergistic effect of specific drug pairs, such as Remdesivir and Thioguanosine or Nelfinavir and Raloxifene, on SARS-CoV-2 infection. Experimental validation of our results demonstrate that our graph can be used to not only explore the involved mechanistic pathways, but also to identify novel combinations of drug repurposing candidates.
Background: Autotaxin (ATX) and its product lysophosphatidic acid (LPA) are considered to be involved in the development of liver fibrosis and elevated levels of serum ATX have been found in patients with hepatitis C virus associated liver fibrosis. However, the clinical role of systemic ATX in the stages of liver cirrhosis was unknown. Here we investigated the relation of ATX serum levels and severity of cirrhosis as well as prognosis of cirrhotic patients.
Methods: Patients with liver cirrhosis were prospectively enrolled and followed until death, liver transplantation or last contact. Blood samples drawn at the day of inclusion in the study were assessed for ATX content by an enzyme-linked immunosorbent assay. ATX levels were correlated with the stage as well as complications of cirrhosis. The prognostic value of ATX was investigated by uni- and multivariate Cox regression analyses. LPA concentration was determined by liquid chromatography-tandem mass spectrometry.
Results: 270 patients were enrolled. Subjects with liver cirrhosis showed elevated serum levels of ATX as compared to healthy subjects (0.814±0.42 mg/l vs. 0.258±0.40 mg/l, P<0.001). Serum ATX levels correlated with the Child-Pugh stage and the MELD (model of end stage liver disease) score and LPA levels (r = 0.493, P = 0.027). Patients with hepatic encephalopathy (P = 0.006), esophageal varices (P = 0.002) and portal hypertensive gastropathy (P = 0.008) had higher ATX levels than patients without these complications. Low ATX levels were a parameter independently associated with longer overall survival (hazard ratio 0.575, 95% confidence interval 0.365–0.905, P = 0.017).
Conclusion: Serum ATX is an indicator for the severity of liver disease and the prognosis of cirrhotic patients.
We report here the nuclear magnetic resonance 19F screening of 14 RNA targets with different secondary and tertiary structure to systematically assess the druggability of RNAs. Our RNA targets include representative bacterial riboswitches that naturally bind with nanomolar affinity and high specificity to cellular metabolites of low molecular weight. Based on counter-screens against five DNAs and five proteins, we can show that RNA can be specifically targeted. To demonstrate the quality of the initial fragment library that has been designed for easy follow-up chemistry, we further show how to increase binding affinity from an initial fragment hit by chemistry that links the identified fragment to the intercalator acridine. Thus, we achieve low-micromolar binding affinity without losing binding specificity between two different terminator structures.
Background: Microdeletions are known to confer risk to epilepsy, particularly at genomic rearrangement ‘hotspot’ loci. However, microdeletion burden not overlapping these regions or within different epilepsy subtypes has not been ascertained.
Objective: To decipher the role of microdeletions outside hotspots loci and risk assessment by epilepsy subtype.
Methods: We assessed the burden, frequency and genomic content of rare, large microdeletions found in a previously published cohort of 1366 patients with genetic generalised epilepsy (GGE) in addition to two sets of additional unpublished genome-wide microdeletions found in 281 patients with rolandic epilepsy (RE) and 807 patients with adult focal epilepsy (AFE), totalling 2454 cases. Microdeletions were assessed in a combined and subtype-specific approaches against 6746 controls.
Results: When hotspots are considered, we detected an enrichment of microdeletions in the combined epilepsy analysis (adjusted p=1.06×10−6,OR 1.89, 95% CI 1.51 to 2.35). Epilepsy subtype-specific analyses showed that hotspot microdeletions in the GGE subgroup contribute most of the overall signal (adjusted p=9.79×10−12, OR 7.45, 95% CI 4.20–13.5). Outside hotspots , microdeletions were enriched in the GGE cohort for neurodevelopmental genes (adjusted p=9.13×10−3,OR 2.85, 95% CI 1.62–4.94). No additional signal was observed for RE and AFE. Still, gene-content analysis identified known (NRXN1, RBFOX1 and PCDH7) and novel (LOC102723362) candidate genes across epilepsy subtypes that were not deleted in controls.
Conclusions: Our results show a heterogeneous effect of recurrent and non-recurrent microdeletions as part of the genetic architecture of GGE and a minor contribution in the aetiology of RE and AFE.
Background: Rare diseases are, by definition, very serious and chronic diseases with a high negative impact on quality of life. Approximately 350 million people worldwide live with rare diseases. The resulting high disease burden triggers health information search, but helpful, high-quality, and up-to-date information is often hard to find. Therefore, the improvement of health information provision has been integrated in many national plans for rare diseases, discussing the telephone as one access option. In this context, this study examines the need for a telephone service offering information for people affected by rare diseases, their relatives, and physicians.
Methods: In total, 107 individuals participated in a qualitative interview study conducted in Germany. Sixty-eight individuals suffering from a rare disease or related to somebody with rare diseases and 39 health care professionals took part. Individual interviews were conducted using a standardized semi-structured questionnaire. Interviews were analysed using the qualitative content analysis, triangulating patients, relatives, and health care professionals. The fulfilment of qualitative data processing standards has been controlled for.
Results: Out of 68 patients and relatives and 39 physicians, 52 and 18, respectively, advocated for the establishment of a rare diseases telephone service. Interviewees expected a helpline to include expert staffing, personal contact, good availability, low technical barriers, medical and psychosocial topics of counselling, guidance in reducing information chaos, and referrals. Health care professionals highlighted the importance of medical topics of counselling—in particular, differential diagnostics—and referrals.
Conclusions: Therefore, the need for a national rare diseases helpline was confirmed in this study. Due to limited financial resources, existing offers should be adapted in a stepwise procedure in accordance with the identified attributes.
Ice particle activation and evolution have important atmospheric implications for cloud formation, initiation of precipitation and radiative interactions. The initial formation of atmospheric ice by heterogeneous ice nucleation requires the presence of a nucleating seed, an ice-nucleating particle (INP), to facilitate its first emergence. Unfortunately, only a few long-term measurements of INPs exist, and as a result, knowledge about geographic and seasonal variations of INP concentrations is sparse. Here we present data from nearly 2 years of INP measurements from four stations in different regions of the world: the Amazon (Brazil), the Caribbean (Martinique), central Europe (Germany) and the Arctic (Svalbard). The sites feature diverse geographical climates and ecosystems that are associated with dissimilar transport patterns, aerosol characteristics and levels of anthropogenic impact (ranging from near pristine to mostly rural). Interestingly, observed INP concentrations, which represent measurements in the deposition and condensation freezing modes, do not differ greatly from site to site but usually fall well within the same order of magnitude. Moreover, short-term variability overwhelms all long-term trends and/or seasonality in the INP concentration at all locations. An analysis of the frequency distributions of INP concentrations suggests that INPs tend to be well mixed and reflective of large-scale air mass movements. No universal physical or chemical parameter could be identified to be a causal link driving INP climatology, highlighting the complex nature of the ice nucleation process. Amazonian INP concentrations were mostly unaffected by the biomass burning season, even though aerosol concentrations increase by a factor of 10 from the wet to dry season. Caribbean INPs were positively correlated to parameters related to transported mineral dust, which is known to increase during the Northern Hemisphere summer. A wind sector analysis revealed the absence of an anthropogenic impact on average INP concentrations at the site in central Europe. Likewise, no Arctic haze influence was observed on INPs at the Arctic site, where low concentrations were generally measured. We consider the collected data to be a unique resource for the community that illustrates some of the challenges and knowledge gaps of the field in general, while specifically highlighting the need for more long-term observations of INPs worldwide.
Size-resolved measurements of atmospheric aerosol and cloud condensation nuclei (CCN) concentrations and hygroscopicity were conducted at the remote Amazon Tall Tower Observatory (ATTO) in the central Amazon Basin over a full seasonal cycle (Mar 2014–Feb 2015). In a companion part 1 paper, we presented an in-depth CCN characterization based on annually as well as seasonally averaged time intervals and discuss different parametrization strategies to represent the Amazonian CCN cycling in modelling studies (M. Pöhlker et al., 2016b). The present part 2 study analyzes the aerosol and CCN variability in original time resolution and, thus, resolves aerosol advection and transformation for the following case studies, which represent the most characteristic states of the Amazonian atmosphere:
1. Near-pristine (NP) conditions, defined as the absence of detectable black carbon (< 0.01 µg m−3), showed their highest occurrence (up to 30 %) in the wet season (i.e., Mar–May). On average, the NP episodes are characterized by a bimodal aerosol size distribution (strong Aitken mode: DAit = 70 nm, NAit = ~ 200 cm−3 vs. weaker accumulation mode: Dacc = 170 nm, Nacc = ~ 60 cm−3), a mostly organic particle composition, and relatively low hygroscopicity levels (κAit = 0.12 vs. κacc = 0.18). The NP CCN efficiency spectrum shows that the CCN population is sensitive to changes in supersaturation (S) over a wide S range.
2. Long-range transport (LRT) conditions frequently mix Saharan dust, African combustion smoke, and sea spray aerosols into the Amazonian wet season atmosphere. The LRT episodes (i.e., Feb–Apr) are characterized by an accumulation mode dominated size distribution (DAit = 80 nm, NAit = 120 cm−3 vs. Dacc = 180 nm, Nacc = 300 cm−3), a clearly increased abundance of dust and salt compounds, and relatively high hygroscopicity levels (κAit = 0.18, κacc = 0.34). The LRT CCN efficiency spectrum shows that the CCN population is highly sensitive to changes in S in the low S regime.
3. Biomass burning (BB) conditions dominate the Amazonian dry season. A selected characteristic BB episode shows a very strong accumulation mode (DAit = 70 nm, NAit = ~ 140 cm−3 vs. Dacc = 170 nm, Nacc = ~ 3400 cm−3), particles with very high organic fractions (> 90 %), and correspondingly low hygroscopicity levels (κAit = 0.14, κacc = 0.17). The BB CCN efficiency spectrum shows that the CCN population is highly sensitive to changes in S in the low S regime.
4. Mixed pollution conditions show the superposition of African (i.e., volcanic) and Amazonian (i.e., biomass burning) aerosol emissions during the dry season. The African aerosols showed a broad monomodal distribution (D = 130 nm, N = ~ 1300 cm−3), with very high sulfate fractions (20 %), and correspondingly high hygroscopicity (κAit = 0.14, κacc = 0.22). This was superimposed by fresh smoke from nearby fires with one strong mode (D = 113 nm, Nacc = ~ 2800 cm−3), an organic-dominated aerosol, and sharply decreased hygroscopicity (κAit = 0.10, κacc = 0.20). These conditions underline the rapidly changing pollution regimes with clear impacts on the aerosol and CCN properties.
Overall, this study provides detailed insights into the CCN cycling in relation to aerosol-cloud interaction in the vulnerable and climate-relevant Amazon region. The detailed analysis of aerosol and CCN key properties and particularly the extracted CCN efficiency spectra with the associated fit parameters provide a basis for an in-depth analysis of aerosol-cloud interaction in the Amazon and beyond.
Size-resolved long-term measurements of atmospheric aerosol and cloud condensation nuclei (CCN) concentrations and hygroscopicity were conducted at the remote Amazon Tall Tower Observatory (ATTO) in the central Amazon Basin over a 1-year period and full seasonal cycle (March 2014–February 2015). The measurements provide a climatology of CCN properties characteristic of a remote central Amazonian rain forest site.
The CCN measurements were continuously cycled through 10 levels of supersaturation (S = 0.11 to 1.10 %) and span the aerosol particle size range from 20 to 245 nm. The mean critical diameters of CCN activation range from 43 nm at S = 1.10 % to 172 nm at S = 0.11 %. The particle hygroscopicity exhibits a pronounced size dependence with lower values for the Aitken mode (κAit = 0.14 ± 0.03), higher values for the accumulation mode (κAcc = 0.22 ± 0.05), and an overall mean value of κmean = 0.17 ± 0.06, consistent with high fractions of organic aerosol.
The hygroscopicity parameter, κ, exhibits remarkably little temporal variability: no pronounced diurnal cycles, only weak seasonal trends, and few short-term variations during long-range transport events. In contrast, the CCN number concentrations exhibit a pronounced seasonal cycle, tracking the pollution-related seasonality in total aerosol concentration. We find that the variability in the CCN concentrations in the central Amazon is mostly driven by aerosol particle number concentration and size distribution, while variations in aerosol hygroscopicity and chemical composition matter only during a few episodes.
For modeling purposes, we compare different approaches of predicting CCN number concentration and present a novel parametrization, which allows accurate CCN predictions based on a small set of input data.
Size-resolved long-term measurements of atmospheric aerosol and cloud condensation nuclei (CCN) concentrations as well as hygroscopicity were conducted at the remote Amazon Tall Tower Observatory (ATTO) in the central Amazon Basin over a one-year period and full seasonal cycle (March 2014 - February 2015). The presented measurements provide a climatology of CCN properties for a characteristic central Amazonian rain forest site.
The CCN measurements were continuously cycled through 10 levels of supersaturation (S = 0.11 to 1.10 %) and span the aerosol particle size range from 20 to 245 nm. The observed mean critical diameters of CCN activation range from 43 nm at S = 1.10 % to 172 nm at S = 0.11 %. The particle hygroscopicity exhibits a pronounced size dependence with lower values for the Aitken mode (κAit = 0.14 ± 0.03), elevated values for the accumulation mode (κAcc = 0.22 ± 0.05), and an overall mean value of κmean = 0.17 ± 0.06, consistent with high fractions of organic aerosol.
The hygroscopicity parameter κ exhibits remarkably little temporal variability: no pronounced diurnal cycles, weak seasonal trends, and few short-term variations during long-range transport events. In contrast, the CCN number concentrations exhibit a pronounced seasonal cycle, tracking the pollution-related seasonality in total aerosol concentration. We find that the variability in the CCN concentrations in the central Amazon is mostly driven by aerosol particle number concentration and size distribution, while variations in aerosol hygroscopicity and chemical composition matter only during a few episodes.
For modelling purposes, we compare different approaches of predicting CCN number concentration and present a novel parameterization, which allows accurate CCN predictions based on a small set of input data.
The energy dependence of multiplicity fluctuations was studied for the most central Pb+Pb collisions at 20A, 30A, 40A, 80A and 158A GeV by the NA49 experiment at the CERN SPS. The multiplicity distribution for negatively and positively charged hadrons is significantly narrower than Poisson one for all energies. No significant structure in energy dependence of the scaled variance of multiplicity fluctuations is observed. The measured scaled variance is lower than the one predicted by the grand-canonical formulation of the hadron-resonance gas model. The results for scaled variance are in approximate agreement with the string-hadronic model UrQMD.
Folding of G-protein coupled receptors (GPCRs) according to the two-stage model (Popot, J. L., and Engelman, D. M. (1990) Biochemistry 29, 4031–4037) is postulated to proceed in 2 steps: partitioning of the polypeptide into the membrane followed by diffusion until native contacts are formed. Herein we investigate conformational preferences of fragments of the yeast Ste2p receptor using NMR. Constructs comprising the first, the first two, and the first three transmembrane (TM) segments, as well as a construct comprising TM1–TM2 covalently linked to TM7 were examined. We observed that the isolated TM1 does not form a stable helix nor does it integrate well into the micelle. TM1 is significantly stabilized upon interaction with TM2, forming a helical hairpin reported previously (Neumoin, A., Cohen, L. S., Arshava, B., Tantry, S., Becker, J. M., Zerbe, O., and Naider, F. (2009) Biophys. J. 96, 3187–3196), and in this case the protein integrates into the hydrophobic interior of the micelle. TM123 displays a strong tendency to oligomerize, but hydrogen exchange data reveal that the center of TM3 is solvent exposed. In all GPCRs so-far structurally characterized TM7 forms many contacts with TM1 and TM2. In our study TM127 integrates well into the hydrophobic environment, but TM7 does not stably pack against the remaining helices. Topology mapping in microsomal membranes also indicates that TM1 does not integrate in a membrane-spanning fashion, but that TM12, TM123, and TM127 adopt predominantly native-like topologies. The data from our study would be consistent with the retention of individual helices of incompletely synthesized GPCRs in the vicinity of the translocon until the complete receptor is released into the membrane interior.
Objectives: To prospectively evaluate lung ultrasound in comparison with radiography and computed tomography (CT) for detecting HIV-related lung diseases.
Methods: Ultrasound examinations in HIV-positive patients were evaluated by three raters; available conventional imaging was evaluated by another rater. Results were compared with each other and the definite diagnosis. Interrater reliability was calculated for each finding.
Results: Eighty HIV-positive patients received lung ultrasound examinations; 74 received conventional imaging. The overall sensitivity was 97.5% for CT, 90.7% for ultrasound and 78.1% for radiography. The most common diagnoses were Pneumocystis jirovecii pneumonia (21 cases) and bacterial pneumonia (17 cases). The most frequent and sensitive ultrasonographic findings were interstitial abnormalities indicated by B-lines, independent of the aetiology. Interrater reliability was high for interstitial abnormalities (ICC=0.82). The interrater reliability for consolidations and effusion increased during the study (r=0.88 and r=0.37, respectively).
Conclusions: Ultrasound is a fast, reliable and sensitive point-of-care tool, particularly in detecting interstitial lung disease, which is common in HIV-associated illness. It does not effectively discriminate between different aetiologies. A longer learning period might be required to reliably identify consolidations and effusions.
Objective: Combination antiretroviral therapy (cART) has markedly increased survival and quality of life in people living with HIV. With the advent of new treatment options, including single-tablet regimens, durability and efficacy of first-line cART regimens are evolving.
Methods: We analyzed data from the prospective multicenter German Clinical Surveillance of HIV Disease (ClinSurv) cohort of the Robert-Koch Institute. Kaplan–Meier and Cox proportional hazards models were run to examine the factors associated with treatment modification. Recovery after treatment initiation was analyzed comparing pre-cART viral load and CD4+ T-cell counts with follow-up data.
Results: We included 8788 patients who initiated cART between 2005 and 2017. The sample population was predominantly male (n = 7040; 80.1%), of whom 4470 (63.5%) were reporting sex with men as the transmission risk factor. Overall, 4210 (47.9%) patients modified their first-line cART after a median time of 63 months (IQR 59–66). Regimens containing integrase strand transfer inhibitors (INSTI) were associated with significantly lower rates of treatment modification (adjusted hazard ratio 0.44; 95% CI 0.39–0.50) compared to protease inhibitor (PI)-based regimens. We found a decreased durability of first-line cART significantly associated with being female, a low CD4+ T-cell count, cART initiation in the later period (2011–2017), being on a multi-tablet regimen (MTR).
Conclusions: Drug class and MTRs are significantly associated with treatment modification. INSTI-based regimens showed to be superior compared to PI-based regimens in terms of durability.
Correction to: Infection (2020) 48:723–733 https://doi.org/10.1007/s15010-020-01469-6. The original version of this article unfortunately contained a mistake. In this article the authors Dirk Schürmann at affiliation Charité, University Medicine, Berlin, Olaf Degen at affiliation University Clinic Hamburg Eppendorf, Hamburg and Heinz-August Horst at affiliation University Hospital Schleswig–Holstein, Kiel, Germany were missing from the author list. The original article has been corrected.
Results are presented on event-by-event fluctuations in transverse momentum of charged particles, produced at forward rapidities in p+p, C+C, Si+Si and Pb+Pb collisions at 158 AGeV. Three different characteristics are discussed: the average transverse momentum of the event, the Phi_pT fluctuation measure and two-particle transverse momentum correlations. In the kinematic region explored, the dynamical fluctuations are found to be small. However, a significant system size dependence of Phi_pT is observed, with the largest value measured in peripheral Pb+Pb interactions. The data are compared with predictions of several models. PACS numbers: 14.20.Jn, 13.75.Cs, 12.39.-x
Electric charge correlations were studied for p+p, C+C, Si+Si, and centrality selected Pb+Pb collisions at sqrt[sNN]=17.2 GeV with the NA49 large acceptance detector at the CERN SPS. In particular, long-range pseudorapidity correlations of oppositely charged particles were measured using the balance function method. The width of the balance function decreases with increasing system size and centrality of the reactions. This decrease could be related to an increasing delay of hadronization in central Pb+Pb collisions.
Evidence for an exotic S=-2, Q=-2 baryon resonance in proton-proton collisions at the CERN SPS
(2004)
Results of resonance searches in the Xi - pi -, Xi - pi +, Xi -bar+ pi -, and Xi -bar+ pi + invariant mass spectra in proton-proton collisions at sqrt[s]=17.2 GeV are presented. Evidence is shown for the existence of a narrow Xi - pi - baryon resonance with mass of 1.862±0.002 GeV/c2 and width below the detector resolution of about 0.018 GeV/c2. The significance is estimated to be above 4.2 sigma . This state is a candidate for the hypothetical exotic Xi --3/2 baryon with S=-2, I=3 / 2, and a quark content of (dsdsu-bar). At the same mass, a peak is observed in the Xi - pi + spectrum which is a candidate for the Xi 03/2 member of this isospin quartet with a quark content of (dsusd-bar). The corresponding antibaryon spectra also show enhancements at the same invariant mass.