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BIAM switch assay coupled to mass spectrometry identifies novel redox targets of NADPH oxidase 4
(2019)
Aim: NADPH oxidase (Nox) -derived reactive oxygen species have been implicated in redox signaling via cysteine oxidation in target proteins. Although the importance of oxidation of target proteins is well known, the specificity of such events is often debated. Only a limited number of Nox-oxidized proteins have been identified thus far; especially little is known concerning redox-targets of the constitutively active NADPH oxidase Nox4.
In this study, HEK293 cells with tetracycline-inducible Nox4 overexpression (HEK-tet-Nox4), as well as podocytes of WT and Nox4-/- mice, were utilized to identify Nox4-dependent redox-modified proteins.
Results: TGFβ1 induced an elevation in Nox4 expression in podocytes from WT but not Nox4-/- mice. Using BIAM based redox switch assay in combination with mass spectrometry and western blot analysis, 142 proteins were identified as differentially oxidized in podocytes from wild type vs. Nox4-/- mice and 131 proteins were differentially oxidized in HEK-tet-Nox4 cells upon Nox4 overexpression. A predominant overlap was found for peroxiredoxins and thioredoxins, as expected. More interestingly, the GRB2-associated-binding protein 1 (Gab1) was identified as being differentially oxidized in both approaches. Further analysis using mass spectrometry-coupled BIAM switch assay and site directed mutagenesis, revealed Cys374 and Cys405 as the major Nox4 targeted oxidation sites in Gab1.
Innovation & conclusion: BIAM switch assay coupled to mass spectrometry is a powerful and versatile tool to identify differentially oxidized proteins in a global untargeted way. Nox4, as a source of hydrogen peroxide, changes the redox-state of numerous proteins. Of those, we identified Gab1 as a novel redox target of Nox4.
Memory enables us to use information from our past experiences to guide new behaviours, calling for the need to integrate or form inference across multiple distinct episodic experiences. Here, we compared children (aged 9–10 years), adolescents (aged 12–13 years), and young adults (aged 19–25 years) on their ability to form integration across overlapping associations in memory. Participants first encoded a set of overlapping, direct AB- and BC-associations (object-face and face-object pairs) as well as non-overlapping, unique DE-associations. They were then tested on these associations and inferential AC-associations. The experiment consisted of four such encoding/retrieval cycles, each consisting of different stimuli set. For accuracy on both unique and inferential associations, young adults were found to outperform teenagers, who in turn outperformed children. However, children were particularly slower than teenagers and young adults in making judgements during inferential than during unique associations. This suggests that children may rely more on making inferences during retrieval, by first retrieving the direct associations, followed by making the inferential judgement. Furthermore, young adults showed a higher correlation between accuracy in direct (AB, BC) and inferential AC-associations than children. This suggests that, young adults relied closely on AB- and BC-associations for making AC decisions, potentially by forming integrated ABC-triplets during encoding or retrieval. Taken together, our findings suggest that there may be an age-related shift in how information is integrated across experienced episodes, namely from relying on making inferences at retrieval during middle childhood to forming integrated representations at different memory processing stages in adulthood.
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.
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.
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.
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.
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.
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.
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.
Background: Posttraumatic stress disorder (PTSD) after childhood abuse (CA) is often related to severe co-occurring psychopathology, such as symptoms of borderline personality disorder (BPD). The ICD-11 has included Complex PTSD as a new diagnosis, which is defined by PTSD symptoms plus disturbances in emotion regulation, self-concept, and interpersonal relationships. Unfortunately, the empirical database on psychosocial treatments for survivors of CA is quite limited. Furthermore, the few existing studies often have either excluded subjects with self-harm behaviour and suicidal ideation — which is common behaviour in subjects suffering from Complex PTSD. Thus, researchers are still trying to identify efficacious treatment programmes for this group of patients.
We have designed DBT-PTSD to meet the specific needs of patients with Complex PTSD. The treatment programme is based on the rules and principles of dialectical behavioural therapy (DBT), and adds interventions derived from cognitive behavioural therapy, acceptance and commitment therapy and compassion-focused therapy. DBT-PTSD can be provided as a comprehensive residential programme or as an outpatient programme. The effects of the residential programme were evaluated in a randomised controlled trial. Data revealed significant reduction of posttraumatic symptoms, with large between-group effect sizes when compared to a treatment-as-usual wait list condition (Cohen’s d = 1.5).
The first aim of this project on hand is to evaluate the efficacy of the outpatient DBT-PTSD programme. The second aim is to identify the major therapeutic variables mediating treatment efficacy. The third aim is to study neural mechanisms and treatment sensitivity of two frequent sequelae of PTSD after CA: intrusions and dissociation.
Methods: To address these questions, we include female patients who experienced CA and who fulfil DSM-5 criteria for PTSD plus borderline features, including criteria for severe emotion dysregulation. The study is funded by the German Federal Ministry of Education and Research, and started in 2014. Participants are randomised to outpatient psychotherapy with either DBT-PTSD or Cognitive Processing Therapy. Formal power analysis revealed a minimum of 180 patients to be recruited. The primary outcome is the change on the Clinician-Administered PTSD Scale for DSM-5.
Discussion: The expected results will be a major step forward in establishing empirically supported psychological treatments for survivors of CA suffering from Complex PTSD.
Trial registration: German Clinical Trials Register: registration number DRKS00005578, date of registration 19 December 2013.
Synthesis and SAR of the antistaphylococcal natural product nematophin from Xenorhabdus nematophila
(2019)
The repeated and improper use of antibiotics had led to an increased number of multiresistant bacteria. Therefore, new lead structures are needed. Here, the synthesis and an expanded structure–activity relationship of the simple and antistaphylococcal amide nematophin from Xenorhabdus nematophila and synthetic derivatives are described. Moreover, the synthesis of intrinsic fluorescent derivatives, incorporating azaindole moieties was achieved for the first time.
Background: While the incidence and aspects of pneumonia in ICU patients has been extensively discussed in the literature, studies on the occurrence of pneumonia in severely injured patients are rare. The aim of the present study is to elucidate factors associated with the occurrence of pneumonia in severely injured patients with thoracic trauma.
Setting: Level-I University Trauma Centres associated with the TraumaRegister DGU®.
Methods: A total of 1162 severely injured adult patients with thoracic trauma documented in the TraumaRegister DGU® (TR-DGU) were included in this study. Demographic data, injury severity, duration of mechanical ventilation (MV), duration of ICU stay, occurrence of pneumonia, bronchoalveolar lavage, aspiration, pathogen details, and incidences of mortality were evaluated. Statistical evaluation was performed using SPSS (Version 25.0, SPSS, Inc.) software.
Results: The overall incidence of pneumonia was 27.5%. Compared to patients without pneumonia, patients with pneumonia had sustained more severe injuries (mean ISS: 32.6 vs. 25.4), were older (mean age: 51.3 vs. 47.5) and spent longer periods under MV (mean: 368.9 h vs. 114.9 h). Age, sex (male), aspiration, and duration of MV were all independent predictors for pneumonia occurrence in a multivariate analysis. The cut-off point for duration of MV that best discriminated between patients who would and would not develop pneumonia during their hospital stay was 102 h. The extent of thoracic trauma (AISthorax), ISS, and presence of pulmonary comorbidities did not show significant associations to pneumonia incidence in our multivariate analysis. No significant difference in mortality between patients with and without pneumonia was observed.
Conclusions: Likelihood of pneumonia increases with age, aspiration, and duration of MV. These parameters were not found to be associated with differences in outcomes between patients with and without pneumonia. Future studies should focus on independent parameters to more clearly identify severely injured subgroups with a high risk of developing pneumonia.
Level of evidence: Level II - Retrospective medical record review.
Glioblastoma is one of the deadliest malignancies and is virtually incurable. Accumulating evidence indicates that a small population of cells with a stem-like phenotype is the major culprit of tumor recurrence. Enhanced DNA repair capacity and expression of stemness marker genes are the main characteristics of these cells. Elimination of this population might delay or prevent tumor recurrence following radiochemotherapy. The aim of this study was to analyze whether interference with the Hedgehog signaling (Hh) pathway or combined Hh/Notch blockade using small-molecule inhibitors can efficiently target these cancer stem cells and sensitize them to therapy. Using tumor sphere lines and primary patient-derived glioma cultures we demonstrate that the Hh pathway inhibitor GANT61 (GANT) and the arsenic trioxide (ATO)-mediated Hh/Notch inhibition are capable to synergistically induce cell death in combination with the natural anticancer agent (−)-Gossypol (Gos). Only ATO in combination with Gos also strongly decreased stemness marker expression and prevented sphere formation and recovery. These synergistic effects were associated with distinct proteomic changes indicating diminished DNA repair and markedly reduced stemness. Finally, using an organotypic brain slice transplantation model, we show that combined ATO/Gos treatment elicits strong growth inhibition or even complete elimination of tumors. Collectively, our data show for the first time that ATO and Gos, two drugs that can be used in the clinic, represent a promising targeted therapy approach for the synergistic elimination of glioma stem-like cells.
Current technologies used to generate CRISPR/Cas gene perturbation reagents are labor intense and require multiple ligation and cloning steps. Furthermore, increasing gRNA sequence diversity negatively affects gRNA distribution, leading to libraries of heterogeneous quality. Here, we present a rapid and cloning-free mutagenesis technology that can efficiently generate covalently-closed-circular-synthesized (3Cs) CRISPR/Cas gRNA reagents and that uncouples sequence diversity from sequence distribution. We demonstrate the fidelity and performance of 3Cs reagents by tailored targeting of all human deubiquitinating enzymes (DUBs) and identify their essentiality for cell fitness. To explore high-content screening, we aimed to generate the largest up-to-date gRNA library that can be used to interrogate the coding and noncoding human genome and simultaneously to identify genes, predicted promoter flanking regions, transcription factors and CTCF binding sites that are linked to doxorubicin resistance. Our 3Cs technology enables fast and robust generation of bias-free gene perturbation libraries with yet unmatched diversities and should be considered an alternative to established technologies.
The paper outlines a method for investigating the speed effect due to a time limit in testing. It is assumed that the time limit enables latent processing speed to influence responses by causing omissions in the case of insufficient speed. Because of processing speed as additional latent source, the customary confirmatory factor model is enlarged by a second latent variable representing latent processing speed. For distinguishing this effect from other method effects, the factor loadings are fixed according to the cumulative normal distribution. With the second latent variable added, confirmatory factor analysis of reasoning data (N=518) including omissions because of a time limit yielded good model fit and discriminated the speed effect from other possible effects due to the item difficulty, the homogeneity of an item subset and the item positions. Because of the crucial role of the cumulative normal distribution for fixing the factor loadings a check of the normality assumption is also reported.
Discovery of key whole-brain transitions and dynamics during human wakefulness and non-REM sleep
(2019)
The modern understanding of sleep is based on the classification of sleep into stages defined by their electroencephalography (EEG) signatures, but the underlying brain dynamics remain unclear. Here we aimed to move significantly beyond the current state-of-the-art description of sleep, and in particular to characterise the spatiotemporal complexity of whole-brain networks and state transitions during sleep. In order to obtain the most unbiased estimate of how whole-brain network states evolve through the human sleep cycle, we used a Markovian data-driven analysis of continuous neuroimaging data from 57 healthy participants falling asleep during simultaneous functional magnetic resonance imaging (fMRI) and EEG. This Hidden Markov Model (HMM) facilitated discovery of the dynamic choreography between different whole-brain networks across the wake-non-REM sleep cycle. Notably, our results reveal key trajectories to switch within and between EEG-based sleep stages, while highlighting the heterogeneities of stage N1 sleep and wakefulness before and after sleep.
Background: Peritonitis is responsible for thousands of deaths annually in Germany alone. Even source control (SC) and antibiotic treatment often fail to prevent severe sepsis or septic shock, and this situation has hardly improved in the past two decades. Most experimental immunomodulatory therapeutics for sepsis have been aimed at blocking or dampening a specific pro-inflammatory immunological mediator. However, the patient collective is large and heterogeneous. There are therefore grounds for investigating the possibility of developing personalized therapies by classifying patients into groups according to biomarkers. This study aims to combine an assessment of the efficacy of treatment with a preparation of human immunoglobulins G, A, and M (IgGAM) with individual status of various biomarkers (immunoglobulin level, procalcitonin, interleukin 6, antigen D-related human leucocyte antigen (HLA-DR), transcription factor NF-κB1, adrenomedullin, and pathogen spectrum).
Methods/design: A total of 200 patients with sepsis or septic shock will receive standard-of-care treatment (SoC). Of these, 133 patients (selected by 1:2 randomization) will in addition receive infusions of IgGAM for 5 days. All patients will be followed for approximately 90 days and assessed by the multiple-organ failure (MOF) score, by the EQ QLQ 5D quality-of-life scale, and by measurement of vital signs, biomarkers (as above), and survival.
Discussion: This study is intended to provide further information on the efficacy and safety of treatment with IgGAM and to offer the possibility of correlating these with the biomarkers to be studied. Specifically, it will test (at a descriptive level) the hypothesis that patients receiving IgGAM who have higher inflammation status (IL-6) and poorer immune status (low HLA-DR, low immunoglobulin levels) have a better outcome than patients who do not receive IgGAM. It is expected to provide information that will help to close the knowledge gap concerning the association between the effect of IgGAM and the presence of various biomarkers, thus possibly opening the way to a personalized medicine.
Trial registration: EudraCT, 2016–001788-34; ClinicalTrials.gov, NCT03334006. Registered on 17 Nov 2017.
Trial sponsor: RWTH Aachen University, represented by the Center for Translational & Clinical Research Aachen (contact Dr. S. Isfort).
Glaubt man Hermann Parzinger, entsteht in Berlin das würdige Zentrum einer Art Welthauptstadt: "Das Humboldt Forum: 'So viel Welt mit sich verbinden als möglich'"– das ist der Titel des 2011 herausgegebenen Folianten der Stiftung Preußischer Kulturbesitz, deren Präsident Parzinger ist. Die markigen Worte umreißen das Ziel des "wichtigsten Kulturprojekts in Deutschland zu Beginn des 21. Jahrhunderts", wie es im Untertitel heißt. "So viel Welt mit sich verbinden als möglich". Von wem stammt dieses werbewirksame Schlagwort? Und: Wie ist dieses Verbinden zu denken? [...] Mich interessiert hier und im Folgenden der erste Kontakt, der sich im Verb "ergreifen" ausdrückt. Offensichtlich setzt die Etablierung einer möglichst engen Verbindung von 'Mensch' und 'Welt' ein initiales Moment voraus, ein aktives Zupacken durch das Subjekt, das in der Folge die Fusion beider allererst ermöglicht. Das Ergreifen von "so viel Welt, als möglich" bildet das Fundament für humanistische Allgemeinbildung im Humboldt’schen Sinne: "[D]iese Aufgabe löst sich allein durch die Verknüpfung unsres Ich mit der Welt zu der allgemeinsten, regesten und freiesten Wechselwirkung." Angesichts der kontrovers geführten Kolonialismus-Debatte um das Humboldt-Forum ist es bemerkenswert, dass Parzingers Werbetext das Ergreifen tilgt, negiert er doch damit auch ein mögliches Gewaltmoment. Schließlich wurden Kolonien zuerst ergriffen, gewaltsam ein-genommen, bevor es zu einem zumindest einseitig produktiven Austausch von Waren, Kunst und dergleichen, zu einer "Verknüpfung" kommen konnte. Indem der Text die Kontaktanbahnung, das Ausgreifen verschweigt, kaschiert er damit auch das preußisch-imperiale Erbe. Wie sehr aber wirkt in jener Humboldt’schen Verbindung von Bildungssubjekt und Welt die initiale Gewalt fort, die an ihrem Anfang steht? Wie ist das Verhältnis von der "freiesten Wechselwirkung", also einer reziproken Interaktion, zum aggressiven, aktiven Ergreifen? Diese Fragen und der imperiale Wunsch, Berlin möge mit dem Humboldt-Forum nun zur "Angelegenheit der gesamten Welt werden", führen zu 'dem' Modell und Phantasma einer Welthauptstadt – zu Rom, genauer zum Rom Johann Wolfgang von Goethes.
In der Erinnerungskultur der Goethezeit spielt das haptische Erleben von Souvenirs eine entscheidende Rolle – im taktilen Umgang mit Andenken werden über Form, Materialität und Funktion Abwesende vergegenwärtigt, Erinnerungen und Gefühle evoziert. Nachvollziehbar wird die Kultivierung und Reflexion dieser Praktik der Erinnerungskultur in dem sehr gut überlieferten Nachlass von Johann Wolfgang von Goethe, der von der Klassik Stiftung Weimar bewahrt wird. Obwohl Goethe dem Tastsinn jegliche Erkenntnisfähigkeit abspricht und ihn als den niedersten der Sinne diskreditiert, werden das Berühren und Berührtwerden von Körpern und Dingen in seinen literarischen Werken sowie insbesondere in seinen privaten Korrespondenzen variantenreich verhandelt. Eingebettet in empfindsame Liebessemantik, assoziiert mit religiösen Praktiken und medizinischen Diskursen oder verknüpft mit erotischen Momenten ist die Berührung ein wiederkehrender Gegenstand expliziter und impliziter Auseinandersetzungen.
Für Aristoteles gleicht das Drama einem 'zóon', einem Lebewesen mit Anfang, Mitte und Ende. Gemeint sind Entstehung, Ausgestaltung und Abschluss der Handlungsstruktur, und zwar als 'psyché', als Seele, des Dramas. Aus einem Blickwinkel, der weniger am 'dráma' und mehr an den körperlichen Dimensionen des Theaters orientiert ist, ließe sich Aristoteles’ Vergleich auch zur Frage nach einer Organologie des Theaters und ihrer politischen und sinnesphysiologischen Implikationen wenden. Darum geht es mir im Folgenden – für ein unterschätztes Organ: für die Füße.
During the past 15 years there have been dramatic changes in the medical landscape, particularly in oncology and regenerative medicine. Cell therapies have played a substantial part in this progress. Cellular immunotherapies can use immune cells, such as T cells or natural killer cells that, after functional modification ex vivo, exert powerful anti-cancer effects when given to the patient. Innovative technologies, such as re-programming terminally differentiated cells into pluripotent stem cells or into other cell types and applying specific enzymes to more precisely edit the human genome, are paving the way towards more potent cell and gene therapies.
Mesenchymal stromal cells are promising cellular immunotherapeutics, which also have potential for use in tissue engineering strategies and other regenerative medicine applications. However, substantial gaps in our knowledge of their biology and therapeutic efficacy present major challenges to their sustainable implementation in the clinical routine.
In this article, progress in the field of cell therapeutics during the past 15 years will be briefly discussed, with a focus on mesenchymal stromal cells, highlighting the impact of this field on patient care.
Memory impairments are a major characteristic of schizophrenia (SZ). In the current study, we used an associative memory task to test the hypothesis that SZ patients and first-degree relatives have altered functional patterns in comparison to healthy controls. We analyzed the fMRI activation pattern during the presentation of a face-name task in 27 SZ patients, 23 first-degree relatives, and 27 healthy controls. In addition, we performed correlation analyses between individual psychopathology, accuracy and reaction time of the task and the beta scores of the functional brain activations. We observed a lower response accuracy and increased reaction time during the retrieval of face-name pairs in SZ patients compared with controls. Deficient performance was accompanied by abnormal functional activation patterns predominantly in DMN regions during encoding and retrieval. No significant correlation between individual psychopathology and neuronal activation during encoding or retrieval of face-name pairs was observed. Findings of first-degree relatives indicated slightly different functional pattern within brain networks in contrast to controls without significant differences in the behavioral task. Both the accuracy of memory performance as well as the functional activation pattern during retrieval revealed alterations in SZ patients, and, to a lesser degree, in relatives. The results are of potential relevance for integration within a comprehensive model of memory function in SZ. The development of a neurophysiological model of cognition in psychosis may help to clarify and improve therapeutic options to improve memory and functioning in the illness.
Numerous cell–cell and cell–matrix interactions within the bone marrow microenvironment enable the controlled lifelong self-renewal and progeny of hematopoietic stem and progenitor cells (HSPCs). On the cellular level, this highly mutual interaction is granted by cell adhesion molecules (CAMs) integrating differentiation, proliferation, and pro-survival signals from the surrounding microenvironment to the inner cell. However, cell–cell and cell–matrix interactions are also critically involved during malignant transformation of hematopoietic stem/progenitor cells. It has become increasingly apparent that leukemia-associated gene products, such as activated tyrosine kinases and fusion proteins resulting from chromosomal translocations, directly regulate the activation status of adhesion molecules, thereby directing the leukemic phenotype. These observations imply that interference with adhesion molecule function represents a promising treatment strategy to target pre-leukemic and leukemic lesions within the bone marrow niche. Focusing on myeloid leukemia, we provide a current overview of the mechanisms by which leukemogenic gene products hijack control of cellular adhesion to subsequently disturb normal hematopoiesis and promote leukemia development.
IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in both childhood and adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Previously, we revealed that COBL is a hotspot for breakpoints in leukemia and could promote IKZF1 deletions. Through an international collaboration, we provide a detailed genetic and clinical picture of B-ALL with COBL rearrangements (COBL-r). Patients with B-ALL and IKZF1 deletion (n = 133) were included. IKZF1 ∆1-8 were associated with large alterations within chromosome 7: monosomy 7 (18%), isochromosome 7q (10%), 7p loss (19%), and interstitial deletions (53%). The latter included COBL-r, which were found in 12% of the IKZF1 ∆1-8 cohort. Patients with COBL-r are mostly classified as intermediate cytogenetic risk and frequently harbor ETV6, PAX5, CDKN2A/B deletions. Overall, 56% of breakpoints were located within COBL intron 5. Cryptic recombination signal sequence motifs were broadly distributed within the sequence of COBL, and no enrichment for the breakpoint cluster region was found. In summary, a diverse spectrum of alterations characterizes ΔIKZF1 and they also include deletion breakpoints within COBL. We confirmed that COBL is a hotspot associated with ΔIKZF1, but these rearrangements are not driven by RAG-mediated recombination.
Background: Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFIs). The objectives of this study were to evaluate the pharmacokinetics (PK), safety, and tolerability of POS oral suspension in pediatric subjects with neutropenia.
Methods: This was a prospective, multicenter, sequential dose-escalation study. Enrolled subjects were divided into 3 age groups: AG1, 7 to <18 years; AG2, 2 to <7 years; and AG3, 3 months to <2 years. AG1 and AG2 were divided into 3 dosage cohorts: DC1, 12 mg/kg/day divided twice daily (BID); DC2, 18 mg/kg/day BID; and DC3, 18 mg/kg/day divided thrice daily (TID). AG3 was also divided into DC1 and DC2; however, no subjects were enrolled in DC2. Subjects received 7–28 days of POS oral suspension. PK samples were collected at predefined time points. The POS PK target was predefined as ~90% of subjects with Cavg (AUC /dosing interval) between 500 and 2500 ng/mL, with an anticipated mean steady state Cavg exposure of ~1200 ng/mL.
Results: The percentage of subjects meeting the PK target was <90% across all age groups and dosage cohorts (range: 31% to 80%). The percentage of subjects that achieved the Cavg target of 500 to 2500 ng/mL on Day 7 ranged from 31% to 80%, with the lowest proportion in subjects 2 to <7 years receiving 12 mg/kg/day BID (AG2/DC1) and the highest proportion in subjects 7 to <18 years receiving 18 mg/kg/day TID (AG1/DC3). At all three dose levels (12 mg/kg/day BID, 18 mg/kg/day BID and 18 mg/kg/day TID), subjects in AG1 (7 to <18 years old) had higher mean PK exposures at steady state than those in AG2. High variability in exposures was observed in all groups. POS oral suspension was generally well tolerated and most of the reported adverse events were related to the subjects’ underlying diseases.
Conclusion: The POS PK target of 90% of subjects with Cavg between 500 and 2500 ng/mL was not achieved in any of the age groups across the different dosage cohorts. New formulations of the molecule with a greater potential to achieve the established PK target are currently under investigation.
Trial registration: ClinicalTrials.gov identifier: NCT01716234
Purpose: To review the role of radiotherapy (RT) in the treatment of renal cell cancer (RCC) in the curative and palliative setting.
Content: Details related to the clinical outcomes of primary, preoperative, postoperative and palliative RT are discussed, along with a presentation of the established role of surgery and systemic therapy. An overview of data derived from mono- and multi-institutional trials is provided.
Conclusion: Radiotherapy has been shown to provide good symptom palliation and local control in RCC depending on the dose that can be delivered. There is emerging data suggesting that with the use of high-precision RT methods the indication spectrum of RT can be exploited covering different clinical situations particularly for unresectable local recurrences and oligometastatic disease.
The interdependence of selective cues during development of regulatory T cells (Treg cells) in the thymus and their suppressive function remains incompletely understood. Here, we analyzed this interdependence by taking advantage of highly dynamic changes in expression of microRNA 181 family members miR-181a-1 and miR-181b-1 (miR-181a/b-1) during late T-cell development with very high levels of expression during thymocyte selection, followed by massive down-regulation in the periphery. Loss of miR-181a/b-1 resulted in inefficient de novo generation of Treg cells in the thymus but simultaneously permitted homeostatic expansion in the periphery in the absence of competition. Modulation of T-cell receptor (TCR) signal strength in vivo indicated that miR-181a/b-1 controlled Treg-cell formation via establishing adequate signaling thresholds. Unexpectedly, miR-181a/b-1–deficient Treg cells displayed elevated suppressive capacity in vivo, in line with elevated levels of cytotoxic T-lymphocyte–associated 4 (CTLA-4) protein, but not mRNA, in thymic and peripheral Treg cells. Therefore, we propose that intrathymic miR-181a/b-1 controls development of Treg cells and imposes a developmental legacy on their peripheral function.
In the current study we compared the molecular signature of expanded mesenchymal stromal cells (MSCs) derived from selected CD271+ bone marrow mononuclear cells (CD271-MSCs) and MSCs derived from non-selected bone marrow mononuclear cells by plastic adherence (PA-MSCs). Transcriptome analysis demonstrated for the first time the upregulation of 115 and downregulation of 131 genes in CD271-MSCs. Functional enrichment analysis showed that the upregulated genes in CD271-MSCs are significantly enriched for extracellular matrix (tenascin XB, elastin, ABI family, member 3 (NESH) binding protein, carboxypeptidase Z, laminin alpha 2 and nephroblastoma overexpressed) and cell adhesion (CXCR7, GPNMB, MYBPH, SVEP1, ARHGAP6, TSPEAR, PIK3CG, ABL2 and NCAM1). CD271-MSCs expressed higher gene transcript levels that are involved in early osteogenesis/chondrogenesis/adipogenesis (ZNF145, FKBP5). In addition, increased transcript levels for early and late osteogenesis (DPT, OMD, ID4, CRYAB, SORT1), adipogenesis (CTNNB1, ZEB, LPL, FABP4, PDK4, ACDC), and chondrogenesis (CCN3/NOV, CCN4/WISP1, CCN5/WISP2 and ADAMTS-5) were detected. Interestingly, CD271-MSCs expressed increased levels of hematopoiesis associated genes (CXCL12, FLT3L, IL-3, TPO, KITL). Down-regulated genes in CD271-MSCs were associated with WNT and TGF-beta signaling, and cytokine/chemokine signaling pathways. In addition to their capacity to support hematopoiesis, these results suggest that CD271-MSCs may contain more osteo/chondro progenitors and/or feature a greater differentiation potential.
Application of blood flow restriction to optimize exercise countermeasures for human space flight
(2019)
In recent years there has been a strong increase in publications on blood flow restriction (BFR) training. In particular, the fact that this type of training requires only low resistance to induce muscle strength and mass gains, makes BFR training interesting for athletes and scientists alike. For the same reason this type of training is particularly interesting for astronauts working out in space. Lower resistance during training would have the advantage of reducing the risk of strain-induced injuries. Furthermore, strength training with lower resistances would have implications for the equipment required for training under microgravity conditions, as significantly lower resistances have to be provided by the training machines. Even though we are only about to understand the effects of blood flow restriction on exercise types other than low-intensity strength training, the available data indicate that BFR of leg muscles is also able to improve the training effects of walking or running at slow speeds. The underlying mechanisms of BFR-induced functional and structural adaptations are still unclear. An essential aspect seems to be the premature fatigue of Type-I muscle fibers, which requires premature recruitment of Type-II muscle fibers to maintain a given force output. Other theories assume that cell swelling, anabolic hormones, myokines and reactive oxygen species are involved in the mediation of BFR training-related effects. This review article is intended to summarize the main advantages and disadvantages, but also the potential risks of such training for astronauts.
We present a study of the elliptic flow and RAA of D and D¯ mesons in Au+Au collisions at FAIR energies. We propagate the charm quarks and the D mesons following a previously applied Langevin dynamics. The evolution of the background medium is modeled in two different ways: (I) we use the UrQMD hydrodynamics + Boltzmann transport hybrid approach including a phase transition to QGP and (II) with the coarse-graining approach employing also an equation of state with QGP. The latter approach has previously been used to describe di-lepton data at various energies very successfully. This comparison allows us to explore the effects of partial thermalization and viscous effects on the charm propagation. We explore the centrality dependencies of the collisions, the variation of the decoupling temperature and various hadronization parameters. We find that the initial partonic phase is responsible for the creation of most of the D/D¯ mesons elliptic flow and that the subsequent hadronic interactions seem to play only a minor role. This indicates that D/D¯ mesons elliptic flow is a smoking gun for a partonic phase at FAIR energies. However, the results suggest that the magnitude and the details of the elliptic flow strongly depend on the dynamics of the medium and on the hadronization procedure, which is related to the medium properties as well. Therefore, even at FAIR energies the charm quark might constitute a very useful tool to probe the quark–gluon plasma and investigate its physics.
Background: Electrochemical signals play an important role in cell communication and behavior. Electrically charged ions transported across cell membranes maintain an electrochemical imbalance that gives rise to bioelectric signaling, called membrane potential or Vmem. Vmem plays a key role in numerous inter- and intracellular functions that regulate cell behaviors like proliferation, differentiation and migration, all playing a critical role in embryonic development, healing, and regeneration.
Methods: With the goal of analyzing the changes in Vmem during cell proliferation and differentiation, here we used direct current electrical stimulation (EStim) to promote cell proliferation and differentiation and simultaneously tracked the corresponding changes in Vmem in adipose derived mesenchymal stem cells (AT-MSC).
Results: We found that EStim caused increased AT-MSC proliferation that corresponded to Vmem depolarization and increased osteogenic differentiation that corresponded to Vmem hyperpolarization. Taken together, this shows that Vmem changes associated with EStim induced cell proliferation and differentiation can be accurately tracked during these important cell functions. Using this tool to monitor Vmem changes associated with these important cell behaviors we hope to learn more about how these electrochemical cues regulate cell function with the ultimate goal of developing new EStim based treatments capable of controlling healing and regeneration.
Hypoxia poses a stress to cells and decreases mitochondrial respiration, in part by electron transport chain (ETC) complex reorganization. While metabolism under acute hypoxia is well characterized, alterations under chronic hypoxia largely remain unexplored. We followed oxygen consumption rates in THP-1 monocytes during acute (16 h) and chronic (72 h) hypoxia, compared to normoxia, to analyze the electron flows associated with glycolysis, glutamine, and fatty acid oxidation. Oxygen consumption under acute hypoxia predominantly demanded pyruvate, while under chronic hypoxia, fatty acid- and glutamine-oxidation dominated. Chronic hypoxia also elevated electron-transferring flavoproteins (ETF), and the knockdown of ETF–ubiquinone oxidoreductase lowered mitochondrial respiration under chronic hypoxia. Metabolomics revealed an increase in citrate under chronic hypoxia, which implied glutamine processing to α-ketoglutarate and citrate. Expression regulation of enzymes involved in this metabolic shunting corroborated this assumption. Moreover, the expression of acetyl-CoA carboxylase 1 increased, thus pointing to fatty acid synthesis under chronic hypoxia. Cells lacking complex I, which experienced a markedly impaired respiration under normoxia, also shifted their metabolism to fatty acid-dependent synthesis and usage. Taken together, we provide evidence that chronic hypoxia fuels the ETC via ETFs, increasing fatty acid production and consumption via the glutamine-citrate-fatty acid axis.
Application of the Luttinger theorem to the Kondo lattice YbRh2Si2 suggests that its large 4f-derived Fermi surface (FS) in the paramagnetic (PM) regime should be similar in shape and volume to that of the divalent local-moment antiferromagnet (AFM) EuRh2Si2 in its PM regime. Here we show by angle-resolved photoemission spectroscopy that paramagnetic EuRh2Si2 has a large FS essentially similar to the one seen in YbRh2Si2 down to 1 K. In EuRh2Si2 the onset of AFM order below 24.5 K induces an extensive fragmentation of the FS due to Brillouin zone folding, intersection and resulting hybridization of the Fermi-surface sheets. Our results on EuRh2Si2 indicate that the formation of the AFM state in YbRh2Si2 is very likely also connected with similar changes in the FS, which have to be taken into account in the controversial analysis and discussion of anomalies observed at the quantum critical point in this system.
Since Inhibitor of Apoptosis (IAP) proteins have been implicated in cellular adaptation to endoplasmic reticulum (ER) stress, we investigated the regulation of ER stress-induced apoptosis by small-molecule second mitochondria-derived activator of caspase (Smac) mimetics that antagonize IAP proteins. Here, we discover that Smac mimetic suppresses tunicamycin (TM)-induced apoptosis via resolution of the unfolded protein response (UPR) and ER stress. Smac mimetics such as BV6 selectively inhibit apoptosis triggered by pharmacological or genetic inhibition of protein N-glycosylation using TM or knockdown of DPAGT1, the enzyme that catalyzes the first step of protein N-glycosylation. In contrast, BV6 does not rescue cell death induced by other typical ER stressors (i.e., thapsigargin (TG), dithiothreitol, brefeldin A, bortezomib, or 2-deoxyglucose). The protection from TM-triggered apoptosis is found for structurally different Smac mimetics and for genetic knockdown of cellular IAP (cIAP) proteins in several cancer types, underlining the broader relevance. Interestingly, lectin microarray profiling reveals that BV6 counteracts TM-imposed inhibition of protein glycosylation. BV6 consistently abolishes TM-stimulated accumulation of ER stress markers such as glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) and reduces protein kinase RNA-like ER kinase (PERK) phosphorylation and X box-binding protein 1 (XBP1) splicing upon TM treatment. BV6-stimulated activation of nuclear factor-κB (NF-κB) contributes to the resolution of ER stress, since NF-κB inhibition by overexpression of dominant-negative IκBα superrepressor counteracts the suppression of TM-stimulated transcriptional activation of CHOP and GRP78 by BV6. Thus, our study is the first to show that Smac mimetic protects from TM-triggered apoptosis by resolving the UPR and ER stress. This provides new insights into the regulation of cellular stress responses by Smac mimetics.
Purpose: To analyze leg pain severity data from a randomized controlled trial (RCT) of lumbar disc surgery using integrated approaches that adjust pain scores collected at scheduled follow-up visits for confounding clinical events occurring between visits. Methods. Data were derived from an RCT of a bone-anchored annular closure device (ACD) following lumbar discectomy versus lumbar discectomy alone (Control) in patients with large postsurgical annular defects. Leg pain was recorded on a 0 to 100 scale at 6 weeks, 3 months, 6 months, 1 year, and 2 years of follow-up. Patients with pain reduction ≥20 points relative to baseline were considered responders. Unadjusted analyses utilized pain scores reported at follow-up visits. Since symptomatic reherniation signifies clinical failure of lumbar discectomy, integrated analyses adjusted pain scores following a symptomatic reherniation by baseline observation carried forward for continuous data or classification as nonresponders for categorical data.
Results: Among 550 patients (272 ACD, 278 Control), symptomatic reherniation occurred in 10.3% of ACD patients and in 21.9% of controls (p < 0.001) through 2 years. There was no difference in leg pain scores at the 2-year visit between ACD and controls (12 versus 14; p = 0.33) in unadjusted analyses, but statistically significant differences favoring ACD (19 versus 29; p < 0.001) in integrated analyses. Unadjusted nonresponder rates were 6.0% with ACD and 6.7% with controls (p = 0.89), but 15.7% and 27.8% (p = 0.001) in integrated analyses. The probability of nonresponse was 16.4% with ACD and 18.3% with controls (p = 0.51) in unadjusted analysis, and 23.7% and 31.2% (p = 0.04) in integrated analyses.
Conclusion: In an RCT of lumbar disc surgery, an integrated analysis of pain severity that adjusted for the confounding effects of clinical failures occurring between follow-up visits resulted in different conclusions compared to an unadjusted analysis of pain scores reported at follow-up visits only.
Music is an effective means of stress-reduction. However, to date there has been no systematic comparison between musical and language-based means of stress reduction in an ambulatory setting. Furthermore, although the aim for listening to music appears to play a role in its effect, this has not yet been investigated thoroughly. We compared musical means, language-based means like guided relaxation or self-enhancement exercises, and a combination of both with respect to their potential to reduce perceived stress. Furthermore, we investigated whether the aim one wants to achieve by listening to these means had an impact on their effect. We tested 64 participants (age: M = 40.09 years; 18 female) for 3–10 days during their everyday life using an app containing three means: musical means, language-based means, and a combination of both. For the music and the combination conditions participants were asked to select an aim: relaxation or activation. We measured perceived stress, relaxation, activation, and electrical skin resistance (ESR) as a marker of sympathetic nervous system (SNS) activity before and after using the app. Participants were instructed to use the app as often as desired. Overall, perceived stress was reduced after using the app, while perceived relaxation and activation were increased. There were no differences between the three means regarding their effect on perceived stress and relaxation, but music led to a greater increase in ESR and perceived activation compared to the other means. There was a decrease in ESR only for music. Moreover, perceived stress was reduced and perceived relaxation was increased to greater extent if the aim “relaxation” had been selected. Perceived activation, however, showed a larger increase if the aim had been “activation,” which was even more marked in the case of music listening. Our results indicate that all three means reduced perceived stress and promoted feelings of relaxation and activation. For enhancing feelings of activation music seems to be more effective than the other means, which was reflected in increased SNS activity as well. Furthermore, the choice of an aim plays an important role for the reduction of stress, and promotion of relaxation and activation.
Background: Transcatheter aortic valve replacement (TAVR) is a therapeutic option for patients with aortic valve stenosis at increased surgical risk. Telomeres are an established marker for cellular senescence and have served to evaluate cardiovascular diseases including severe aortic valve stenosis. In our study, we hypothesized that telomere length may be a predictor for outcome and associated with comorbidities in patients with TAVR.
Methods and results: We analyzed leucocyte telomere length from 155 patients who underwent TAVR and correlated the results with 1-year mortality and severe comorbidities. The cohort was subdivided into 3 groups according to telomere length. Although a trend for a positive correlation of telomere length with a lower EuroSCORE could be found, telomere length was not associated with survival, aortic valve opening area or cardiovascular comorbidities (peripheral, coronary or cerebrovascular disease). Interestingly, long telomeres were significantly correlated to a reduced left ventricular ejection fraction (LVEF).
Conclusion: In elderly patients with severe aortic valve stenosis, leucocyte telomere length did not predict post-procedural survival. The correlation between long telomere length and reduced LVEF in these patients deserves further attention.
Der Beitrag liest Hebbels Judith (1840) vor dem Hintergrund der politischen Ereignisse im postrevolutionären und postrestaurativen Europa, wobei das Interesse der imaginären Dimension der Politik gilt. Ausgehend von einer gespenstischen Hand im Theatertext und der jungfräulichen Titelfigur als Guillotine wiederholt das Drama die brutale Enthauptung, die Europa im ausgehenden 18. Jahrhundert erschütterte und eine kopflose Gemeinschaft hinterließ. Eine unheimliche Hand, die sich "aus der schwarzen Erde" ausstreckt, lässt den Theatertext zunächst nicht nur zwischen einer restaurativen und revolutionären Politik, sondern auch zwischen einer idealistisch-romantischen und realistischen Kunst oszillieren. Die dramatische Aufführungspraxis rechnet dabei zum einen mit der Romantik ab. Zum anderen lässt sich anhand von Modi des realistischen Darstellens auf der Theaterbühne beobachten, wie die restaurative Politik mit den Anfängen des realistischen Erzählens zusammenfällt.
Der Artikel schlägt vor, die Frage nach dem Berühren indirekt, d.h. ausgehend von einer Unhaltbarkeit der Unbetroffenheit aufzugreifen. In 'Schiffbruch mit Zuschauer' diskutiert Hans Blumenberg den Verlust der Zuschauerposition als einen rezeptionsgeschichtlichen Umschlagpunkt. Entscheidend hierfür sind die von Jacob Burckhardt beschriebenen Aporien der Geschichtsschreibung im "Revolutionszeitalter". Ein Blick auf Burckhardts Metaphernkonstellationen kann zeigen, dass die beschriebene "Krisis" die Logik der großen historischen Instanzen gerade unberührt lässt. Demgegenüber lässt sich mit Blumenbergs bereits 1979 angekündigter 'Theorie der Unbegrifflichkeit' eine Variante möglichen Distanzverlusts erschließen, die sich keinem hintergründigen Spiel historisch wirksamer Kräfte, sondern der immanenten – und darin keineswegs ahistorischen – Destruktion der Leistung des Begriffs verdankt. Unter dem Titel der Berührbarkeit wird die Wiederkehr des Sinnlichen zunächst als eine Krise methodischer Sicherungen reformulierbar.
Der Artikel arbeitet an Platons Gastmahl ein semantisches Netz rund um das Konzept des 'Berührens' heraus. Dabei bildet das Verb ἅπτομαι ein zentrales Relais, das zwischen dem vieldiskutierten 'philosophischen Gehalt' des Textes und der in ihrem performativen Beitrag meist unterschätzten Rahmenhandlung vermittelt. Im Nachvollzug der Konstellationen des Berührens zeigt sich, dass dem Berühren, als Berühren, nicht begrifflich beizukommen ist – es entzieht sich dem aneignenden Zugriff. Berühren ist eben nicht Begriff. Deshalb muss sich das Gastmahl der Berührung auf andere Weise nähern, nämlich berührend – wofür die narratologische Konstruktion des Textes von entscheidender Wichtigkeit ist. Er praktiziert Philo-Logie, d.h. nutzt die Macht der Worte, die genau daraus entsteht, dass sie in einer sehr präzisen Weise zwischen den Beteiligten aus einer konstitutiven Distanz heraus wirken.
Philologie der Hand
(2019)
Mit größter Selbstverständlichkeit spricht die Wissensgeschichte der Philologie von einer "Philologie des Ohrs" und einer "Philologie des Auges". Während sich die Ohrenphilologie in der Tradition des Phono(logo)zentrismus eingerichtet hat, beruft sich die Augenphilologie darauf, dass Literatur als Schrifttum zunächst optisch wahrgenommen werden müsse, bevor aus gesehenen Texten auch gelesene würden. Wie verkürzt beide Schulen argumentieren, zeigt sich nicht nur an Schriftsystemen, die den Tastsinn adressieren, oder an Sprachformen, die sich wesentlich auf die Handgeste stützen. Ein näherer Blick auf die Geschichte der Literatur enthüllt, dass die vermeintlich klare Aufteilung des philologischen Territoriums zwischen Akustik und Optik deutlich komplexer ist, denn die Dyade Auge-Ohr unterliegt permanenten Triangulierungen durch die Hand. Der Beitrag zeichnet diese Dreiecksbeziehungen mit ‚Blick‘ auf drei vernachlässigte Paradigmen der Moderne nach: Die Poetik der Geste, die Poetik des Werkzeugs und die Poetik der Berührung. Im Zentrum stehen dabei Konzepte des russischen Formalismus, der konstruktivistischen Produktionsliteratur, der symbolistischen Lautlehre und der futuristischen Haptologie.
Körper und ihre Sinneswahrnehmung gehören zu den Voraussetzungen von Literatur und, Philosophie; die Bestimmung ihrer Funktion zählt zugleich zu einer der schwierigsten und umstrittensten Aufgaben dieser Künste und Disziplinen. Der Komplex um das Berühren, zu dem Haptik, Taktilität und Gefühl, Motorik, Sensorik und Affektivität gleichermaßen gehören, ist in der Körper- und Sinnesgeschichte notorisch von Vernachlässigung bedroht, hat in den Kultur- und Medienwissenschaften aber zuletzt neue Aufmerksamkeit erfahren. Philologische Ansätze befinden sich derzeit noch am Rand dieser Debatten, obwohl ihre Begriffe und Verfahren sogar als besonders 'berührungsaffin' gelten können. Genaue philologische Lektüren bieten die Möglichkeit, das je singuläre Verhältnis von Affektion und Sinnlichkeit und die Bedeutung des Tastsinns im Zusammenspiel mit anderen Sinnen zu erfassen. Philologische Verfahren können das metaphorische Potenzial des Berührens ebenso ausloten wie sein Verhältnis zum 'Realen'. Die Beiträge dieses Bandes zur europäischen Literatur, aber auch zur Philosophie von der Antike bis ins späte 20. Jahrhundert untersuchen das Berühren als relationale Figur, in der poetische Gestaltung und Materialität, Bildlichkeit und Buchstäblichkeit, Begreifen und Ergreifen, Anschauung und Affizierung in Beziehung treten. Im Zentrum stehen Fragen nach dem Verhältnis von Gemeinschaft und Individualität, von Literatur und Philosophie sowie nach der Funktion von Ansteckungs- und Distanzierungsverfahren in diesen Zusammenhängen. Dabei geraten gerade auch Wahrnehmungsräume in den Blick, die zumeist unter dem Primat des Visuellen verhandelt wurden. In Re- und Gegenlektüren schlagen die Beiträge eine Ausweitung der Sinnesbezüge vor.
Paclitaxel is a frontline drug for the treatment of epithelial ovarian cancer (EOC). However, following paclitaxel-platinum based chemotherapy, tumor recurrence occurs in most ovarian cancer patients. Chromosomal instability (CIN) is a hallmark of cancer and represents genetic variation fueling tumor adaptation to cytotoxic effects of anticancer drugs. In this study, our Kaplan-Meier analysis including 263 ovarian cancer patients (stages I/II) revealed that high Polo-like kinase (PLK) 1 expression correlates with bad prognosis. To evaluate the role of PLK1 as potential cancer target within a combinatorial trial, we induced strong mitotic arrest in ovarian cancer cell lines by synergistically co-targeting microtubules (paclitaxel) and PLK1 (BI6727) followed by pharmaceutical inhibition of the Anaphase-Promoting Complex (APC/C) using proTAME. In short- and long-term experiments, this triple treatment strongly activated apoptosis in cell lines and primary ovarian cells derived from cancer patients. Mechanistically, BI6727/paclitaxel/proTAME stabilize Cyclin B1 and trigger mitotic arrest, which initiates mitochondrial apoptosis by inactivation of antiapoptotic BCL-2 family proteins, followed by activation of caspase-dependent effector pathways. This triple treatment prevented endoreduplication and reduced CIN, two mechanisms that are associated with aggressive tumors and the acquisition of drug resistance. This “two-punch strategy” (strong mitotic arrest followed by blocking mitotic exit) has important implications for developing paclitaxel-based combinatorial treatments in ovarian cancer.
Global response of diacylglycerol kinase towards substrate binding observed by 2D and 3D MAS NMR
(2019)
Escherichia coli diacylglycerol kinase (DGK) is an integral membrane protein, which catalyses the ATP-dependent phosphorylation of diacylglycerol (DAG) to phosphatic acid (PA). It is a unique trimeric enzyme, which does not share sequence homology with typical kinases. It exhibits a notable complexity in structure and function despite of its small size. Here, chemical shift assignment of wild-type DGK within lipid bilayers was carried out based on 3D MAS NMR, utilizing manual and automatic analysis protocols. Upon nucleotide binding, extensive chemical shift perturbations could be observed. These data provide evidence for a symmetric DGK trimer with all of its three active sites concurrently occupied. Additionally, we could detect that the nucleotide substrate induces a substantial conformational change, most likely directing DGK into its catalytic active form. Furthermore, functionally relevant interprotomer interactions are identified by DNP-enhanced MAS NMR in combination with site-directed mutagenesis and functional assays.
Background: The clinical presentation of gastroesophageal reflux disease (GERD) shows a large symptom variation also in different intensities among patients. As several studies have shown, there is a large overlap in the symptomatic spectrum between proven GERD and other disorders such as dyspepsia, functional heartburn and/or somatoform disorders.
Aim: To prospectively evaluate the GERD patients with and without somatoform disorders before and after laparoscopic antireflux surgery.
Methods: In a tertiary referral center for foregut surgery over a period of 3 years patients with GERD, qualifying for the indication of laparoscopic antireflux surgery, were investigated prospectively regarding their symptomatic spectrum in order to identify GERD and associated somatoform disorders. Assessment of symptoms was performed by an instrument for the evaluation of somatoform disorders [Somatoform Symptom Index (SSI) > 17]. Quality of life was evaluated by Gastrointestinal Quality of Life Index (GIQLI).
Results: In 123 patients an indication for laparoscopic antireflux surgery was established and in 43 patients further medical therapy was suggested. The portion of somatoform tendencies in the total patient population was 20.48% (34 patients). Patients with a positive SSI had a preoperative GIQLI of 77 (32-111). Patients with a normal SSI had a GIQLI of 105 (29-140) (P < 0.0001). In patients with GERD the quality of life could be normalized from preoperative reduced values of GIQLI 102 (47-140) to postoperative values of 117 (44-144). In patients with GERD and somatoform disorders, the GIQLI was improved from preoperative GIQLI 75 (47-111) to postoperative 95 (44-122) (P < 0.0043).
Conclusion: Patients with GERD and associated somatoform disorders have significantly worse levels of quality of life. The latter patients can also benefit from laparoscopic fundoplication, however they will not reach a normal level.
Global impact models represent process-level understanding of how natural and human systems may be affected by climate change. Their projections are used in integrated assessments of climate change. Here we test, for the first time, systematically across many important systems, how well such impact models capture the impacts of extreme climate conditions. Using the 2003 European heat wave and drought as a historical analogue for comparable events in the future, we find that a majority of models underestimate the extremeness of impacts in important sectors such as agriculture, terrestrial ecosystems, and heat-related human mortality, while impacts on water resources and hydropower are overestimated in some river basins; and the spread across models is often large. This has important implications for economic assessments of climate change impacts that rely on these models. It also means that societal risks from future extreme events may be greater than previously thought.
The TP53-induced glycolysis and apoptosis regulator (TIGAR) has been shown to decrease glycolysis, to activate the pentose phosphate pathway, and to provide protection against oxidative damage. Hypoxic regions are considered characteristic of glioblastoma and linked with resistance to current treatment strategies. Here, we established that LNT-229 glioma cell lines stably expressed shRNA constructs targeting TIGAR, and exposed them to hypoxia, irradiation and temozolomide. The disruption of TIGAR enhanced levels of reactive oxygen species and cell death under hypoxic conditions, as well as the effectiveness of irradiation and temozolomide. In addition, TIGAR was upregulated by HIF-1α. As a component of a complex network, TIGAR contributes to the metabolic adjustments that arise from either spontaneous or therapy-induced changes in tumor microenvironment.
Background: Here we examined myocardial microRNA (miRNA) expression profile in a sensory neuropathy model with cardiac diastolic dysfunction and aimed to identify key mRNA molecular targets of the differentially expressed miRNAs that may contribute to cardiac dysfunction. Methods: Male Wistar rats were treated with vehicle or capsaicin for 3 days to induce systemic sensory neuropathy. Seven days later, diastolic dysfunction was detected by echocardiography, and miRNAs were isolated from the whole ventricles. Results: Out of 711 known miRNAs measured by miRNA microarray, the expression of 257 miRNAs was detected in the heart. As compared to vehicle-treated hearts, miR-344b, miR-466b, miR-98, let-7a, miR-1, miR-206, and miR-34b were downregulated, while miR-181a was upregulated as validated also by quantitative real time polymerase chain reaction (qRT-PCR). By an in silico network analysis, we identified common mRNA targets (insulin-like growth factor 1 (IGF-1), solute carrier family 2 facilitated glucose transporter member 12 (SLC2a-12), eukaryotic translation initiation factor 4e (EIF-4e), and Unc-51 like autophagy activating kinase 2 (ULK-2)) targeted by at least three altered miRNAs. Predicted upregulation of these mRNA targets were validated by qRT-PCR. Conclusion: This is the first demonstration that sensory neuropathy affects cardiac miRNA expression network targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2, which may contribute to cardiac diastolic dysfunction. These results further support the need for unbiased omics approach followed by in silico prediction and validation of molecular targets to reveal novel pathomechanisms.
Introduction: Colorectal cancers (CRCs) deficient in the DNA mismatch repair protein MutL homolog 1 (MLH1) display distinct clinicopathological features and require a different therapeutic approach compared to CRCs with MLH1 proficiency. However, the molecular basis of this fundamental difference remains elusive. Here, we report that MLH1-deficient CRCs exhibit reduced levels of the cytoskeletal scaffolding protein non-erythroid spectrin αII (SPTAN1), and that tumor progression and metastasis of CRCs correlate with SPTAN1 levels.
Methods and results: To investigate the link between MLH1 and SPTAN1 in cancer progression, a cohort of 189 patients with CRC was analyzed by immunohistochemistry. Compared with the surrounding normal mucosa, SPTAN1 expression was reduced in MLH1-deficient CRCs, whereas MLH1-proficient CRCs showed a significant upregulation of SPTAN1. Overall, we identified a strong correlation between MLH1 status and SPTAN1 expression. When comparing TNM classification and SPTAN1 levels, we found higher SPTAN1 levels in stage I CRCs, while stages II to IV showed a gradual reduction of SPTAN1 expression. In addition, SPTAN1 expression was lower in metastatic compared with non-metastatic CRCs. Knockdown of SPTAN1 in CRC cell lines demonstrated decreased cell viability, impaired cellular mobility and reduced cell-cell contact formation, indicating that SPTAN1 plays an important role in cell growth and cell attachment. The observed weakened cell-cell contact of SPTAN1 knockdown cells might indicate that tumor cells expressing low levels of SPTAN1 detach from their primary tumor and metastasize more easily.
Conclusion: Taken together, we demonstrate that MLH1 deficiency, low SPTAN1 expression, and tumor progression and metastasis are in close relation. We conclude that SPTAN1 is a candidate molecule explaining the tumor progression and metastasis of MLH1-deficient CRCs. The detailed analysis of SPTAN1 is now mandatory to substantiate its relevance and its potential value as a candidate protein for targeted therapy, and as a predictive marker of cancer aggressiveness.
A world dataset on the geographic distributions of Solenidae razor clams (Mollusca: Bivalvia)
(2019)
Background: Using this dataset, we examined the global geographical distributions of Solenidae species in relation to their endemicity, species richness and latitudinal ranges and then predicted their distributions under future climate change using species distribution modelling techniques (Saeedi et al. 2016a, Saeedi et al. 2016b). We found that the global latitudinal species richness in Solenidae is bi-modal, dipping at the equator most likely derived by high sea surface temperature (Saeedi et al. 2016b). We also found that most of the Solenidae species will shift their distribution ranges polewards due to global warming (Saeedi et al. 2016a). We also provided a comprehensive review of the taxon to test whether the latitudinal gradient in species richness was uni-modal with a peak in the tropics or northern hemisphere or asymmetric and bimodal as proposed previously (Chaudhary et al. 2016).
New information: This paper presents an integrated global geographic distribution dataset for 77 Solenidae taxa, including 3,034 geographic distribution records. This dataset was compiled after a careful data-collection and cleaning procedure over four years. Data were collected using field sampling, literature and from open-access databases. Then all the records went through quality control procedures such as validating the taxonomy of the species by examining and re-identifying the specimens in museum collections and using taxonomic and geographic data quality control tools in the World Register of Marine Species (WoRMS) and the r-OBIS package (Provoost and Bosch 2017). This dataset can thus be further used for taxonomical and biogeographical studies of Solenidae.
Background: Polyploidy and apomixis are important factors influencing plant distributions often resulting in range shifts, expansions and geographical parthenogenesis. We used the Ranunculus auricomus complex as a model to asses if the past and present distribution and climatic preferences were determined by these phenomena.
Results: Ecological differentiation among diploids and polyploids was tested by comparing the sets of climatic variables and distribution modelling using 191 novel ploidy estimations and 561 literature data. Significant differences in relative genome size on the diploid level were recorded between the “auricomus” and “cassubicus” groups and several new diploid occurrences were found in Slovenia and Hungary. The current distribution of diploids overlapped with the modelled paleodistribution (22 kyr BP), except Austria and the Carpathians, which are proposed to be colonized later on from refugia in the Balkans. Current and historical presence of diploids from the R. auricomus complex is suggested also for the foothills of the Caucasus. Based on comparisons of the climatic preferences polyploids from the R. auricomus complex occupy slightly drier and colder habitats than the diploids.
Conclusions: The change of reproductive mode and selection due to competition with the diploid ancestors may have facilitated the establishment of polyploids within the R. auricomus complex in environments slightly cooler and drier, than those tolerated by diploid ancestors. Much broader distribution of polyploid apomicts may have been achieved due to faster colonization mediated by uniparental reproductive system.
The arrangement of the contents of real-world scenes follows certain spatial rules that allow for extremely efficient visual exploration. What remains underexplored is the role different types of objects hold in a scene. In the current work, we seek to unveil an important building block of scenes—anchor objects. Anchors hold specific spatial predictions regarding the likely position of other objects in an environment. In a series of three eye tracking experiments we tested what role anchor objects occupy during visual search. In all of the experiments, participants searched through scenes for an object that was cued in the beginning of each trial. Critically, in half of the scenes a target relevant anchor was swapped for an irrelevant, albeit semantically consistent, object. We found that relevant anchor objects can guide visual search leading to faster reaction times, less scene coverage, and less time between fixating the anchor and the target. The choice of anchor objects was confirmed through an independent large image database, which allowed us to identify key attributes of anchors. Anchor objects seem to play a unique role in the spatial layout of scenes and need to be considered for understanding the efficiency of visual search in realistic stimuli.
Objectives: Combined electric-acoustic stimulation (EAS) is a well-accepted therapeutic treatment for cochlear implant (CI) users with residual hearing in the low frequencies but severe to profound hearing loss in the high frequencies. The recently introduced SONNETeas audio processor offers different microphone directionality (MD) settings and wind noise reduction (WNR) as front-end processing. The aim of this study was to compare speech perception in quiet and noise between two EAS audio processors DUET 2 and SONNETeas, to assess the impact of MD and WNR on speech perception in EAS users in the absence of wind. Furthermore, subjective rating of hearing performance was registered.
Method: Speech perception and subjective rating with SONNETeas or DUET 2 audio processor were assessed in 10 experienced EAS users. Speech perception was measured in quiet and in a diffuse noise setup (MSNF). The SONNETeas processor was tested with three MD settings omnidirectional/natural/adaptive and with different intensities of WNR. Subjective rating of auditory benefit and sound quality was rated using two questionnaires.
Results: There was no significant difference between DUET 2 and SONNETeas processor using the omnidirectional microphone in quiet and in noise. There was a significant improvement in SRT with MD settings natural (2.2 dB) and adaptive (3.6 dB). No detrimental effect of the WNR algorithm on speech perception was found in the absence of wind. Sound quality was rated as “moderate” for both audio processors.
Conclusions: The different MD settings of the SONNETeas can provide EAS users with better speech perception compared to an omnidirectional microphone. Concerning speech perception in quiet and quality of life, the performance of the DUET 2 and SONNETeas audio processors was comparable.
Acinetobacter baumannii is a Gram-negative pathogen that causes a multitude of nosocomial infections. The Acinetobacter trimeric autotransporter adhesin (Ata) belongs to the superfamily of trimeric autotransporter adhesins which are important virulence factors in many Gram-negative species. Phylogenetic profiling revealed that ata is present in 78% of all sequenced A. baumannii isolates but only in 2% of the closely related species A. calcoaceticus and A. pittii. Employing a markerless ata deletion mutant of A. baumannii ATCC 19606 we show that adhesion to and invasion into human endothelial and epithelial cells depend on Ata. Infection of primary human umbilical cord vein endothelial cells (HUVECs) with A. baumannii led to the secretion of interleukin (IL)-6 and IL-8 in a time- and Ata-dependent manner. Furthermore, infection of HUVECs by WT A. baumannii was associated with higher rates of apoptosis via activation of caspases-3 and caspase-7, but not necrosis, in comparison to ∆ata. Ata deletion mutants were furthermore attenuated in their ability to kill larvae of Galleria mellonella and to survive in larvae when injected at sublethal doses. This indicates that Ata is an important multifunctional virulence factor in A. baumannii that mediates adhesion and invasion, induces apoptosis and contributes to pathogenicity in vivo.
Heart valve disease is a major clinical problem worldwide. Cardiac valve development and homeostasis need to be precisely controlled. Hippo signaling is essential for organ development and tissue homeostasis, while its role in valve formation and morphology maintenance remains unknown. VGLL4 is a transcription cofactor in vertebrates and we found it was mainly expressed in valve interstitial cells at the post-EMT stage and was maintained till the adult stage. Tissue specific knockout of VGLL4 in different cell lineages revealed that only loss of VGLL4 in endothelial cell lineage led to valve malformation with expanded expression of YAP targets. We further semi-knockout YAP in VGLL4 ablated hearts, and found hyper proliferation of arterial valve interstitial cells was significantly constrained. These findings suggest that VGLL4 is important for valve development and manipulation of Hippo components would be a potential therapy for preventing the progression of congenital valve disease.
We report on the observation of coherent terahertz (THz) emission from the quasi-one-dimensional charge-density wave (CDW) system, blue bronze (K0.3MoO3), upon photo-excitation with ultrashort near-infrared optical pulses. The emission contains a broadband, low-frequency component due to the photo-Dember effect, which is present over the whole temperature range studied (30–300 K), as well as a narrow-band doublet centered at 1.5 THz, which is only observed in the CDW state and results from the generation of coherent transverse-optical phonons polarized perpendicular to the incommensurate CDW b-axis. As K0.3MoO3 is centrosymmetric, the lowest-order generation mechanism which can account for the polarization dependence of the phonon emission involves either a static surface field or quadrupolar terms due to the optical field gradients at the surface. This phonon signature is also present in the ground-state conductivity, and decays in strength with increasing temperature to vanish above $T\sim 100\,{\rm{K}}$, i.e. significantly below the CDW transition temperature. The temporal behavior of the phonon emission can be well described by a simple model with two coupled modes, which initially oscillate with opposite polarity.
Spheroids resemble features of tissues and serve as model systems to study cell–cell and cell–ECM interactions in non-adhesive three-dimensional environments. Although it is generally accepted that mature spheroids resemble tissue properties very well, no studies relate different phases in the spheroid formation processes that contribute to tissue integrity. Tissue integrity involves the cellular processes adhesion formation, adhesion reinforcement, rearrangement as well as proliferation. They maintain the structure and function of tissues and, upon dysregulation, contribute to malignancy. We investigated spheroid formation dynamics in cell lines of different metastatic potential. We dissected spheroid formation into phases of aggregation, compaction and growth to identify the respective contributions of E-cadherin, actin, microtubules and FAK. E-cadherin, actin and microtubules drive the first two phases. Microtubules and FAK are involved in the proliferation phase. FAK activity correlates with the metastatic potential of the cells. A robust computational model based on a very large number of experiments reveals the temporal resolution of cell adhesion. Our results provide novel hypotheses to unveil the general mechanisms that contribute to tissue integrity.
Background: Pulmonary nocardiosis (PN) is an uncommon but potentially life-threatening infection. Most of our knowledge is derived from case reports or smaller case series. Recently, increasing PN incidence rates have been reported. We aim to describe the clinical course of and risk factors for PN in four Western European countries and to estimate population-based annual hospitalization rates.
Methods: Retrospective evaluation (1995 to 2011) of the clinical course of and risk factors for PN in patients from 11 hospitals in four European countries (Germany, Austria, Switzerland and The Netherlands). Calculation of population-based estimates of hospitalization rates of PN in Germany (2005 to 2011) using official German nationwide diagnosis-related groups (DRG) hospital statistics.
Results: Forty-three patients fulfilled stringent criteria for proven (n = 8) and probable (n = 35) PN; seven with extrapulmonary dissemination. Within the 43 patients, major PN risk factors were immunocompromising (83.7%) and/or pulmonary (58.1%; in 27.9% as only comorbidity) comorbidities. Median duration of PN targeted therapy was 12 weeks. Distinguished patterns of resistance were observed (imipenem susceptibility: N. farcinica 33.3%; N. asteroides 66.7%). Overall mortality rate was 18.9%; in disseminated PN 50%. Over time, annual PN hospitalization rates remained unchanged at around 0.04/100′000 with the highest rate among men aged 75–84 years (0.24/100′000).
Conclusion: PN is rare, but potentially life-threatening, and mainly affects immunocompromised elder males. Overall annual hospitalization rates remained stable between 2005 and 2011.
Heat stress transcription factors (HSFs) regulate transcriptional response to a large number of environmental influences, such as temperature fluctuations and chemical compound applications. Plant HSFs represent a large and diverse gene family. The HSF members vary substantially both in gene expression patterns and molecular functions. HEATSTER is a web resource for mining, annotating, and analyzing members of the different classes of HSFs in plants. A web-interface allows the identification and class assignment of HSFs, intuitive searches in the database and visualization of conserved motifs, and domains to classify novel HSFs.
Objective: Inhaled particulate matter (PM) in secondhand smoke (SHS) is deleterious for smokers and non-smokers. Different additives in cigarettes might effect the amount of PM. This study aimed to assess the influence of additives on the PM emissions from different cigarette types in SHS.
Design: An experimental study of PM measuring in SHS of cigarettes without exposition of any person.
Method: The concentrations of PM (PM10, PM2.5 and PM1) in SHS of four different types of cigarettes of the brand Lucky Strike, two types with additives (Original Red, Original Blue) and two types without additives (Straight Red, Straight Blue), in comparison to the reference cigarette 3R4F were analysed. An automatic environmental tobacco smoke emitter generated SHS in an enclosed space with a volume of 2.88 m3. PM was measured with a laser aerosol spectrometer (Grimm model 1.109). Afterwards, the measuring values of the four Lucky Strike brands and the reference cigarette were statistically evaluated and visualised.
Results: Lucky Strike Straight Blue, a cigarette type without additives and lower tar amount, showed 10% to 25% lower PM mean values compared with the other tested Lucky Strike products, but 21% (PM1) respectively 27% (PM2.5,PM10) higher mean values than the reference cigarette. The PM mean of all measured smoke-free baseline values (clean air) was 1.6 µg/m³. It increased up to about 1800 µg/m³ for the reference cigarette and up to about 3070 µg/m³ for the Lucky Strike Original Blue.
Conclusions: The findings of this study show the massive increase of PM amount by smoking cigarettes in enclosed spaces and suggest that additives in tobacco products increase the PM amount in SHS. For validation, further comparative studies are necessary focusing on the comparison of the PM concentration of cigarettes with and without additives.
Implications: Due to the exposure to SHS, 890 000 people die each year worldwide. PM in SHS endangers the health of both non-smokers and smokers. This study considers the effect of additives like aromatics and humectant agents in cigarettes on PM in SHS. Do additives in tobacco products increase the amount of PM?
By running a temperature series of molecular dynamics (MD) simulations starting from the known low-temperature phase, the experimentally observed phase transition in a `jumping crystal' was captured, thereby providing a prediction of the unknown crystal structure of the high-temperature phase and clarifying the phase-transition mechanism. The phase transition is accompanied by a discontinuity in two of the unit-cell parameters. The structure of the high-temperature phase is very similar to that of the low-temperature phase. The anisotropic displacement parameters calculated from the MD simulations readily identified libration as the driving force behind the phase transition. Both the predicted crystal structure and the phase-transition mechanism were verified experimentally using TLS (translation, libration, screw) refinement against X-ray powder diffraction data.
Feathers are arranged in a precise pattern in avian skin. They first arise during development in a row along the dorsal midline, with rows of new feather buds added sequentially in a spreading wave. We show that the patterning of feathers relies on coupled fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) signalling together with mesenchymal cell movement, acting in a coordinated reaction-diffusion-taxis system. This periodic patterning system is partly mechanochemical, with mechanical-chemical integration occurring through a positive feedback loop centred on FGF20, which induces cell aggregation, mechanically compressing the epidermis to rapidly intensify FGF20 expression. The travelling wave of feather formation is imposed by expanding expression of Ectodysplasin A (EDA), which initiates the expression of FGF20. The EDA wave spreads across a mesenchymal cell density gradient, triggering pattern formation by lowering the threshold of mesenchymal cells required to begin to form a feather bud. These waves, and the precise arrangement of feather primordia, are lost in the flightless emu and ostrich, though via different developmental routes. The ostrich retains the tract arrangement characteristic of birds in general but lays down feather primordia without a wave, akin to the process of hair follicle formation in mammalian embryos. The embryonic emu skin lacks sufficient cells to enact feather formation, causing failure of tract formation, and instead the entire skin gains feather primordia through a later process. This work shows that a reaction-diffusion-taxis system, integrated with mechanical processes, generates the feather array. In flighted birds, the key role of the EDA/Ectodysplasin A receptor (EDAR) pathway in vertebrate skin patterning has been recast to activate this process in a quasi-1-dimensional manner, imposing highly ordered pattern formation.
Increasing atmospheric CO2 stimulates photosynthesis which can increase net primary production (NPP), but at longer timescales may not necessarily increase plant biomass. Here we analyse the four decade-long CO2-enrichment experiments in woody ecosystems that measured total NPP and biomass. CO2 enrichment increased biomass increment by 1.05 ± 0.26 kg C m−2 over a full decade, a 29.1 ± 11.7% stimulation of biomass gain in these early-secondary-succession temperate ecosystems. This response is predictable by combining the CO2 response of NPP (0.16 ± 0.03 kg C m−2 y−1) and the CO2-independent, linear slope between biomass increment and cumulative NPP (0.55 ± 0.17). An ensemble of terrestrial ecosystem models fail to predict both terms correctly. Allocation to wood was a driver of across-site, and across-model, response variability and together with CO2-independence of biomass retention highlights the value of understanding drivers of wood allocation under ambient conditions to correctly interpret and predict CO2 responses.
Golgi phosphoprotein 3 (GOLPH3) is a conserved protein of the Golgi apparatus that in humans has been implicated in tumorigenesis. However, the precise function of GOLPH3 in malignant transformation is still unknown. Nevertheless, clinicopathological data shows that in more than a dozen kinds of cancer, including gliomas, GOLPH3 could be found overexpressed, which correlates with poor prognosis. Experimental data shows that overexpression of GOLPH3 leads to transformation of primary cells and to tumor growth enhancement. Conversely, the knocking down of GOLPH3 in GOLPH3-overexpressing tumor cells reduces tumorigenic features, such as cell proliferation and cell migration and invasion. The cumulative evidence indicate that GOLPH3 is an oncoprotein that promotes tumorigenicity by a mechanism that impact at different levels in different types of cells, including the sorting of Golgi glycosyltransferases, signaling pathways, and the actin cytoskeleton. How GOLPH3 connects mechanistically these processes has not been determined yet. Further studies are important to have a more complete understanding of the role of GOLPH3 as oncoprotein. Given the genetic diversity in cancer, a still outstanding aspect is how in this inherent heterogeneity GOLPH3 could possibly exert its oncogenic function. We have aimed to evaluate the contribution of GOLPH3 overexpression in the malignant phenotype of different types of tumor cells. Here, we analyzed the effect on cell migration that resulted from stable, RNAi-mediated knocking down of GOLPH3 in T98G cells of glioblastoma multiforme, a human glioma cell line with unique features. We found that the reduction of GOLPH3 levels produced dramatic changes in cell morphology, involving rearrangements of the actin cytoskeleton and reduction in the number and dynamics of focal adhesions. These effects correlated with decreased cell migration and invasion due to affected persistence and directionality of cell motility. Moreover, the knocking down of GOLPH3 also caused a reduction in autoactivation of focal adhesion kinase (FAK), a cytoplasmic tyrosine kinase that regulates focal adhesions. Our data support a model in which GOLPH3 in T98G cells promotes cell migration by stimulating the activity of FAK.
The trade in bear parts for medicine and for status is a conservation challenge throughout Asia. The Asiatic black bear (Ursus thibetanus) and the sun bear (Helarctos malayanus) are endemic to this region, and populations are estimated to have declined throughout their ranges due to widespread illegal killing of bears and trade in parts, combined with loss of habitat. Previous studies have indicated that legislation alone is insufficient to prevent illegal hunting and trade, indicating instead a need to address demand for bear parts and products. We conducted mixed-method surveys in Cambodia to understand the key motivators for individuals to consume bear parts, and to understand whether specialised questioning techniques are applicable in this context. Bear part use is illegal in Cambodia and may therefore be considered a sensitive behaviour, in that individuals may be reluctant to admit to it. To counteract possible biases, four specialised questioning techniques were used in this study: randomised response technique (RRT), unmatched count technique (UCT), nominative technique (NT), and false consensus bias (FCB). All four methods serve to shield a respondent’s admittance of a sensitive behaviour from the interviewer. The results presented here show that great variability exists in anonymous methods’ efficacy in certain contexts. However, the results overall indicate that individuals in Cambodia are under-reporting their consumption of bear parts when directly asked, and that the prevalence of bear part use in Cambodia may be as high as 15% of the population, representing a significant conservation challenge.
The hepatitis C virus (HCV) RNA replication cycle is a dynamic intracellular process occurring in three-dimensional space (3D), which is difficult both to capture experimentally and to visualize conceptually. HCV-generated replication factories are housed within virus-induced intracellular structures termed membranous webs (MW), which are derived from the Endoplasmatic Reticulum (ER). Recently, we published 3D spatiotemporal resolved diffusion–reaction models of the HCV RNA replication cycle by means of surface partial differential equation (sPDE) descriptions. We distinguished between the basic components of the HCV RNA replication cycle, namely HCV RNA, non-structural viral proteins (NSPs), and a host factor. In particular, we evaluated the sPDE models upon realistic reconstructed intracellular compartments (ER/MW). In this paper, we propose a significant extension of the model based upon two additional parameters: different aggregate states of HCV RNA and NSPs, and population dynamics inspired diffusion and reaction coefficients instead of multilinear ones. The combination of both aspects enables realistic modeling of viral replication at all scales. Specifically, we describe a replication complex state consisting of HCV RNA together with a defined amount of NSPs. As a result of the combination of spatial resolution and different aggregate states, the new model mimics a cis requirement for HCV RNA replication. We used heuristic parameters for our simulations, which were run only on a subsection of the ER. Nevertheless, this was sufficient to allow the fitting of core aspects of virus reproduction, at least qualitatively. Our findings should help stimulate new model approaches and experimental directions for virology.