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Here we present a comprehensive attempt to correlate aragonitic Na / Ca ratios from Lophelia pertusa, Madrepora oculata and a caryophylliid cold-water coral (CWC) species with different seawater parameters such as temperature, salinity and pH. Living CWC specimens were collected from 16 different locations and analyzed for their Na / Ca content using solution-based inductively coupled plasma-optical emission spectrometry (ICP-OES) measurements. The results reveal no apparent correlation with salinity (30.1–40.57 g/kg) but a significant inverse correlation with temperature (−0.31 mmol/mol/°C). Other marine aragonitic organisms such as Mytilus edulis (inner aragonitic shell portion) and Porites sp. exhibit similar results highlighting the consistency of the calculated CWC regressions. Corresponding Na / Mg ratios show a similar temperature sensitivity to Na / Ca ratios, but the combination of two ratios appear to reduce the impact of vital effects and domain-dependent geochemical variation. The high degree of scatter and elemental heterogeneities between the different skeletal features in both Na / Ca and Na / Mg however limit the use of these ratios as a proxy and/or make a high number of samples necessary. Additionally, we explore two models to explain the observed temperature sensitivity of Na / Ca ratios for an open and semi-enclosed calcifying space based on temperature sensitive Na and Ca pumping enzymes and transport proteins that change the composition of the calcifying fluid and consequently the skeletal Na / Ca ratio.
Prescribing practice of pregabalin/gabapentin in pain therapy : an evaluation of German claim data
(2019)
Objectives: To analyse the prevalence and incidence of pregabalin and gabapentin (P/G) prescriptions, typical therapeutic uses of P/G with special attention to pain-related diagnoses and discontinuation rates.
Design: Secondary data analysis.
Setting: Primary and secondary care in Germany.
Participants: Four million patients in the years 2009–2015 (anonymous health insurance data).
Intervention: None.
Primary and secondary outcome measures: P/G prescribing rates, P/G prescribing rates associated with pain therapy, analysis of pain-related diagnoses leading to new P/G prescriptions and the discontinuation rate of P/G.
Results: In 2015, 1.6% of insured persons received P/G prescriptions. Among the patients with pain first treated with P/G, as few as 25.7% were diagnosed with a typical neuropathic pain disorder. The remaining 74.3% had either not received a diagnosis of neuropathic pain or showed a neuropathic component that was pathophysiologically conceivable but did not support the prescription of P/G. High discontinuation rates were observed (85%). Among the patients who had discontinued the drug, 61.1% did not receive follow-up prescriptions within 2 years.
Conclusion: The results show that P/G is widely prescribed in cases of chronic pain irrespective of neuropathic pain diagnoses. The high discontinuation rate indicates a lack of therapeutic benefits and/or the occurrence of adverse effects.
Electron cryo-microscopy analyzes the structure of proteins and protein complexes in vitrified solution. Proteins tend to adsorb to the air-water interface in unsupported films of aqueous solution, which can result in partial or complete denaturation. We investigated the structure of yeast fatty acid synthase at the air-water interface by electron cryo-tomography and single-particle image processing. Around 90% of complexes adsorbed to the air-water interface are partly denatured. We show that the unfolded regions face the air-water interface. Denaturation by contact with air may happen at any stage of specimen preparation. Denaturation at the air-water interface is completely avoided when the complex is plunge-frozen on a substrate of hydrophilized graphene.
Dass Emotionen den Subjekten eine wichtige Orientierungshilfe in jeglichen Situationen des Alltags bieten, gilt innerhalb der soziologischen Emotionsforschung mittlerweile als Allgemeingut. Was allerdings, wenn uns unsere Gefühle im Stich lassen, da sie nicht klar eingeordnet oder expliziert werden können? Was also, wenn widersprüchliche Emotionen Zweifel nähren, uns an Entscheidungen hadern lassen oder gar Entscheidungen verunmöglichen? Die hieraus resultierenden Unsicherheiten und sich daran anschließenden Handlungsprobleme sind Gegenstand des Buches. Neben Strategien des Umgangs mit emotionalen Ambivalenzerfahrungen stehen auch die individuellen Lösungswege im Mittelpunk der Analyse.
An accelerating Brewer-Dobson circulation (BDC) is a robust signal of climate change in model predictions but has been questioned by trace gas observations. We analyze stratospheric mean age of air and the full age spectrum as measures for the BDC and its trend. Age of air is calculated with the Chemical Lagrangian Model of the Stratosphere (CLaMS) driven by ERA-Interim, JRA-55 and MERRA-2 reanalysis data to assess the robustness of the representation of the BDC in current generation meteorological reanalyses. We find that climatological mean age significantly depends on the reanalysis, with JRA-55 showing the youngest and MERRA-2 the oldest mean age. Consideration of the age spectrum indicates that the older age for MERRA-2 is related to a stronger spectrum tail, likely related to weaker tropical upwelling and stronger recirculation. Seasonality of stratospheric transport is robustly represented in reanalyses, with similar mean age variations and age spectrum peaks. Long-term changes over 1989–2015 turn out to be similar for the reanalyses with mainly decreasing mean age accompanied by a shift of the age spectrum peak towards shorter transit times, resembling the forced response in climate model simulations to increasing greenhouse gas concentrations. For the shorter periods 1989–2001 and 2002–2015 age of air changes are less robust. Only ERA-Interim shows the hemispheric dipole pattern in age changes during 2002–2015 as viewed by recent satellite observations. Consequently, the representation of decadal variability of the BDC in current generation reanalyses appears less robust and a major uncertainty of modelling the BDC.
Cysteinyl leukotriene receptor 1 antagonists (CysLT1RA) are frequently used as add-on medication for the treatment of asthma. Recently, these compounds have shown protective effects in cardiovascular diseases. This prompted us to investigate their influence on soluble epoxide hydrolase (sEH) and peroxisome proliferator activated receptor (PPAR) activities, two targets known to play an important role in CVD and the metabolic syndrome. Montelukast, pranlukast and zafirlukast inhibited human sEH with IC50 values of 1.9, 14.1, and 0.8 μM, respectively. In contrast, only montelukast and zafirlukast activated PPARγ in the reporter gene assay with EC50 values of 1.17 μM (21.9% max. activation) and 2.49 μM (148% max. activation), respectively. PPARα and δ were not affected by any of the compounds. The activation of PPARγ was further investigated in 3T3-L1 adipocytes. Analysis of lipid accumulation, mRNA and protein expression of target genes as well as PPARγ phosphorylation revealed that montelukast was not able to induce adipocyte differentiation. In contrast, zafirlukast triggered moderate lipid accumulation compared to rosiglitazone and upregulated PPARγ target genes. In addition, we found that montelukast and zafirlukast display antagonistic activities concerning recruitment of the PPARγ cofactor CBP upon ligand binding suggesting that both compounds act as PPARγ modulators. In addition, zafirlukast impaired the TNFα triggered phosphorylation of PPARγ2 on serine 273. Thus, zafirlukast is a novel dual sEH/PPARγ modulator representing an excellent starting point for the further development of this compound class.
Selection and prioritization of patients with HCC for LT are based on pretransplant imaging diagnostic, taking the risk of incorrect diagnosis. According to the German waitlist guidelines, imaging has to be reported to the allocation organization (Eurotransplant) and pathology reports have to be submitted thereafter. In order to assess current procedures we performed a retrospective multicenter analysis in all German transplant centers with focus on accuracy of imaging diagnostic and tumor classification. 1168 primary LT for HCC were conducted between 2007 and 2013 in Germany. Patients inside the Milan, UCSF, and up-to-seven criteria were misclassified with definitive histologic results in 18%, 15%, and 11%, respectively. Patients pretransplant outside the Milan, UCSF, and up-to-seven criteria were otherwise misclassified in 34%, 43%, and 41%. Recurrence-free survival correlated with classification by posttransplant histological report, but not pretransplant imaging diagnostic. Univariate analysis revealed tumor size, vascular invasion, and grading as significant parameters for outcome, while tumor grading was the only parameter persisting by multivariate testing. Conclusion. There was a relevant percentage (15-40%) of patients misclassified by imaging diagnosis at a time prior to LI-RADS and guidelines to improve imaging of HCC. Outcome analysis showed a good correlation to histological, in contrast poor correlation to imaging diagnosis, suggesting an adjustment of the LT selection and prioritization criteria.
Background: Hepatitis C virus (HCV) is currently classified into 8 genotypes and 86 subtypes. The objective of this study was to characterize novel HCV subtypes and to investigate the impact of subtypes on treatment outcome.
Methods: Full-genome sequencing was performed on HCV plasma samples with <85% sequence homology of NS3, NS5A, and/or NS5B to HCV genotype (GT) 1–8 reference strains.
Results: A total of 14 653 patients with GT1–6 HCV infection were enrolled in clinical studies of sofosbuvir-based regimens. For the majority of the patients, a specific subtype could be assigned based on a close genetic relationship to previously described subtypes. However, for 19 patients, novel subtypes were identified with <85% homology compared with previously described subtypes. These novel subtypes had the following genotypes: 9 in GT2, 5 in GT4, 2 in GT6, and 1 each in GT1, GT3, and GT5. Despite the presence of polymorphisms at resistance-associated substitution positions, 18 of the 19 patients treated with sofosbuvir-containing therapy achieved SVR12.
Conclusions: Nineteen novel HCV subtypes were identified, suggesting an even greater genetic diversity of HCV subtypes than previously recognized.
Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders with significant and often lifelong effects on social, emotional, and cognitive functioning. Influential neurocognitive models of ADHD link behavioral symptoms to altered connections between and within functional brain networks. Here, we investigate whether network-based theories of ADHD can be generalized to understanding variations in ADHD-related behaviors within the normal (i.e., clinically unaffected) adult population. In a large and representative sample, self-rated presence of ADHD symptoms varied widely; only eight out of 291 participants scored in the clinical range. Subject-specific brain-network graphs were modeled from functional MRI resting-state data and revealed significant associations between (non-clinical) ADHD symptoms and region-specific profiles of between-module and within-module connectivity. Effects were located in brain regions associated with multiple neuronal systems including the default-mode network, the salience network, and the central executive system. Our results are consistent with network perspectives of ADHD and provide further evidence for the relevance of an appropriate information transfer between task-negative (default-mode) and task-positive brain regions. More generally, our findings support a dimensional conceptualization of ADHD and contribute to a growing understanding of cognition as an emerging property of functional brain networks.
B-cell development and function depend on stage-specific signaling through the B-cell antigen receptor (BCR). Signaling and intracellular trafficking of the BCR are connected, but the molecular mechanisms of this link are incompletely understood. Here, we investigated the role of the endosomal adaptor protein and member of the LAMTOR/Ragulator complex LAMTOR2 (p14) in B-cell development. Efficient conditional deletion of LAMTOR2 at the pre-B1 stage using mb1-Cre mice resulted in complete developmental arrest. Deletion of LAMTOR2 using Cd19-Cre mice permitted analysis of residual B cells at later developmental stages, revealing that LAMTOR2 was critical for the generation and activation of mature B lymphocytes. Loss of LAMTOR2 resulted in aberrant BCR signaling due to delayed receptor internalization and endosomal trafficking. In conclusion, we identify LAMTOR2 as critical regulator of BCR trafficking and signaling that is essential for early B-cell development in mice.
Short Summary: Extracellular vesicles (EVs), released during tissue/cell injury, contain a "barcode" indicating specific microRNAs (miRs) that can uncover their origin. We examined whether systemic EVs possessing hepatic miR-signatures would indicate ongoing liver injury and clinical complications in trauma patients (TP). We grouped the patients of alcoholic drinkers into "alcohol-drinkers with liver injury (LI)" (EtOH with LI) or "alcohol-drinkers without LI" (EtOH w/o LI) and we compared these groups to "non-drinkers" (no EtOH). When we examined patient blood from the EtOH with LI group we found the total number of EVs to be increased, along with an increase in miR-122 and let7f—two EV-associated miRNAs—and several inflammation-associating cytokines, such as interleukin (IL)-6 and IL-33. In contrast, all of the aforementioned readouts were found to be decreased in the EtOH w/o LI group. These novel data demonstrate that hepatocyte damage in alcohol-intoxicated trauma patients presenting with liver injury can be reflected by an increase in circulating serum EVs, their specific miR-"barcode" and the concomitant increase of systemic inflammatory markers IL-6 and IL-33. Anti-inflammatory effect of alcohol-drinking in EtOH w/o LI can be presented by a reduced number of hepato-derived EVs, no upregulation of IL-6 and IL-33, and a miR "barcode" different from patients presenting with liver injury.
Background: Alcohol abuse is associated with (neuro)protective effects related to (head) injuries, and with negative effects regarding infection rates and survival in severely injured trauma patients (TP). Extracellular vesicles (EVs), which are released during tissue and/or cell injury, can contain a "barcode" including specific microRNAs (miRs) that uncover their origin. We examined whether EVs with a hepatic miR signature can be systemically measured, and whether they can indicate ongoing liver injury in alcohol-intoxicated TP and foretell clinical complications.
Patients/Methods: We enrolled 35 TP and measured blood EVs, IL-6, TNF-alpha, IL-1beta, IL-10 and IL-33, alcohol (ethanol, EtOH) concentration (BAC), GLDH, GGT, AST, ALT, leukocytes, platelets, and bilirubin. Within circulating EVs we measured the expression levels of miR-122, let7f, miR21, miR29a, miR-155, and miR-146a. Patients of alcohol-drinkers were grouped into "alcohol drinkers with liver injury (LI)" (EtOH with LI) or "alcohol drinkers without LI" (EtOH w/o LI) and compared to "non-drinkers" (no EtOH). We assessed systemic injury characteristics and the outcome of hospitalization with regard to sepsis, septic shock, pneumonia, or mortality.
Results: EtOH with LI patients had significantly increased rates of pneumonia vs. the EtOH w/o LI group. EVs, IL-6, and IL-33 levels were significantly increased in EtOH with LI vs. EtOH w/o LI group (p < 0.05). EV number correlated positively with ALT and IL-6 (p < 0.0001). Two miRs, miR-122 and let7f, were increased only in the blood EVs from the EtOH with LI group (p < 0.05). Five miRs, miR-122, let7f, miR-21, miR-29a, and miR-146a, were reduced in the blood EVs from the EtOH w/o LI group, vs. no EtOH (p < 0.05). Notably miR-122 correlated significantly with increased bilirubin levels in the EtOH with LI group (p < 0.05).
Conclusions: Liver injury in alcohol-intoxicated TP is reflected by increased EV numbers, their specific miR barcode, and the correlated increase of systemic inflammatory markers IL-6 and IL-33. Interestingly, severely injured TP without liver injury were found to have a reduced number of liver-derived EVs, no observed inflammatory infiltration and reduced specific miR "barcode."
Objectives: Large-scale clinical studies investigating associations between intestinal microbiota signatures and human diseases usually rely on stool samples. However, the timing of repeated stool sample collection cannot be predefined in longitudinal settings. Rectal swabs, being straightforward to obtain, have the potential to overcome this drawback. Therefore, we assessed the usability of rectal swabs for microbiome sampling in a cohort of hematological and oncological patients.
Study design: We used a pipeline for intestinal microbiota analysis from deep rectal swabs which was established and validated with test samples and negative controls. Consecutively, a cohort of patients from hematology and oncology wards was established and weekly deep rectal swabs taken during their admissions and re-admissions.
Results: Validation of our newly developed pipeline for intestinal microbiota analysis from rectal swabs revealed consistent and reproducible results. Over a period of nine months, 418 rectal swabs were collected longitudinally from 41 patients. Adherence to the intended sampling protocol was 97%. After DNA extraction, sequencing, read pre-processing and filtering of chimeric sequences, 405 of 418 samples (96.9%) were eligible for further analyses. Follow-up samples and those taken under current antibiotic exposure showed a significant decrease in alpha diversity as compared to baseline samples. Microbial domination occurred most frequently by Enterococcaceae (99 samples, 24.4%) on family level and Enterococcus (90 samples, 22.2%) on genus level. Furthermore, we noticed a high abundance of potential skin commensals in 99 samples (24.4%).
Summary: Deep rectal swabs were shown to be reliable for microbiome sampling and analysis, with practical advantages related to high sampling adherence, easy timing, transport and storage. The relatively high abundance of putative skin commensals in this patient cohort may be of potential interest and should be further investigated. Generally, previous findings on alpha diversity dynamics obtained from stool samples were confirmed.
Objectives: The objective of this review is to provide an overview of PK/PD models, focusing on drug-specific PK/PD models and highlighting their value-added in drug development and regulatory decision-making.
Key findings: Many PK/PD models, with varying degrees of complexity and physiological understanding, have been developed to evaluate the safety and efficacy of drug products. In special populations (e.g. pediatrics), in cases where there is genetic polymorphism and in other instances where therapeutic outcomes are not well described solely by PK metrics, the implementation of PK/PD models is crucial to assure the desired clinical outcome. Since dissociation between the pharmacokinetic and pharmacodynamic profiles is often observed, it is proposed that physiologically-based pharmacokinetic (PBPK) and PK/PD models be given more weight by regulatory authorities when assessing the therapeutic equivalence of drug products.
Summary: Modeling and simulation approaches already play an important role in drug development. While slowly moving away from “one-size fits all” PK methodologies to assess therapeutic outcomes, further work is required to increase confidence in PK/PD models in translatability and prediction of various clinical scenarios to encourage more widespread implementation in regulatory decision-making.
Tolerizing CTL by sustained hepatic PD-L1 expression provides a new therapy spproach in mouse sepsis
(2019)
Cytotoxic T lymphocyte (CTL) activation contributes to liver damage during sepsis, but the mechanisms involved are largely unknown. Understanding the underlying principle will permit interference with CTL activation and thus, provide a new therapeutic option.
Methods: To elucidate the mechanism leading to CTL activation we used the Hepa1-6 cell line in vitro and the mouse model of in vivo polymicrobial sepsis, following cecal-ligation and -puncture (CLP) in wildtype, myeloid specific NOX-2, global NOX2 and NOX4 knockout mice, and their survival as a final readout. In this in vivo setting, we also determined hepatic mRNA and protein expression as well as clinical parameters of liver damage - aspartate- and alanine amino-transaminases. Hepatocyte specific overexpression of PD-L1 was achieved in vivo by adenoviral infection and transposon-based gene transfer using hydrodynamic injection.
Results: We observed downregulation of PD-L1 on hepatocytes in the murine sepsis model. Adenoviral and transposon-based gene transfer to restore PD-L1 expression, significantly improved survival and reduced the release of liver damage, as PD-L1 is a co-receptor that negatively regulates T cell function. Similar protection was observed during pharmacological intervention using recombinant PD-L1-Fc. N-acetylcysteine blocked the downregulation of PD-L1 suggesting the involvement of reactive oxygen species. This was confirmed in vivo, as we observed significant upregulation of PD-L1 expression in NOX4 knockout mice, following sham operation, whereas its expression in global as well as myeloid lineage NOX2 knockout mice was comparable to that in the wild type animals. PD-L1 expression remained high following CLP only in total NOX2 knockouts, resulting in significantly reduced release of liver damage markers.
Conclusion: These results suggest that, contrary to common assumption, maintaining PD-L1 expression on hepatocytes improves liver damage and survival of mice during sepsis. We conclude that administering recombinant PD-L1 or inhibiting NOX2 activity might offer a new therapeutic option in sepsis.
Site-specific cleavage of RNAs derived from the PIM1 3′-UTR by a metal-free artificial ribonuclease
(2019)
Oligonucleotide conjugates of tris(2-aminobenzimidazole) have been reported previously to cleave complementary RNA strands with high levels of sequence and site specificity. The RNA substrates used in these studies were oligonucleotides not longer than 29-mers. Here we show that ~150–400-mer model transcripts derived from the 3′-untranslated region of the PIM1 mRNA reacted with rates and specificities comparable to those of short oligonucleotide substrates. The replacement of DNA by DNA/LNA mixmers further increased the cleavage rate. Tris(2-aminobenzimidazoles) were designed to interact with phosphates and phosphate esters. A cell, however, contains large amounts of phosphorylated species that may cause competitive inhibition of RNA cleavage. It is thus important to note that no loss in reaction rates was observed in phosphate buffer. This opens the way to in-cell applications for this type of artificial nuclease. Furthermore, we disclose a new synthetic method giving access to tris(2-aminobenzimidazoles) in multigram amounts.
The Paleocene-Eocene Thermal Maximum (PETM) offers insight into massive short-term carbon cycle perturbations that caused significant warming during a high-pCO2 world, affecting both marine and terrestrial ecosystems. PETM records from the marine-terrestrial interface (e.g. estuarine swamps and mire deposits) are, therefore, of great interest as their present-day counterparts are highly vulnerable to future climate and sea level change. Here, we assess paleoenvironmental changes of mid-latitudinal Late Paleocene-Early Eocene peat mire records along the paleo-North Sea coast. We provide carbon isotope data of bulk organic matter (δ13CTOC), organic carbon content (%TOC), and palynological data from an extensive peat mire deposited at a mid-latitudinal (ca. 41 °N) coastal site (Schöningen, Germany). The δ13CTOC data show a carbon isotope excursion (CIE) of −1.7 ‰ coeval with a conspicuous Apectodinium acme, calling for the presence of the PETM in this coastal section. Due to the exceptionally large stratigraphic thickness of the PETM at Schöningen (10 m of section) we established a detailed palynological record that indicates only minor changes in paleovegetation leading to and during the PETM. Instead, paleovegetation changes mostly follow natural successions in response to changes along the marine-terrestrial interface. Compared to other available peat mire records (Cobham, UK; Vasterival, France) it appears that wetland deposits around the Paleogene North Sea have a typical CIE magnitude of ca. −1.3 ‰ in δ13CTOC. Moreover, the Schöningen record shares major characteristics with the Cobham Lignite, including evidence for increased fire activity prior to the PETM, minor PETM-related plant species changes, a reduced CIE in δ13CTOC, and drowning of the mire (marine ingressions) during much of the PETM. This suggests that paleoenvironmental conditions during the Late Paleocene-Early Eocene, including the PETM, consistently affected major segments of the paleo-North Sea coast.
Curcumin—a rhizomal phytochemical from the plant Curcuma longa—is well known to inhibit cell proliferation and to induce apoptosis in a broad range of cell lines. In previous studies we showed that combining low curcumin concentrations and subsequent ultraviolet A radiation (UVA) or VIS irradiation induced anti-proliferative and pro-apoptotic effects. There is still debate whether curcumin induces apoptosis via the extrinsic or the intrinsic pathway. To address this question, we investigated in three epithelial cell lines (HaCaT, A431, A549) whether the death receptors CD95, tumor necrosis factor (TNF)-receptor I and II are involved in apoptosis induced by light and curcumin. Cells were incubated with 0.25–0.5 µg/mL curcumin followed by irradiation with 1 J/cm2 UVA. This treatment was combined with inhibitors specific for distinct membrane-bound death receptors. After 24 h apoptosis induction was monitored by quantitative determination of cytoplasmic histone-associated-DNA-fragments. Validation of our test system showed that apoptosis induced by CH11 and TNF-α could be completely inhibited by their respective antagonists. Interestingly, apoptosis induced by curcumin/light treatment was reversed by none of the herein examined death receptor antagonists. These results indicate a mechanism of action independent from classical death receptors speaking for intrinsic activation of apoptosis. It could be speculated that a shift in cellular redox balance might prompt the pro-apoptotic processes
Influence of structured reporting of tooth-colored indirect restorations on clinical decision-making
(2019)
The aim of the present study was to discover what influence structured reporting (study group = A) of toothcoloured lab-fabricated restorations has on clinical decision-making following international guidelines. By way of comparison, the conventional approach in the form of short reporting with 5 items (control group = B) was used as gold standard. The study was carried out in the first clinical semester of dentistry (n = 68) at the Goethe University in Frankfurt am Main. In the study group, indirect ceramic restorations were assessed on a scale of 1 (very good) to 5 (insufficient) using structured reporting (7 items, each with 5 subgroups) in accordance to World Dental Federation (FDI) - standards. Following this, the clinical decision on the insertion of the restoration was made. To evaluate the quality of the structured reporting, sensitivity, specificity, confidence intervals (Cl) and the respective predictive values (positive = PPV, negative= NPV) were determined. Based on FDI reporting, a ceramic inlay is also favored with a great degree of certainty in clinical decisions: this was the true in 34 procedures out of a total of 38 clinically incorporated ceramic inlays [sensitivity 67% (95% CI: 46%83%); specificity 89% (95% Cl: 75%-97%); PPV 82%, NPV 79%]. In the control group, sensitivity was 56% (95% CI: 35%-75%); specificity 92% (95% CI: 79%-98%); PPV 83%, NPV 74%. No significant differences could be determined between A and B (p = 0.813).
Due to the higher sensitivity and efficiency given comparable specificity, structured reporting of tooth-coloured lab-fabricated restorations based on FDI criteria, appears more recommendable than short reporting. It is also suitable for promoting decision-making in quality assessment, thus improving the durability of dental restorations.
In global hydrological models, groundwater storages and flows are generally simulated by linear reservoir models. Recently, the first global gradient-based groundwater models were developed in order to improve the representation of groundwater-surface water interactions, capillary rise, lateral flows and human water use impacts. However, the reliability of model outputs is limited by a lack of data as well as model assumptions required due to the necessarily coarse spatial resolution. The impact of data quality is presented by showing the sensitivity of a groundwater model to changes in the only available global hydraulic conductivity data-set. To better understand the sensitivity of model output to uncertain spatially distributed parameter inputs, we present the first application of a global sensitivity method for a global-scale groundwater model using nearly 2000 steady-state model runs of the global gradient-based groundwater model G3M. By applying the Morris method in a novel domain decomposition approach that identifies global hydrological response units, spatially distributed parameter sensitivities are determined for a computationally expensive model. Results indicate that globally simulated hydraulic heads are equally sensitive to hydraulic conductivity, groundwater recharge and surface water body elevation, though parameter sensitivities vary regionally. For large areas of the globe, rivers are simulated to be either losing or gaining, depending on the parameter combination, indicating a high uncertainty of simulating the direction of flow between the two compartments. Mountainous and dry regions show a high variance in simulated head due to numerical difficulties of the model, limiting the reliability of computed sensitivities in these regions. This instability is likely caused by the uncertainty in surface water body elevation. We conclude that maps of spatially distributed sensitivities can help to understand complex behaviour of models that incorporate data with varying spatial uncertainties. The findings support the selection of possible calibration parameters and help to anticipate challenges for a transient coupling of the model.
The anti-cancer properties of curcumin in vitro have been documented. However, its clinical use is limited due to rapid metabolization. Since irradiation of curcumin has been found to increase its anti-cancer effect on several tumor types, this investigation was designed to determine whether irradiation with visible light may enhance the anti-tumor effects of low-dosed curcumin on renal cell carcinoma (RCC) cell growth and proliferation. A498, Caki1, and KTCTL-26 cells were incubated with curcumin (0.1–0.4 µg/mL) and irradiated with 1.65 J/cm2 visible light for 5 min. Controls were exposed to curcumin or light alone or remained untreated. Curcumin plus light, but not curcumin or light exposure alone altered growth, proliferation, and apoptosis of all three RCC tumor cell lines. Cells were arrested in the G0/G1 phase of the cell cycle. Phosphorylated (p) CDK1 and pCDK2, along with their counter-receptors Cyclin B and A decreased, whereas p27 increased. Akt-mTOR-signaling was suppressed, the pro-apoptotic protein Bcl-2 became elevated, and the anti-apoptotic protein Bax diminished. H3 acetylation was elevated when cells were treated with curcumin plus light, pointing to an epigenetic mechanism. The present findings substantiate the potential of combining low curcumin concentrations and light as a new therapeutic concept to increase the efficacy of curcumin in RCC.
Based on accumulating evidence of a role of lipid signaling in many physiological and pathophysiological processes including psychiatric diseases, the present data driven analysis was designed to gather information needed to develop a prospective biomarker, using a targeted lipidomics approach covering different lipid mediators. Using unsupervised methods of data structure detection, implemented as hierarchal clustering, emergent self-organizing maps of neuronal networks, and principal component analysis, a cluster structure was found in the input data space comprising plasma concentrations of d = 35 different lipid-markers of various classes acquired in n = 94 subjects with the clinical diagnoses depression, bipolar disorder, ADHD, dementia, or in healthy controls. The structure separated patients with dementia from the other clinical groups, indicating that dementia is associated with a distinct lipid mediator plasma concentrations pattern possibly providing a basis for a future biomarker. This hypothesis was subsequently assessed using supervised machine-learning methods, implemented as random forests or principal component analysis followed by computed ABC analysis used for feature selection, and as random forests, k-nearest neighbors, support vector machines, multilayer perceptron, and naïve Bayesian classifiers to estimate whether the selected lipid mediators provide sufficient information that the diagnosis of dementia can be established at a higher accuracy than by guessing. This succeeded using a set of d = 7 markers comprising GluCerC16:0, Cer24:0, Cer20:0, Cer16:0, Cer24:1, C16 sphinganine, and LacCerC16:0, at an accuracy of 77%. By contrast, using random lipid markers reduced the diagnostic accuracy to values of 65% or less, whereas training the algorithms with randomly permuted data was followed by complete failure to diagnose dementia, emphasizing that the selected lipid mediators were display a particular pattern in this disease possibly qualifying as biomarkers.
Compartmentalization of immune response and microbial translocation in decompensated cirrhosis
(2019)
Background: Acquired dysfunctional immunity in cirrhosis predisposes patients to frequent bacterial infections, especially spontaneous bacterial peritonitis (SBP), leading to systemic inflammation that is associated with poor outcome. But systemic inflammation can also be found in the absence of a confirmed infection. Detection of bacterial DNA has been investigated as a marker of SBP and as a predictor of prognosis. Data is, however, contradictory. Here we investigated whether levels of IL-6 and IL-8 putatively produced by myeloid cells in ascites are associated with systemic inflammation and whether inflammation depends on the presence of specific bacterial DNA.
Methods and Materials: We enrolled 33 patients with decompensated liver cirrhosis from whom we collected paired samples of blood and ascites. IL-6 and IL-8 were measured in serum samples of all patients using ELISA. In a subset of 10 representative patients, bacterial DNA was extracted from ascites and whole blood, followed by 16S rRNA gene amplicon sequencing.
Results: There were significantly higher levels of IL-6 in ascites fluid compared to blood samples in all patients. Interestingly, IL-6 levels in blood correlated tightly with disease severity and surrogates of systemic inflammation, while IL-6 levels in ascites did not. Moreover, patients with higher blood CRP levels showed greater SBP prevalence compared to patients with lower levels, despite similar positive culture results. Bacterial richness was also significantly higher in ascites compared to the corresponding patient blood. We identified differences in microbial composition and diversity between ascites and blood, but no tight relationship with surrogates of systemic inflammation could be observed.
Discussion: In decompensated cirrhosis, markers of systemic inflammation and microbiota composition seem to be dysregulated in ascites and blood. While a relationship between systemic inflammation and microbiota composition seems to exist in blood, this is not the case for ascites in our hands. These data may suggest compartmentalization of the immune response and interaction of the latter with the microbiota especially in the blood compartment.
In this article, we explore civil society mobilisation and the impact of organised interests on the energy policies of two post-communist countries—Hungary and Czechia—and specifically nuclear energy. Drawing on numerous hypotheses from the literature on organised interests, we explore how open both political systems are for civil society input and what interest group-specific and socio-economic factors mediate the influence of organised interests. Based on the preference attainment method, our case studies focus on the extent to which organised interests have succeeded bringing nuclear energy legislation in line with their preferences. We find that while both democracies are open to civil society input, policy-making is generally conducted in state-industrial circles, whereby anti-nuclear and renewable energy advocates are at best able to make minor corrections to already pre-determined policies.
From the colour glass condensate to filamentation: systematics of classical Yang–Mills theory
(2019)
The non-equilibrium early time evolution of an ultra-relativistic heavy ion collision is often described by classical lattice Yang–Mills theory, starting from the colour glass condensate (CGC) effective theory with an anisotropic energy momentum tensor as initial condition. In this work we investigate the systematics associated with such studies and their dependence on various model parameters (IR, UV cutoffs and the amplitude of quantum fluctuations) which are not yet fixed by experiment. We perform calculations for SU() and SU(), both in a static box and in an expanding geometry. Generally, the dependence on model parameters is found to be much larger than that on technical parameters like the number of colours, boundary conditions or the lattice spacing. In a static box, all setups lead to isotropisation through chromo-Weibel instabilities, which is illustrated by the accompanying filamentation of the energy density. However, the associated time scale depends strongly on the model parameters and in all cases is longer than the phenomenologically expected one. In the expanding system, no isotropisation is observed for any parameter choice. We show how investigations at fixed initial energy density can be used to better constrain some of the model parameters.
Retrophylogenomics in rorquals indicate large ancestral population sizes and a rapid radiation
(2019)
Background: Baleen whales (Mysticeti) are the largest animals on earth and their evolutionary history has been studied in detail, but some relationships still remain contentious. In particular, reconstructing the phylogenetic position of the gray whales (Eschrichtiidae) has been complicated by evolutionary processes such as gene flow and incomplete lineage sorting (ILS). Here, whole-genome sequencing data of the extant baleen whale radiation allowed us to identify transposable element (TE) insertions in order to perform phylogenomic analyses and measure germline insertion rates of TEs. Baleen whales exhibit the slowest nucleotide substitution rate among mammals, hence we additionally examined the evolutionary insertion rates of TE insertions across the genomes.
Results: In eleven whole-genome sequences representing the extant radiation of baleen whales, we identified 91,859 CHR-SINE insertions that were used to reconstruct the phylogeny with different approaches as well as perform evolutionary network analyses and a quantification of conflicting phylogenetic signals. Our results indicate that the radiation of rorquals and gray whales might not be bifurcating. The morphologically derived gray whales are placed inside the rorqual group, as the sister-species to humpback and fin whales. Detailed investigation of TE insertion rates confirm that a mutational slow down in the whale lineage is present but less pronounced for TEs than for nucleotide substitutions.
Conclusions: Whole genome sequencing based detection of TE insertions showed that the speciation processes in baleen whales represent a rapid radiation. Large genome-scale TE data sets in addition allow to understand retrotransposition rates in non-model organisms and show the potential for TE calling methods to study the evolutionary history of species.
Background: Approximately 90% of German surface waters do not meet the objectives of the European Water Framework Directive (EU-WFD). This is primarily due to deficits in water body structure and biological quality components, which in turn are negatively affected by chemical pollution. In this context, hydromorphological restoration measures have often been conducted to improve habitat and species diversity and, therefore, the ecological status of water bodies. However, habitat improvement is not necessarily accompanied by biota enhancement and thus by the improvement of the ecological status of rivers. To prioritize water management measures, decision criteria for the water management practice are necessary, which enable the prognosis, whether chemical pollution and its resulting effects or other factors, such as structural deficits of the water bodies, are the main cause for the failure to meet the objective of a good ecological status.
Results: To address this need, we applied the freshwater mudsnail Potamopyrgus antipodarum and the amphipod Gammarus fossarum in active monitoring campaigns and in laboratory experiments with combined water/sediment samples and analyzed water and sediment samples with in vitro assays quarterly over the course of 1 year to provide evidence and guideline to assess if chemical contamination is a relevant stress factor for the aquatic biodiversity in rivers of the Nidda catchment (Hessen, Germany). On the basis of these results, an ecotoxicological, WFD–compliant assessment system was developed which, in comparison with the ecological status classes of the EU-WFD, permits the identification of the probable causes for the failure to meet the objectives of the EU-WFD. From these findings, recommendations for action were derived for the implementation of priority measures in water management practice. For the rivers Nidda, Usa, and Horloff, we identified a need for action to improve water and sediment quality at all investigated sampling sites except for the reference sites in the headwaters. The ecotoxicological assessment system also highlighted that hydromorphological restoration measures on their own will not lead to a good ecological status of rivers, as long as water and sediment quality are deficient.
Conclusion: Hydromorphological restoration measures should be performed in conjunction with measures to reduce chemical contamination to achieve a good ecological status of the rivers Nidda, Usa, and Horloff.
Background: By performing case management, general practitioners and health care assistants can provide additional benefits to their chronically ill patients. However, the economic effects of such case management interventions often remain unclear although how to manage the burden of chronic disease is a key question for policy-makers. This analysis aimed to compare the cost-effectiveness of 24 months of primary care case management for patients with a long-term indication for oral anticoagulation therapy with usual care.
Methods: This analysis is part of the cluster-randomized controlled Primary Care Management for Optimized Antithrombotic Treatment (PICANT) trial. A sample of 680 patients with German statutory health insurance was initially considered for the cost analysis (92% of all participants at baseline). Costs included all disease-related direct health care costs from the payer’s perspective (German statutory health insurers) plus case management costs for the intervention group. A-Quality Adjusted Life Year (QALY) measurement (EQ-5D-3 L instrument) was used to evaluate utility, and incremental cost-effectiveness ratio (ICER) to assess cost-effectiveness. Mean differences were calculated and displayed with 95%-confidence intervals (CI) from non-parametric bootstrapping (1000 replicates).
Results: N = 505 patients (505/680, 74%) were included in the cost analysis (complete case analysis with a follow-up after 12 and 24 months as well as information on cost and QALY). After two years, the mean difference of direct health care costs per patient (€115, 95% CI [− 201; 406]) and QALYs (0.03, 95% CI [− 0.04; 0.11]) in the two groups was small and not significant. The costs of case management in the intervention group caused mean total costs per patient in this group to rise significantly (mean difference €503, 95% CI [188; 794]). The ICER was €16,767 per QALY. Regardless of the willingness of insurers to pay per QALY, the probability of the intervention being cost-effective never rose above 70%.
Conclusions: A primary care case management for patients with a long-term indication for oral anticoagulation therapy improved QALYs compared to usual care, but was more costly. However, the results may help professionals and policy-makers allocate scarce health care resources in such a way that the overall quality of care is improved at moderate costs, particularly for chronically ill patients.
Trial registration: Current Controlled Trials ISRCTN41847489.
We investigate the transmission of central bank liquidity to bank deposits and loan spreads in Europe over the January 2006 to June 2010 period. We find evidence consistent with an impaired transmission channel due to bank risk. Central bank liquidity does not translate into lower loan spreads for high-risk banks, even as it lowers deposit rates for both high-risk and low-risk banks. This adversely affects the balance sheets of high-risk bank borrowers, leading to lower payouts, lower capital expenditures, and lower employment. Overall, our results suggest that banks’ capital constraints at the time of an easing of monetary policy pose a challenge to the effectiveness of the bank lending channel and the effectiveness of the central bank as a lender of last resort.
Change ahead—emerging life-course transitions as practical accomplishments of growing old(er)
(2019)
With the aging of the "Baby Boomer" cohort, more and more adults are transiting from work into retirement. In public discourse, this development is framed as one of the major challenges of today's welfare societies. To develop social innovations that consider the everyday lives of older people requires a deeper theoretical understanding of the retiring process. In age studies, retiring has been approached from various theoretical perspectives, most prominently disengagement perspectives (retirement as the withdrawal from social roles and responsibilities) and rational choice perspectives (retiring as a rational decision based on incentives and penalties). Whereas, the former have been accused of promoting a deficient image of aging, the latter are criticized for concealing the socially stratified constraints older people experience. This paper proposes a practice-theoretical perspective on retiring, understanding it as a processual, practical accomplishment that involves various social practices, sites, and human, as well as non-human, actors. To exemplify this approach, I draw upon data from the project "Doing Retiring" that follows 30 older adults in Germany from 1 year before to 3 years after retirement. Results depict retiring as a complex process of change, assembled by social practices that are scattered across time, space, and carriers. Practice sequences and constellations differ significantly between older adults who retire expectedly and unexpectedly, for example through sudden job loss or illness. However, even among those who envisaged retiring "on their own terms," the agency to retire was distributed across the network of employers, retirement schemes, colleagues, laws, families, workplaces, bodies and health, and the future retiree themselves. Results identified a distinct set of sequentially organized practices that were temporally and spatially configured. Many study participants expressed an idea about a "right time to retire" embedded in the imagination of a chrononormative life-course, and they often experienced spatio-temporal withdrawal from the workplace (e.g., reduction of working hours) which entailed affective disengagement from work as well. In conclusion, a practice-theoretical perspective supports social innovations that target more than just the retiring individual.
In this paper, we investigate whether timing in monolingual acquisition interacts with age of onset and input effects in child bilingualism. Six different morpho-syntactic and semantic phenomena acquired early, late or very late are considered, with their timing in L1 acquisition varying between age 3 (subject-verb agreement) and after age 6 (case marking). Data from simultaneous bilingual children (2L1) whose mean age of onset to German was 3 months are compared with data from early second language learners of German (eL2) whose mean age of onset to German was 35 months as well as with data from monolingual children. To explore change over time, children were tested twice at the ages of 4;4 and 5;8 years. The main findings were that 2L1 children had an advantage over their eL2 peers in early acquired phenomena, which disappeared with time, whereas in late acquired phenomena 2L1 and eL2 children did not differ. Moreover, 2L1 children performed like monolingual children in early acquired phenomena but had a disadvantage in the late acquired phenomena with the amount of delay decreasing with time. We conclude that age of onset effects are modulated by effects of timing in monolingual acquisition. Contrary to expectation, input in terms of language dominance, measured as the dominant language used at home, did not affect simultaneous bilingual children’s performance in any of the phenomena. We discuss the implications of our findings for the hypothesis that acquisition of late phenomena is determined by input alone and suggest an alternative concept: the learner’s internal need for time to master a phenomenon, which is determined by its complexity and cross-linguistic robustness.
Orthologs document the evolution of genes and metabolic capacities encoded in extant and ancient genomes. However, the similarity between orthologs decays with time, and ultimately it becomes insufficient to infer common ancestry. This leaves ancient gene set reconstructions incomplete and distorted to an unknown extent. Here we introduce the "evolutionary traceability" as a measure that quantifies, for each protein, the evolutionary distance beyond which the sensitivity of the ortholog search becomes limiting. Using yeast, we show that genes that were thought to date back to the last universal common ancestor are of high traceability. Their functions mostly involve catalysis, ion transport, and ribonucleoprotein complex assembly. In turn, the fraction of yeast genes whose traceability is not sufficient to infer their presence in last universal common ancestor is enriched for regulatory functions. Computing the traceabilities of genes that have been experimentally characterized as being essential for a self-replicating cell reveals that many of the genes that lack orthologs outside bacteria have low traceability. This leaves open whether their orthologs in the eukaryotic and archaeal domains have been overlooked. Looking at the example of REC8, a protein essential for chromosome cohesion, we demonstrate how a traceability-informed adjustment of the search sensitivity identifies hitherto missed orthologs in the fast-evolving microsporidia. Taken together, the evolutionary traceability helps to differentiate between true absence and nondetection of orthologs, and thus improves our understanding about the evolutionary conservation of functional protein networks. "protTrace," a software tool for computing evolutionary traceability, is freely available at https://github.com/BIONF/protTrace.git; last accessed February 10, 2019.
Job loss expectations, durable consumption and household finances : evidence from linked survey data
(2019)
Job security is important for durable consumption and household savings. Using surveys, workers express a probability that they will lose their job in the next 12 months. In order to assess the empirical content of these probabilities, we link survey data to administrative data with labor market outcomes. Workers predict job loss quite well, in particular those whose job loss is followed by unemployment. Workers with higher job loss expectations acquire cheaper cars, and are less likely to buy new cars. In line with models of precautionary saving, higher job loss expectations are associated with more savings and less exposure to risky assets.
Introduction: Chronic heart failure (CHF) is a heterogeneous condition requiring complex treatment from diverse healthcare services. An increasingly holistic understanding of healthcare has resulted in contextual factors such as perceived quality of care, as well as patients’ acceptance, preferences and subjective expectations of health services, all gaining in importance. How patients with CHF experience the use of healthcare services has not been studied within the scope of a systematic review in a German healthcare context. The aim of this scoping review is therefore to review systematically the experiences of patients affected by CHF with healthcare services in Germany in the literature and to map the research foci. Further objectives are to identify gaps in evidence, develop further research questions and to inform decision makers concerned with improving healthcare of patients living with CHF.
Methods and analysis: This scoping review will be based on a broad search strategy involving systematic and comprehensive electronic database searches in MEDLINE, EMBASE, PsycINFO, PSYNDEX, CINAHL and Cochrane’s Database of Systematic Reviews, grey literature searches, as well as hand searches through reference lists and non-indexed key journals. The methodological procedure will be based on an established six-stage framework for conducting scoping reviews that includes two independent reviewers. Data will be systematically extracted, qualitatively and quantitatively analysed and summarised both narratively and visually. To ensure the research questions and extracted information are meaningful, a patient representative will be involved.
Ethics and dissemination: Ethical approval will not be required to conduct this review. Results will be disseminated through a clearly illustrated report that will be part of a wider research project. Furthermore, it is intended that the review’s findings should be made available to relevant stakeholders through conference presentations and publication in peer-reviewed journals (knowledge transfer). Protocol registration in PROSPERO is not applicable for scoping reviews.
Glioblastoma (GBM), WHO grade IV, is the most aggressive primary brain tumor in adults. The median survival time using standard therapy is only 12–15 months with a 5-year survival rate of around 5%. Thus, new and effective treatment modalities are of significant importance. Signal transducer and activator of transcription 3 (Stat3) is a key signaling protein driving major hallmarks of cancer and represents a promising target for the development of targeted glioblastoma therapies. Here we present data showing that the therapeutic application of siRNAs, formulated in nanoscale lipopolyplexes (LPP) based on polyethylenimine (PEI) and the phospholipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), represents a promising new approach to target Stat3 in glioma. We demonstrate that the LPP-mediated delivery of siRNA mediates efficient knockdown of Stat3, suppresses Stat3 activity and limits cell growth in murine (Tu2449) and human (U87, Mz18) glioma cells in vitro. In a therapeutic setting, intracranial application of the siRNA-containing LPP leads to knockdown of STAT3 target gene expression, decreased tumor growth and significantly prolonged survival in Tu2449 glioma-bearing mice compared to negative control-treated animals. This is a proof-of-concept study introducing PEI-based lipopolyplexes as an efficient strategy for therapeutically targeting oncoproteins with otherwise limited druggability.
A case of Lymphangioleiomyomatosis (LAM) of the lung in a patient with a history of breast cancer
(2019)
Background: Lymphangioleiomyomatosis (LAM) is a rare progressive cystic and nodular disease of the lung characterized by smooth muscle cell proliferation. LAM predominantly affects young premenopausal women. This report is of a case of LAM presenting in a 47-year-old woman with a past history of breast cancer and discusses the possibility of an association between the two conditions.
Case report: A 47-year-old woman presented as an emergency with an exacerbation of a four-month history of shortness of breath and dry cough. Her symptoms began following the start of anti-hormonal treatment with letrozole and goserelin acetate for a moderately differentiated (grade 2) invasive ductal carcinoma of the breast (pT2, pN0, M0) which was positive for expression of estrogen receptor (ER+), progesterone receptor (PR+), and human epidermal growth factor receptor 2 (HER2+). Until the previous four months, she had breast-conserving treatment with radiotherapy and tamoxifen therapy. Following hospital admission, she was found to be in type I respiratory failure. Chest X-ray, lung computed tomography (CT), and positron-emission tomography (PET) showed diffuse cystic and nodular lung lesions, consistent with a diagnosis of LAM, and antihormonal therapy was discontinued. She developed pericarditis that was treated with the anti-inflammatory agent, colchicine. Treatment with letrozole and sirolimus improved her respiratory symptoms.
Conclusions: A rare case of LAM is presented in a woman with a recent history of breast cancer. Because both tumors were hormone-dependent, this may support common underlying gene associations and signaling pathways between the two types of tumor.
This study aims to elaborate the relevance of trauma severity and traumatic injury pattern in different multiple and/or polytrauma models by comparing five singular trauma to two different polytrauma (PT) models with high and one multiple trauma (MT) model with low injury-severity score (ISS). The aim is to provide a baseline for reducing animal harm according to 3Rs by providing less injury as possible in polytrauma modeling. Mice were randomly assigned to 10 groups: controls (Ctrl; n = 15), Sham (n = 15); monotrauma groups: hemorrhagic shock (HS; n = 15), thoracic trauma (TxT; n = 18), osteotomy with external fixation (Fx; n = 16), bilateral soft tissue trauma (bSTT; n = 16) or laparotomy (Lap; n = 16); two PT groups: PT I (TxT + HS + Fx; ISS = 18; n = 18), PT II (TxT + HS + Fx + Lap; ISS = 22; n = 18), and a MT group (TxT + HS + bSTT + Lap, ISS = 13; n = 18). Activity and mortality were assessed. Blood gas analyses and organ damage markers were determined after 6 h. Significant mortality occurred in TxT, PT and MT (11.7%). Activity decreased significantly in TxT, HS, both polytrauma and MT vs. Ctrl/Sham. PT-groups and MT had significantly decreased activity vs. bsTT, Lap or Fx. MT had significantly lower pCO2 vs. Ctrl/Sham, Lap or bsTT. Transaminases increased significantly in PT-groups and MT vs. Ctrl, Sham or monotrauma. Traumatic injury pattern is of comparable relevance as injury severity for experimental multiple or (poly)trauma modeling.
Up to 50% of patients initially treated for prostate cancer in a curative intent experience biochemical recurrence, possibly requiring adjuvant treatment. However, salvage treatment decisions, such as lymph node dissection or radiation therapy, are typically based on prostate specific antigen (PSA) recurrence. Importantly, common imaging modalities (e.g., computed tomography [CT], magnetic resonance imaging, and bone scan) are limited and the detection of recurrent disease is particularly challenging if PSA is low. Prostate specific membrane antigen (PSMA) positron-emission tomography/computed tomography (PET/CT) is a novel and promising imaging modality which aims to overcome the incapability of early identification of distant and regional metastases. Within this review, we summarize the current evidence related to PSMA-PET/CT in prostate cancer men diagnosed with biochemical recurrence after local treatment with curative intent. We discuss detection rates of PSMA-PET/CT stratified by PSA-levels and its impact on clinical decision making. Furthermore, we compare different imagefusion techniques such as PSMA-PET vs. F-/C-Choline-PET scans vs. PSMA-single photon emission computed tomography/CT. Finally, we touch upon the contemporary role of radio-guided-PSMA salvage lymphadenectomy.
After removal of a dental implant or extraction of a tooth in the upper jaw, the closure of an oroantral fistula (OAF) or oroantral communication (OAC) can be a difficult problem confronting the dentist and surgeon working in the oral and maxillofacial region. Oroantral communication (OAC) acts as a pathological pathway for bacteria and can cause infection of the antrum, which further obstructs the healing process as it is an unnatural communication between the oral cavity and the maxillary sinus. There are different ways to perform the surgical closure of the OAC. The decision-making in closure of oroantral communication and fistula is influenced by many factors. Consequently, it requires a combination of knowledge, experience, and information gathering. Previous narrative research has focused on assessments and comparisons of various surgical techniques for the closure of OAC/OAF. Thus, the decision-making process has not yet been described comprehensively.
The present study aims to illustrate all the factors that have to be considered in the management of OACs and OAFs that determine optimal treatment.
Die Steuerung biochemischer Prozesse oder die Verbesserung von Materialien erfordert zunächst ein tiefgründiges Verständnis über die zugrundeliegenden Systeme. Zur Untersuchung eignet sich Licht als ideales Werkzeug, da hiermit nützliche Informationen über die chemische Struktur, ihre Eigenschaften sowie den zusammenhängenden, schnellen Reaktionsabläufen erhalten werden können. Um die Aufklärung zu erleichtern können kleine, chemische Verbindungen eingeführt werden, welche beispielsweise ein Fluoreszenzmarker, eine photolabile Schutzgruppe oder eine photoschaltbare Verbindung sein können. Von jeweils einem Vertreter dieser Moleküle wurden unterschiedliche Studien durchgeführt, dessen Ergebnisse in dieser Arbeit in insgesamt drei Projekten zusammengefasst werden.
Zunächst wurde die Funktionalität der Helikase RhlB untersucht, die der Familie der DEAD-Box Proteine zugeordnet wird, und RNA-Duplexe in ihre Einzelstränge entwindet. Als RNA-Modellduplex diente JM2h, an dem ein RNA-Einzelstrang fluoreszenzmarkiert war (M2AP6). Die Einführung dieses Markers ermöglichte die Durchführung von statischen Fluoreszenzmessungen sowie von Mischexperimenten, die mit Hilfe der stopped-flow-Technik durchgeführt wurden. In den einleitenden Studien wurde die Helikase weggelassen, wodurch der Fokus auf den Fluoreszenzeigenschaften der RNA gelegt wurde. Die Ergebnisse hierzu zeigten, dass die Fluoreszenzintensität des Einzelstrangs durch Zugabe des komplementären Strangs deutlich abnimmt, wobei das Minimum bei einem äquimolaren Verhältnis erreicht wird. Die dazugehörigen stopped-flow-Messungen zeigten eine Beschleunigung der Hybridisierungsreaktion, wenn höhere Konzentrationen des Gegenstrangs in der Lösung vorhanden waren. Nach anschließender Zugabe der Helikase zur Lösung wurde ein Anstieg der Fluoreszenzintensität erwartet, der vom separierten Einzelstrang M2AP6 herrühren sollte. Dieser Anstieg wurde jedoch erst nach weiterer Zugabe von ATP beobachtet, der auf eine ATP-Abhängigkeit der Entwindungsreaktion von RhlB hindeutet. Diese Abhängigkeit wurde auch bereits für andere Helikasen der DEAD-Box Familie entdeckt. Die korrekte Funktionalität sowie die ATP-Abhängigkeit wurden in stopped-flow-Messungen verfiziert, bei denen der Fluoreszenzanstieg auch zeitaufgelöst betrachtet werden konnte. Für die spektralen Korrekturen der Fluoreszenzspektren wurde ein selbstgeschriebenes MATLAB-Programm namens FluCY verwendet (engl.: Fluorescence Correction & Quantum yield), welches eine schnelle und fehlerfreie Verarbeitung des Datensatzes ermöglichte.
Die zwei im folgenden beschriebenen Projekte handeln von photoaktivierbaren Molekülen. Zum einen photolabile Verbindungen, welche die Funktion z.B. eines Biomoleküls durch eine chemische Modifikation deaktivieren können. Durch eine lichtinduzierte Reaktion kommt es zur Abspaltung der Modifikation und die Funktion ist wiederhergestellt. In dieser Arbeit wurden verschiedene photolabile Schutzgruppen untersucht, die denselben Chromophor BIST (BIsStyryl-Thiophen) tragen. Durch die Einführung dieses Chromophors absorbierten sämtliche untersuchte Verbindungen sehr effizient sichtbares Licht (epsilon(445)=55.700 M^(-1) cm^(-1)), wodurch der photoinduzierte Bindungsbruch mit Wellenlängen durchgeführt werden, die bei einer biologischen Anwendungen keinen Schaden an der Zelle anrichten würden. Hieraufhin wurden in statischen und zeitaufgelösten Absorptionsmessungen Teilschritte der Freisetzungsreaktion untersucht, indem nach Photoanregung die Absorptionsänderungen auf verschiedenen Zeitskalen analysiert wurden. Die ultraschnelle Dynamik im Piko- bis Nanosekundenbereich (10^(-12)-10^(-9) s) wird durch eine spektral breite, positive Absorptionsänderng dominiert. Diese impliziert, dass die Deaktivierung über den Triplettpfad abläuft, der die vergleichsweise niedrigen Freisetzungsausbeuten erklärt (phi(u) < 5). Aufgrund des hohen Extinktionskoeffizienten reichen dennoch bereits niedrige Strahlungsdosen aus, um eine Freisetzung zu initiieren. Der geschwindigkeitsbestimmende Schritt dieser Reaktion ist dem Zerfall des aci-nitro Intermediats zugeordnet. Für ein sekundäres Amin, welches mit BIST geschützt wurde, ist eine Lebensdauer des Intermediats von 71 µs gefunden worden.
In einigen Fällen ist es erwünscht, eine vorliegende Aktivität nicht nur ein-, sondern auch ausschalten zu können, wofür photochrome Verbindungen (oder Photoschalter) verwendet werden. Die in dieser Arbeit untersuchte Verbindung ceCAM ist ein Alken-Photoschalter und vollführt bei Bestrahlung mit Licht eine cis/trans-Isomerisierung. ceCAM ist das Cyanoester-Derivat (ce) von Cumarin-substituierten Allylidenmalonat, von denen beide Konformere sehr effizient sichtbares Licht absorbieren trans: epsilon(489)=50.300 M^(-1) cm^(-1); cis: epsilon(437)=18.600 M^(-1) cm^(-1)). Andere photophysikalische Eigenschaften umfassen u.a. hohe thermische und photochemische Stabilität. Letztere wurde über ein Experiment nachgewiesen, bei dem die lichtinduzierte Isomerisierung alternierend durchgeführt wurde und selbst bei über 250 Zyklen keine signifikate Abnahme der Absorption beobachtet werden konnte. Des Weiteren konnte die Reaktion mit Quantenausbeuten von 39% (trans) und 42% (cis) induziert werden, wobei im photostationären Gleichgewicht auch hohe Isomerenverhältnisse mit bis zu 80% (trans) und 96% (cis) akkumuliert werden konnten. Die Geschwindigkeit der Reaktion wurde mit Hilfe der Ultakurzzeit-Spektroskopie untersucht. Die Dynamik im Zeitbereich von ps-ns zeigte, dass die trans/cis-Isomerisierung unterhalb von 0,5 ns und die umgekehrte Reaktion noch viel schneller (wenige ps) abgeschlossen ist. Durch die Untersuchungen in dieser Arbeit an den BIST-Verbindungen und ceCAM sind viele vorteilhafte, photophysikalische Eigenschaften charakterisiert worden, wodurch sie als verbesserte Alternative zu den bisher bekannten photolabilen Schutzgruppen oder Photoschaltern anzusehen sind.
5-lipoxygenase (5-LO) is the key enzyme in the biosynthesis of leukotrienes and specialized proresolving lipid mediators (SPM). It is mainly expressed in leukocytes and is part of the innate immune system. 5-LO can shuttle between the cytosol and the nucleus. Upon cell activation the protein translocates from soluble cellular compartments to the nuclear membrane. Besides FLAP which is required for cellular leukotriene and SPM formation, 5-LO interacts with other proteins like coactosin-like protein (CLP), Dicer, β-catenin and p53. In this review, the factors involved in the regulation of 5-LO expression, the role of 5-LO in the regulation of stem cell proliferation and differentiation and its biological functions apart from leukotriene and SPM formation are summarized.
Chirality is omnipresent in living nature. On the single molecule level, the response of a chiral species to a chiral probe depends on their respective handedness. A prominent example is the difference in the interaction of a chiral molecule with left or right circularly polarized light. In the present study, we show by Coulomb explosion imaging that circularly polarized light can also induce a chiral fragmentation of a planar and thus achiral molecule. The observed enantiomer strongly depends on the orientation of the molecule with respect to the light propagation direction and the helicity of the ionizing light. This finding might trigger new approaches to improve laser-driven enantioselective chemical synthesis.
CRFVoter : gene and protein related object recognition using a conglomerate of CRF-based tools
(2019)
Background: Gene and protein related objects are an important class of entities in biomedical research, whose identification and extraction from scientific articles is attracting increasing interest. In this work, we describe an approach to the BioCreative V.5 challenge regarding the recognition and classification of gene and protein related objects. For this purpose, we transform the task as posed by BioCreative V.5 into a sequence labeling problem. We present a series of sequence labeling systems that we used and adapted in our experiments for solving this task. Our experiments show how to optimize the hyperparameters of the classifiers involved. To this end, we utilize various algorithms for hyperparameter optimization. Finally, we present CRFVoter, a two-stage application of Conditional Random Field (CRF) that integrates the optimized sequence labelers from our study into one ensemble classifier.
Results: We analyze the impact of hyperparameter optimization regarding named entity recognition in biomedical research and show that this optimization results in a performance increase of up to 60%. In our evaluation, our ensemble classifier based on multiple sequence labelers, called CRFVoter, outperforms each individual extractor’s performance. For the blinded test set provided by the BioCreative organizers, CRFVoter achieves an F-score of 75%, a recall of 71% and a precision of 80%. For the GPRO type 1 evaluation, CRFVoter achieves an F-Score of 73%, a recall of 70% and achieved the best precision (77%) among all task participants.
Conclusion: CRFVoter is effective when multiple sequence labeling systems are to be used and performs better then the individual systems collected by it.
Congenitally blind individuals have been shown to activate the visual cortex during non-visual tasks. The neuronal mechanisms of such cross-modal activation are not fully understood. Here, we used an auditory working memory training paradigm in congenitally blind and in sighted adults. We hypothesized that the visual cortex gets integrated into auditory working memory networks, after these networks have been challenged by training. The spectral profile of functional networks was investigated which mediate cross-modal reorganization following visual deprivation. A training induced integration of visual cortex into task-related networks in congenitally blind individuals was expected to result in changes in long-range functional connectivity in the theta-, beta- and gamma band (imaginary coherency) between visual cortex and working memory networks. Magnetoencephalographic data were recorded in congenitally blind and sighted individuals during resting state as well as during a voice-based working memory task; the task was performed before and after working memory training with either auditory or tactile stimuli, or a control condition. Auditory working memory training strengthened theta-band (2.5-5 Hz) connectivity in the sighted and beta-band (17.5-22.5 Hz) connectivity in the blind. In sighted participants, theta-band connectivity increased between brain areas typically involved in auditory working memory (inferior frontal, superior temporal, insular cortex). In blind participants, beta-band networks largely emerged during the training, and connectivity increased between brain areas involved in auditory working memory and as predicted, the visual cortex. Our findings highlight long-range connectivity as a key mechanism of functional reorganization following congenital blindness, and provide new insights into the spectral characteristics of functional network connectivity.
We study how the informativeness of stock prices changes with the presence of high-frequency trading (HFT). Our estimate is based on the staggered start of HFT participation in a panel of international exchanges. With HFT presence, market prices are a less reliable predictor of future cash flows and investment, even more so for longer horizons. Further, firm-level idiosyncratic volatility decreases, and the holdings and trades by institutional investors deviate less from the market-capitalization weighted portfolio as a benchmark. Our results document that the informativeness of prices decreases subsequent to the start of HFT. These findings are consistent with theoretical models of HFTs' ability to anticipate informed order flow, resulting in decreased incentives to acquire fundamental information.
Purpose: Prisoners have a higher risk of suicide compared to non-incarcerated individuals. One aim of suicide prevention for prisoners is to identify risk factors in order to put stronger support mechanisms in place for the more vulnerable detainees. This study investigates the suicide risk (SR) in offence-related sub-populations in a representative German sample and differentiates between SR for adolescent and adult prisoners.
Methods: Conducting a national study with data from public German records on the entire prison population from 2000 to 2016 and suicide numbers in German prisons in the same period, SR was calculated for the total male prison population as well as for both subgroups, adolescent and adult male prisoners.
Results: In the study period, male prisoners spent 959.584 life years (LY) in German criminal detention. Among those, 524 prisoners died of suicide. SR was higher for detainees imprisoned for an offence resulting in extensive physical harm for another person, e.g. homicide (suicide rate = 134,8 suicides per 100.000 LY; OR = 2,47; CI95%: 1,98–3,08), bodily injury (suicide rate = 87,3; OR = 1,60; CI95%: 1,29–1,99), and sexual offences (suicide rate = 84,2; OR = 1,54; CI95%: 1,18–2,01) compared with the SR of the total prison population (suicide rate = 54.6). Age differences between offence-related SR were found for theft, with adolescents (suicide rate = 69,3; OR = 1,25; CI95%: 0,85–1,84) showing higher SR than adults (suicide rate = 38,2; OR = 0,7; CI95%: 0,54–0,92).
Conclusion: The index offence of detainees is associated with SR and age-related differences exist. Suicide prevention in prisons should take both into account to determine populations at risk.
We study the well-known resonance ψ(4040), corresponding to a 33S1 charm–anticharm vector state ψ(3S), within a QFT approach, in which the decay channels into DD, D∗D, D∗D∗, DsDs and D∗s Ds are considered. The spectral function shows sizable deviations from a Breit–Wigner shape (an enhancement, mostly generated by DD∗loops, occurs); moreover, besides the c ¯ c pole of ψ(4040), a second dynamically generated broad pole at 4 GeV emerges. Naively, it is tempting to identify this new pole with the unconfirmed state Y (4008). Yet, this state was not seen inthe reaction e+e− → ψ(4040) → DD∗, but in processes with π+π−J/ψ in the final state. A detailed study shows a related but different mechanism: a broad peak at 4GeV in the process e+e− → ψ(4040) → DD∗ → π+π−J/ψ appears when DD∗ loops are considered. Its existence in this reaction is not necessarily connected to the existence of a dynamically generated pole, but the underlying mechanism – the strong coupling of c ¯ c to DD∗ loops – can generate both of them. Thus, the controversial state Y (4008) may not be a genuine resonance, but a peak generated by the ψ(4040) and D∗D loops with π+π−J/ψ in the final state.