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„Die eiserne Maske der Freiheit“: Hans Magnus Enzensberger and Karl Marx During the 1960s and 1970s the poetic reception of Karl Marx begins to increase in Germany. In this regard, it can be observed that Hans Magnus Enzensberger’s poetic and essayistic reception of Marx is not only quite complex, but also unorthodox. By focusing on the anthology „Gespräche mit Marx und Engels,“ edited by Enzensberger, his comedy „Der Untergang der Titanic“ and his poem „Karl Heinrich Marx,“ the diverse forms of reference to this philosopher are analyzed. It can be demonstrated that Enzensberger uses the montage technique masterly to avoid one-dimensional confessions.

Background Bintrafusp alfa, a first-in-class bifunctional fusion protein targeting transforming growth factor-β (TGF-β) and programmed cell death ligand 1, has demonstrated encouraging efficacy as second-line treatment in patients with non-small cell lung cancer (NSCLC) in a dose expansion cohort of the phase 1, open-label clinical trial (NCT02517398). Here, we report the safety, efficacy, and biomarker analysis of bintrafusp alfa in a second expansion cohort of the same trial (biomarker cohort).Methods Patients with stage IIIb/IV NSCLC who were either immune checkpoint inhibitor (ICI)-naïve (n=18) or ICI-experienced (n=23) were enrolled. The primary endpoint was the best overall response. Paired biopsies (n=9/41) and peripheral blood (n=14/41) pretreatment and on-treatment were studied to determine the immunological effects of treatment and for associations with clinical activity.Results Per independent review committee assessment, objective responses were observed in the ICI-naïve group (overall response rate, 27.8%). No new or unexpected safety signals were identified. Circulating TGF-β levels were reduced (>97%; p

The combination of computer vision with deep learning has become a popular tool for automation of labor-intensive monitoring tasks in modern livestock farming. However, uncontrolled and varying environmental conditions, which usually prevail in farmhouses, influence the performance of vision-based applications. Image quality can be reduced, for instance by occlusions, illumination or motions of the animals, which can influence the reliability of those applications. To address this issue, this study proposes an approach for the identification of uncertain neural-network predictions to improve the overall prediction quality. It proposes the direct quantification of aleatoric and epistemic uncertainty on the one hand and indirect estimation of uncertainty through the prediction of occlusions on the other hand. Our approach simultaneously integrates the different methods into an end-to-end trainable instance segmentation and regression model. The objective of this study was to first investigate how well the different measures can quantify the uncertainty of a prediction by comparing them to human uncertainty assessments. Then, it was analyzed whether the uncertainty estimations are capable to identify and reject erroneous predictions by evaluating the correlation between the predictive error and the uncertainty estimations. Finally, individual predictions were rejected based on the estimated uncertainties to analyze the effect on the overall accuracy. As a use-case, the developed methods were applied to the prediction of plumage conditions of chickens but also examined in a separate domain. The results showed that the outputs of our approaches for the estimation of aleatoric and epistemic uncertainty correlate to the predictive error of the model, and lead to increased performance when uncertain predictions are rejected. In contrast, the indirect method to identify occluded samples did not serve as a reliable indicator for uncertainty and could therefore not be used to improve the accuracy of the model outputs.

Abstract Background One barrier to hand hygiene compliance is overestimation of one’s own performance. Overconfidence research shows that overestimation tends to be higher for difficult tasks, which suggests that the magnitude of overestimation also depends on how it is assessed. Thus, we tested the hypothesis that overestimation was stronger for hand hygiene indications with low compliance (i.e., high difficulty), and the hypothesis that self-reported overall compliance based on a single item is higher than based on “5 Moments of Hand Hygiene” (WHO-5) items, since the single item implies an aggregation across indications. Methods In the WACH trial (German Clinical Trials Register [DRKS] ID: DRKS00015502), a questionnaire survey was conducted among physicians and nurses in nine surgical clinics (general/visceral surgery or orthopedics/trauma surgery) of six German hospitals. Self-reported compliance was assessed both by a single item and the WHO-5-items using percentage scales. These were compared with each other and with direct observations. Relative frequencies of the WHO-5 indications used to calculate the WHO-5-based self-reported overall compliance rate were estimated by a systematized review of the literature (see appendix). In analysis, t-tests, Chi2-tests and multiple linear regressions were used. Results Ninety-three physicians (response rate: 28.4%) and 225 nurses (30.4%) participated. Significant compliance differences between physicians and nurses were found for direct observations and were in favor of nurses, while no such differences were found for self-reports. Across the WHO-5, overestimation showed inverse correlations with observed compliance (physicians: r = −0.88, p = 0.049; nurses: r = −0.81, p = 0.093). Support for the hypothesis that the self-reported overall compliance based on one item is higher than that based on WHO-5 items was found for physicians (M = 87.2 vs. 84.1%, p = 0.041; nurses: 84.4 vs. 85.5%, p = 0.296). Exploratory analyses showed that this effect was confined to orthopedic/trauma surgeons (89.9 vs. 81.7%, p = 0.006). Conclusion Among physicians, results indicate stronger hand hygiene overestimation for low-compliance indications, and when measurements are based on a single item versus the five WHO-5 items. For practice, results contribute to infection prevention and control’s understanding of overestimation as a psychological mechanism that is relevant to professional hand hygiene.

Abstract Background Structured and harmonized implementation of molecular tumor boards (MTB) for the clinical interpretation of molecular data presents a current challenge for precision oncology. Heterogeneity in the interpretation of molecular data was shown for patients even with a limited number of molecular alterations. Integration of high-dimensional molecular data, including RNA- (RNA-Seq) and whole-exome sequencing (WES), is expected to further complicate clinical application. To analyze challenges for MTB harmonization based on complex molecular datasets, we retrospectively compared clinical interpretation of WES and RNA-Seq data by two independent molecular tumor boards. Methods High-dimensional molecular cancer profiling including WES and RNA-Seq was performed for patients with advanced solid tumors, no available standard therapy, ECOG performance status of 0–1, and available fresh-frozen tissue within the DKTK-MASTER Program from 2016 to 2018. Identical molecular profiling data of 40 patients were independently discussed by two molecular tumor boards (MTB) after prior annotation by specialized physicians, following independent, but similar workflows. Identified biomarkers and resulting treatment options were compared between the MTBs and patients were followed up clinically. Results A median of 309 molecular aberrations from WES and RNA-Seq (n = 38) and 82 molecular aberrations from WES only (n = 3) were considered for clinical interpretation for 40 patients (one patient sequenced twice). A median of 3 and 2 targeted treatment options were identified per patient, respectively. Most treatment options were identified for receptor tyrosine kinase, PARP, and mTOR inhibitors, as well as immunotherapy. The mean overlap coefficient between both MTB was 66%. Highest agreement rates were observed with the interpretation of single nucleotide variants, clinical evidence levels 1 and 2, and monotherapy whereas the interpretation of gene expression changes, preclinical evidence levels 3 and 4, and combination therapy yielded lower agreement rates. Patients receiving treatment following concordant MTB recommendations had significantly longer overall survival than patients receiving treatment following discrepant recommendations or physician’s choice. Conclusions Reproducible clinical interpretation of high-dimensional molecular data is feasible and agreement rates are encouraging, when compared to previous reports. The interpretation of molecular aberrations beyond single nucleotide variants and preclinically validated biomarkers as well as combination therapies were identified as additional difficulties for ongoing harmonization efforts.

Antarctic sea ice plays a critical role in the Earth system, influencing energy, heat and freshwater fluxes, air–sea gas exchange, ice shelf dynamics, ocean circulation, nutrient cycling, marine productivity and global carbon cycling. However, accurate simulation of recent sea-ice changes remains challenging and, therefore, projecting future sea-ice changes and their influence on the global climate system is uncertain. Reconstructing past changes in sea-ice cover can provide additional insights into climate feedbacks within the Earth system at different timescales. This paper is the first of two review papers from the Cycles of Sea Ice Dynamics in the Earth system (C-SIDE) working group. In this first paper, we review marine- and ice core-based sea-ice proxies and reconstructions of sea-ice changes throughout the last glacial–interglacial cycle. Antarctic sea-ice reconstructions rely mainly on diatom fossil assemblages and highly branched isoprenoid (HBI) alkenes in marine sediments, supported by chemical proxies in Antarctic ice cores. Most reconstructions for the Last Glacial Maximum (LGM) suggest that winter sea ice expanded all around Antarctica and covered almost twice its modern surface extent. In contrast, LGM summer sea ice expanded mainly in the regions off the Weddell and Ross seas. The difference between winter and summer sea ice during the LGM led to a larger seasonal cycle than today. More recent efforts have focused on reconstructing Antarctic sea ice during warm periods, such as the Holocene and the Last Interglacial (LIG), which may serve as an analogue for the future. Notwithstanding regional heterogeneities, existing reconstructions suggest that sea-ice cover increased from the warm mid-Holocene to the colder Late Holocene with pervasive decadal- to millennial-scale variability throughout the Holocene. Studies, supported by proxy modelling experiments, suggest that sea-ice cover was halved during the warmer LIG when global average temperatures were ∼2 ∘C above the pre-industrial (PI). There are limited marine (14) and ice core (4) sea-ice proxy records covering the complete 130 000 year (130 ka) last glacial cycle. The glacial–interglacial pattern of sea-ice advance and retreat appears relatively similar in each basin of the Southern Ocean. Rapid retreat of sea ice occurred during Terminations II and I while the expansion of sea ice during the last glaciation appears more gradual especially in ice core data sets. Marine records suggest that the first prominent expansion occurred during Marine Isotope Stage (MIS) 4 and that sea ice reached maximum extent during MIS 2. We, however, note that additional sea-ice records and transient model simulations are required to better identify the underlying drivers and feedbacks of Antarctic sea-ice changes over the last 130 ka. This understanding is critical to improve future predictions.

At the onset of COVID-19, many Local Government Areas (LGAs) indicated they were struggling to communicate effectively with multilingual migrant communities. Communities were isolated from vital LGA support due to factors including the digital divide, barriers to language access, and top-down communication strategies. The pandemic also provided insights into the ways migrant communities mitigate hardship by engaging in placemaking and place-shaping, using existing networks and resources to provide vital support during crisis, which requires significant invisible labour. In this article, we present three case studies from a larger community-based project which began in early 2020 with an LGA in Western Australia. We use case narratives to illustrate and analyse three common actions migrant women used to engage their communities prior to, and during, COVID-19 recovery. These simple, yet profound actions, which include visiting communities, acknowledging challenges, and identifying opportunities further evidence the ways community leaders facilitate culturally sustaining placemaking, even during crisis; they underscore the intense emotional, cultural, and linguistic labour required to enact support in contexts where resources are inaccessible or misaligned with community stories. We argue it is only in partnership with communities that LGAs can learn to address some of the long-standing issues COVID-19 highlights. [ABSTRACT FROM AUTHOR]

Abstract Telomerases elongate the ends of chromosomes required for cell immortality through their reverse transcriptase activity. By using the model organism Saccharomyces cerevisiae we defined the order in which the holoenzyme matures. First, a longer precursor of the telomerase RNA, TLC1 is transcribed and exported into the cytoplasm, where it associates with the protecting Sm-ring, the Est and the Pop proteins. This partly matured telomerase is re-imported into the nucleus via Mtr10 and a novel TLC1-import factor, the karyopherin Cse1. Remarkably, while mutations in all known transport factors result in short telomere ends, mutation in CSE1 leads to the amplification of Y′ elements in the terminal chromosome regions and thus elongated telomere ends. Cse1 does not only support TLC1 import, but also the Sm-ring stabilization on the RNA enableling Mtr10 contact and nuclear import. Thus, Sm-ring formation and import factor contact resembles a quality control step in the maturation process of the telomerase. The re-imported immature TLC1 is finally trimmed into the 1158 nucleotides long mature form via the nuclear exosome. TMG-capping of TLC1 finalizes maturation, leading to mature telomerase.

The importance of Antarctic sea ice and Southern Ocean warming has come into the focus of polar research during the last couple of decades. Especially around West Antarctica, where warm water masses approach the continent and where sea ice has declined, the distribution and evolution of sea ice play a critical role in the stability of nearby ice shelves. Organic geochemical analyses of marine seafloor surface sediments from the Antarctic continental margin allow an evaluation of the applicability of biomarker-based sea-ice and ocean temperature reconstructions in these climate-sensitive areas. We analysed highly branched isoprenoids (HBIs), such as the sea-ice proxy IPSO25 and phytoplankton-derived HBI-trienes, as well as phytosterols and isoprenoidal glycerol dialkyl glycerol tetraethers (GDGTs), which are established tools for the assessment of primary productivity and ocean temperatures respectively. The combination of IPSO25 with a phytoplankton marker (i.e. the PIPSO25 index) permits semi-quantitative sea-ice reconstructions and avoids misleading over- or underestimations of sea-ice cover. Comparisons of the PIPSO25-based sea-ice distribution patterns and TEX86L- and RI-OH′-derived ocean temperatures with (1) sea-ice concentrations obtained from satellite observations and (2) instrument measurements of sea surface and subsurface temperatures corroborate the general capability of these proxies to determine oceanic key variables properly. This is further supported by model data. We also highlight specific aspects and limitations that need to be taken into account for the interpretation of such biomarker data and discuss the potential of IPSO25 as an indicator for the former occurrence of platelet ice and/or the export of ice-shelf water.

Plasmablastic lymphoma (PBL) is an aggressive lymphoma subtype characterized by poor prognosis but the molecular knowledge of the disease is limited. Here, the authors perform whole exome sequencing and copy number determination of primary samples highlighting IRF4 and JAK-STAT pathways as therapeutic targets for PBL.

OBJECTIVES:. Mechanical power (MP) is a way of estimating the energy delivered by the ventilator to the patient. For both volume-controlled ventilation (VCV) and pressure-controlled ventilation (PCV) methods have been described to calculate the MP. The pressure-volume (PV) loop, from which the MP is calculated, is different for VCV compared with PCV. We aimed to compare the MP of VCV with zero pause time (VCV-0), VCV with 10% pause time (VCV-10), and PCV within patients in different patient categories based on severity of lung injury. DESIGN:. In a proof-of-concept study, we enrolled 46 mechanically ventilated patients without spontaneous breathing efforts. Baseline measurements were done in pressure-controlled mode. Subsequently, measurements were done in VCV-0 and VCV-10. Tidal volume and all other settings were kept the same. SETTING:. ICU, single university medical center. PATIENTS:. Fifty-eight cases in 46 patients on controlled ventilation modes. INTERVENTIONS:. Comparison between the MP of PCV, VCV-0, and VCV-10. MEASUREMENT AND MAIN RESULTS:. The mean MP of VCV-0, VCV-10, and PCV was 19.30, 21.80, and 20.87 J/min, respectively (p < 0.05 for all comparisons). The transpulmonary MP of VCV-0, VCV-10, and PCV was 6.75, 8.60, and 7.99 J/min, respectively (p < 0.05 for all comparisons). CONCLUSIONS:. In patients ventilated in a controlled mode, VCV without pause time had the lowest MP followed by PCV. VCV with 10% pause time had the highest MP.

Active bone-conducting hearing devices (aBCHD; e.g., MEDEL Bonebridge® (BB)) and active middle ear implants (aMEI; e.g., MEDEL Vibrant Soundbridge® (VSB)) use radio frequency transmission to send information from an external microphone and sound processor to an internally implanted transducer. These devices potentially have an advantage over devices with percutaneous links because the skin is closed over the implantable components, which should reduce the risk of skin problems and infection. On the other hand, surgical procedures are more complex, with a greater risk of damage due to surgery. The objectives of this research were to quantify the reliability and long-term survival of MEDEL VSB and BB devices, determine the adverse and serious adverse device-related complications, and consider associated causes. A multi-center observational retrospective and prospective study was conducted at eleven auditory implant centers in the United Kingdom. Data was collected using a surgical questionnaire and audiological reports. Data were obtained from patient notes or from prospective cases that had a minimum follow-up of one year post-implant. Consecutive patient records were reviewed. Datasets from 109 BB and 163 VSB were reviewed. Of these, 205 were retrospective case note reviews, and 67 were prospective cases. The mean follow-up was 4 and 6 years, respectively, for BB and VSB. Kaplan–Meier Survival analyses indicated that the BB survival was 97% and 93.3% at 1 and 5 years, respectively, and the VSB was 92.1% and 87% at the same time points. This is a large cohort study for the field and has indicated that BB and VSB are safe interventions. Care should be taken to monitor magnet strength in the first few months. For the majority of device-related effects, there was no apparent association with etiology. However, an interesting pattern emerged for individuals who exhibited an inflammatory response, e.g., adhesions or device extrusion, and those with a history of chronic suppurative otitis media. This should be considered in future work and is not surprising given that many VSB recipients have a complicated hearing history, often associated with otitis media.

Background Sex‐specific differences in vasodilation are mediated in part by differences in cytosolic Ca2+ handling, but how variations in mitochondrial Ca2+ contributes to this effect remains unknown. Here, we investigated the extent to which mitochondrial Ca2+ entry via the MCU (mitochondrial Ca2+ uniporter) drives sex differences in vasoreactivity in resistance arteries. Methods and Results Enhanced vasodilation of mesenteric resistance arteries to acetylcholine (ACh) was reduced to larger extent in female compared with male mice in 2 genetic models of endothelial MCU ablation. Ex vivo Ca2+ imaging of mesenteric arteries with Fura‐2AM confirmed higher cytosolic Ca2+ transients triggered by ACh in arteries from female mice versus male mice. MCU inhibition both strongly reduced cytosolic Ca2+ transients and blocked mitochondrial Ca2+ entry. In cultured human aortic endothelial cells, treatment with physiological concentrations of estradiol enhanced cytosolic Ca2+ transients, Ca2+ buffering capacity, and mitochondrial Ca2+ entry in response to ATP or repeat Ca2+ boluses. Further experiments to establish the mechanisms underlying these effects did not reveal significant differences in the expression of MCU subunits, at either the mRNA or protein level. However, estradiol treatment was associated with an increase in mitochondrial mass, mitochondrial fusion, and the mitochondrial membrane potential and reduced mitochondrial superoxide production. Conclusions Our data confirm that mitochondrial function in endothelial cells differs by sex, with female mice having enhanced Ca2+ uptake capacity, and that these differences are attributable to the presence of more mitochondria and a higher mitochondrial membrane potential in female mice rather than differences in composition of the MCU complex.

The design of many pneumatic soft actuators is based on multiple chambers in parallel alignment. The Cosserat beam theory is an established technique for modeling this kind of actuator, where existing approaches mainly differ in the parameters being required for simulation. The modeling approach presented in this study particularly aims at finding the beam parameters necessary for a simulation even with limited experimental methods. Importantly, it provides a straightforward relationship between the bending stiffness, the extensional stiffness and the axial stretch of the actuator. If the actuator to be modeled has an elementary design, axial measurements are sufficient to identify the parameters to perform three-dimensional simulations, which is of interest to adopters with limited testing equipment. The experimentally parameterized model of such an actuator of elementary design shows high accuracy. Both without load and with a weight of 1N applied to the tip, the mean error of the tip position in vertical orientation is less than 3.4% for a constant extensional stiffness and less than 2.7% for a pressure-dependent extensional stiffness. Further reduction of the error could be achieved by more refined identification techniques that decompose the complex interrelationship of pressurization, forces and material stiffness.

Spatial hearing is critical for communication in everyday sound-rich environments. It is important to gain an understanding of how well users of bilateral hearing devices function in these conditions. The purpose of this work was to evaluate a Virtual Acoustics (VA) version of the Spatial Speech in Noise (SSiN) test, the SSiN-VA. This implementation uses relatively inexpensive equipment and can be performed outside the clinic, allowing for regular monitoring of spatial-hearing performance. The SSiN-VA simultaneously assesses speech discrimination and relative localization with changing source locations in the presence of noise. The use of simultaneous tasks increases the cognitive load to better represent the difficulties faced by listeners in noisy real-world environments. Current clinical assessments may require costly equipment which has a large footprint. Consequently, spatial-hearing assessments may not be conducted at all. Additionally, as patients take greater control of their healthcare outcomes and a greater number of clinical appointments are conducted remotely, outcome measures that allow patients to carry out assessments at home are becoming more relevant. The SSiN-VA was implemented using the 3D Tune-In Toolkit, simulating seven loudspeaker locations spaced at 30° intervals with azimuths between −90° and +90°, and rendered for headphone playback using the binaural spatialization technique. Twelve normal-hearing participants were assessed to evaluate if SSiN-VA produced patterns of responses for relative localization and speech discrimination as a function of azimuth similar to those previously obtained using loudspeaker arrays. Additionally, the effect of the signal-to-noise ratio (SNR), the direction of the shift from target to reference, and the target phonetic contrast on performance were investigated. SSiN-VA led to similar patterns of performance as a function of spatial location compared to loudspeaker setups for both relative localization and speech discrimination. Performance for relative localization was significantly better at the highest SNR than at the lowest SNR tested, and a target shift to the right was associated with an increased likelihood of a correct response. For word discrimination, there was an interaction between SNR and word group. Overall, these outcomes support the use of virtual audio for speech discrimination and relative localization testing in noise.

Fusarium keratoplasticum is the Fusarium species most commonly associated with human infections (fusariosis). Antifungal treatment of fusariosis is often hampered by limited treatment options due to resistance towards azole antifungals. The mechanisms of antifungal resistance and sterol biosynthesis in fusaria are poorly understood. Therefore, in this study we assessed the transcriptional response of F. keratoplasticum when exposed to voriconazole. Our results revealed a group of dramatically upregulated ergosterol biosynthesis gene duplicates, most notably erg6A (912-fold), cyp51A (52-fold) and ebp1 (20-fold), which are likely part of an alternative ergosterol biosynthesis salvage pathway. The presence of human cholesterol biosynthesis gene homologs in F. keratoplasticum (ebp1, dhcr7 and dhcr24_1, dhcr24_2 and dhcr24_3) suggests that additional sterol biosynthesis pathways may be induced in fusaria under other growth conditions or during host invasion. Voriconazole also induced the expression of a number of ABC efflux pumps. Further investigations suggested that the highly conserved master regulator of ergosterol biosynthesis, FkSR, and the pleiotropic drug resistance network that induces zinc-cluster transcription factor FkAtrR coordinate the response of FSSC species to azole antifungal exposure. In-depth genome mining also helped clarify the ergosterol biosynthesis pathways of moulds and provided a better understanding of antifungal drug resistance mechanisms in fusaria.

Fusarium infections in humans (fusariosis) and in economically important plants involve species of several Fusarium species complexes. Species of the Fusarium solani species complex (FSSC) are the most frequent cause of human fusariosis. The FSSC comprises more than 60 closely related species that can be separated into three major clades by multi-locus sequence typing (MLST) using translation elongation factor 1-alpha (TEF1-α) and RNA polymerase II (RPB2) DNA sequences. The MLST nomenclature for clade 3 of the FSSC assigns numbers to species types (e.g., FSSC 2) and lowercase letters to identify unique haplotypes. The aim of this study was to analyse the genotypic and phenotypic characteristics of 15 environmental and 15 clinical FSSC isolates from Malaysia. MLST was used for the genotypic characterisation of FSSC isolates from various locations within Malaysia, which was complemented by their morphological characterisation on potato dextrose and carnation leaf agar. MLST identified eight different FSSC species: thirteen Fusarium keratoplasticum (i.e., FSSC 2), six Fusarium suttonianum (FSSC 20), five Fusarium falciforme (FSSC 3+4), two Fusarium cyanescens (FSSC 27), and one each of Fusarium petroliphilum (FSSC 1), Fusarium waltergamsii (FSSC 7), Fusarium sp. (FSSC 12), and Fusarium striatum (FSSC 21). Consistent with previous reports from Malaysia, most (11 of 15) clinical FSSC isolates were F. keratoplasticum and the majority (9 of 15) of environmental isolates were F. suttonianum (5) or F. falciforme (4) strains. The taxonomic relationships of the isolates were resolved phylogenetically. The eight Fusarium species also showed distinct morphological characteristics, but these were less clearly defined and reached across species boundaries. Although TEF1-α and RPB2 sequences were sufficient for the species identification of most FSSC isolates, a more precise MLST scheme needs to be established to reliably assign individual isolates of the species-rich FSSC to their geographically-, epidemiologically-, and host-associated sub-lineages.

Fusarium keratoplasticum is arguably the most common Fusarium solani species complex (FSSC) species associated with human infections. Invasive fusariosis is a life-threatening fungal infection that is difficult to treat with conventional azole antifungals. Azole drug resistance is often caused by the increased expression of pleiotropic drug resistance (PDR) ATP-binding cassette (ABC) transporters of the ABCG sub-family. Most investigations of Fusarium ABC transporters associated with azole antifungal drug resistance are limited to plant pathogens. Through the manual curation of the entire ABCG protein family of four FSSC species including the fully annotated genome of the plant pathogen Nectria haematococca we identified PDR transporters ABC1 and ABC2 as the efflux pump candidates most likely to be associated with the innate azole resistance phenotype of Fusarium keratoplasticum. An initial investigation of the transcriptional response of logarithmic phase F. keratoplasticum cells to 16 mg/L voriconazole confirmed strong upregulation (372-fold) of ABC1 while ABC2 mRNA levels were unaffected by voriconazole exposure over a 4 h time-period. Overexpression of F. keratoplasticum ABC1 and ABC2 in the genetically modified Saccharomyces cerevisiae host ADΔΔ caused up to ∼1,024-fold increased resistance to a number of xenobiotics, including azole antifungals. Although ABC1 and ABC2 were only moderately (20% and 10%, respectively) expressed compared to the Candida albicans multidrug efflux pump CDR1, overexpression of F. keratoplasticum ABC1 caused even higher resistance levels to certain xenobiotics (e.g., rhodamine 6G and nigericin) than CDR1. Our investigations suggest an important role for ABC1 orthologues in the innate azole resistance phenotype of FSSC species.

On 5 July 2023, the European Commission proposed a regulation aiming to ease the requirements for the marketing authorisation of plants obtained through certain new genomic techniques (NGTs) within the European Union (EU). While NGTs are expected to become more attractive to breeders and farmers, the complexity of the intellectual property (IP) landscape surrounding these techniques and resulting products may negatively impact technology diffusion and innovation. Given numerous concerns related to IP protection for NGTs and NGT-derived plants, this Position Statement from the Max Planck Institute for Innovation and Competition presents a set of policy recommendations for facilitating access to and utilisation of IP-protected NGTs and NGT-derived products in the breeding sector. [ABSTRACT FROM AUTHOR]

The relation between poetry and cognition has seldom been discussed theoretically due to the assumption that poetry has more to do with emotion than with cognition. The following article attempts to survey this field. It distinguishes between three types of cognition in poetry referring mostly to European and American poems of the 20th century: cognition that is caused by poems, cognition that is imparted in poems, and cognition that is formed in poems.

The realisation of 4D light fields, where longitudinal polarisation represents the fourth dimension, has been limited by the lack of appropriate analysis techniques. Here, the authors use interaction with self-assembled monolayers of fluorescent molecules, which allow for identification of non-paraxial light fields based on a single image frame.

Little is known about interactions between two antiaromatic molecules. Here, the authors synthesised a cyclophane, in which two antiaromatic porphyrin moieties adopt a stacked face-to-face geometry with a distance shorter than the sum of the van der Waals radii of the atoms involved.

Abstract Background Diagnosis and treatment decisions in cancer increasingly depend on a detailed analysis of the mutational status of a patient’s genome. This analysis relies on previously published information regarding the association of variations to disease progression and possible interventions. Clinicians to a large degree use biomedical search engines to obtain such information; however, the vast majority of scientific publications focus on basic science and have no direct clinical impact. We develop the Variant-Information Search Tool (VIST), a search engine designed for the targeted search of clinically relevant publications given an oncological mutation profile. Results VIST indexes all PubMed abstracts and content from ClinicalTrials.gov. It applies advanced text mining to identify mentions of genes, variants and drugs and uses machine learning based scoring to judge the clinical relevance of indexed abstracts. Its functionality is available through a fast and intuitive web interface. We perform several evaluations, showing that VIST’s ranking is superior to that of PubMed or a pure vector space model with regard to the clinical relevance of a document’s content. Conclusion Different user groups search repositories of scientific publications with different intentions. This diversity is not adequately reflected in the standard search engines, often leading to poor performance in specialized settings. We develop a search engine for the specific case of finding documents that are clinically relevant in the course of cancer treatment. We believe that the architecture of our engine, heavily relying on machine learning algorithms, can also act as a blueprint for search engines in other, equally specific domains. VIST is freely available at https://vist.informatik.hu-berlin.de/

This essay proposes a theory of the lyrical poem which differs decisively from the traditional definition of poetry as metered speech. The essential statement of the theory is the definition of the lyrical poem as single speech in verse. In order to correspond to the conception of the lyrical genre in the understanding of Dieter Lamping a text has to meet two conditions: On the one hand the lyrical poem, a term which is employed synonymously to poetry, is to be distinguished from both dramatic and epic poems as it is considered as single speech in verses. On the other hand lyrical poems need to fulfill the formal criterion of composition in verses as well as the structural criterion of single speech. These criteria are related to the form of speech and the structure of speech. This minimal definition of lyrical texts as single speech in verses, which claims a constitutive interconnection between form and structure of speech, matches the aesthetic complexity and the plurality of poetry. It offers a universally valid description of poetry and a distinction of the lyrical poem from other types of poetic speech. In the end it provides in particular an appropriate approach to analyze modern poetry which disengages from the commitments of poetic traditions due to its pursuit of freedom.

Overexpression of the fungal pleiotropic drug resistance (PDR) transporter Cdr1 is a major cause of antifungal drug resistance in Candida albicans

Background Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor (TGF)-βRII (a TGF-β ‘trap’) fused to a human IgG1 mAb blocking programmed cell death ligand 1. This is the largest analysis of patients with advanced, pretreated human papillomavirus (HPV)-associated malignancies treated with bintrafusp alfa.Methods In these phase 1 (NCT02517398) and phase 2 trials (NCT03427411), 59 patients with advanced, pretreated, checkpoint inhibitor-naive HPV-associated cancers received bintrafusp alfa intravenously every 2 weeks until progressive disease, unacceptable toxicity, or withdrawal. Primary endpoint was best overall response per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1; other endpoints included safety.Results As of April 17, 2019 (phase 1), and October 4, 2019 (phase 2), the confirmed objective response rate per RECIST V.1.1 in the checkpoint inhibitor-naive, full-analysis population was 30.5% (95% CI, 19.2% to 43.9%; five complete responses); eight patients had stable disease (disease control rate, 44.1% (95% CI, 31.2% to 57.6%)). In addition, three patients experienced a delayed partial response after initial disease progression, for a total clinical response rate of 35.6% (95% CI, 23.6% to 49.1%). An additional patient with vulvar cancer had an unconfirmed response. Forty-nine patients (83.1%) experienced treatment-related adverse events, which were grade 3/4 in 16 patients (27.1%). No treatment-related deaths occurred.Conclusion Bintrafusp alfa showed clinical activity and manageable safety and is a promising treatment in HPV-associated cancers. These findings support further investigation of bintrafusp alfa in patients with advanced, pretreated HPV-associated cancers.

In the fungal pathogen Aspergillus fumigatus, resistance to azole antifungals is often linked to mutations in CYP51A, a gene that encodes the azole antifungal drug target lanosterol 14α-demethylase. The aim of this study was to investigate whether similar changes could be associated with azole resistance in a Malaysian Fusarium solani species complex (FSSC) isolate collection. Most (11 of 15) clinical FSSC isolates were Neocosmospora keratoplastica and the majority (6 of 10) of environmental isolates were Neocosmospora suttoniana strains. All 25 FSSC isolates had high minimum inhibitory concentrations (MICs) for itraconazole and posaconazole, low MICs for amphotericin B, and various (1 to >32 mg/l) voriconazole susceptibilities. There was a tight association between a 23 bp CYP51A promoter deletion and high (>32 mg/l) voriconazole MICs; of 19 FSSC strains sequenced, nine isolates had voriconazole MICs > 32 mg/l, and they all contained the 23 bp CYP51A promoter deletion, although it was absent in the ten remaining isolates with low (≤12 mg/l) voriconazole MICs. Surprisingly, this association between voriconazole resistance and the 23 bp CYP51A promoter deletion held true across species boundaries. It was randomly distributed within and across species boundaries and both types of FSSC isolates were found among environmental and clinical isolates. Three randomly selected N. keratoplastica isolates with low (≤8 mg/l) voriconazole MICs had significantly lower (1.3–7.5 times) CYP51A mRNA expression levels than three randomly selected N. keratoplastica isolates with high (>32 mg/l) voriconazole MICs. CYP51A expression levels, however, were equally strongly induced (~6,500-fold) by voriconazole in two representative strains reaching levels, after 80 min of induction, that were comparable to those of CYP51B. Our results suggest that FSSC isolates with high voriconazole MICs have a 23 bp CYP51A promoter deletion that provides a potentially useful marker for voriconazole resistance in FSSC isolates. Early detection of possible voriconazole resistance is critical for choosing the correct treatment option for patients with invasive fusariosis.

Abstract Background Since early antimicrobial therapy is mandatory in septic patients, immediate diagnosis and distinction from non-infectious SIRS is essential but hampered by the similarity of symptoms between both entities. We aimed to develop a diagnostic model for differentiation of sepsis and non-infectious SIRS in critically ill children based on routinely available parameters (baseline characteristics, clinical/laboratory parameters, technical/medical support). Methods This is a secondary analysis of a randomized controlled trial conducted at a German tertiary-care pediatric intensive care unit (PICU). Two hundred thirty-eight cases of non-infectious SIRS and 58 cases of sepsis (as defined by IPSCC criteria) were included. We applied a Random Forest approach to identify the best set of predictors out of 44 variables measured at the day of onset of the disease. The developed diagnostic model was validated in a temporal split-sample approach. Results A model including four clinical (length of PICU stay until onset of non-infectious SIRS/sepsis, central line, core temperature, number of non-infectious SIRS/sepsis episodes prior to diagnosis) and four laboratory parameters (interleukin-6, platelet count, procalcitonin, CRP) was identified in the training dataset. Validation in the test dataset revealed an AUC of 0.78 (95% CI: 0.70–0.87). Our model was superior to previously proposed biomarkers such as CRP, interleukin-6, procalcitonin or a combination of CRP and procalcitonin (maximum AUC = 0.63; 95% CI: 0.52–0.74). When aiming at a complete identification of sepsis cases (100%; 95% CI: 87–100%), 28% (95% CI: 20–38%) of non-infectious SIRS cases were assorted correctly. Conclusions Our approach allows early recognition of sepsis with an accuracy superior to previously described biomarkers, and could potentially reduce antibiotic use by 30% in non-infectious SIRS cases. External validation studies are necessary to confirm the generalizability of our approach across populations and treatment practices. Trial registration ClinicalTrials.gov number: NCT00209768; registration date: September 21, 2005.