julilili42/papers huggingface dataset:
In Vitro Metabolism and p53 Activation of Genotoxic Chemicals: Abiotic CYP Enzyme vs Liver Microsomes
2024-06-20

Chemicals often require metabolic activation to become genotoxic. Established test guidelines recommend the use of the rat liver S9 fraction or microsomes to introduce metabolic competence to <i>in vitro</i> cell-based bioassays, but the use of animal-derived components in cell culture raises ethical concerns and may lead to quality issues and reproducibility problems. The aim of the present study was to compare the metabolic activation of cyclophosphamide (CPA) and benzo[<i>a</i>]pyrene (BaP) by induced rat liver microsomes and an abiotic cytochrome P450 (CYP) enzyme based on a biomimetic porphyrine catalyst. For the detection of genotoxic effects, the chemicals were tested in a reporter gene assay targeting the activation of the cellular tumor protein p53. Both chemicals were metabolized by the abiotic CYP enzyme and the microsomes. CPA showed no activation of p53 and low cytotoxicity without metabolic activation, but strong activation of p53 and increased cytotoxicity upon incubation with liver microsomes or abiotic CYP enzyme. The effect concentration causing a 1.5-fold induction of p53 activation was very similar with both metabolization systems (within a factor of 1.5), indicating that genotoxic metabolites were formed at comparable concentrations. BaP also showed low cytotoxicity and no p53 activation without metabolic activation. The activation of p53 was detected for BaP upon incubation with active and inactive microsomes at similar concentrations, indicating experimental artifacts caused by the microsomes or NADPH. The activation of BaP with the abiotic CYP enzyme increased the cytotoxicity of BaP by a factor of 8, but no activation of p53 was detected. The results indicate that abiotic CYP enzymes may present an alternative to rat liver S9 fraction or microsomes for the metabolic activation of test chemicals, which are completely free of animal-derived components. However, an amendment of existing test guidelines would require testing of more chemicals and genotoxicity end points.
‘Yet, they didn’t sign me’: the production of precarity in amateur and semi-professional football in Nigeria
2024-06-20

This paper investigated how the experiences of precarity are produced in amateur and semi-professional football in Nigeria through qualitative interviews with former amateur and semi-professional footballers. Though a few studies have highlighted the precarities that football career aspirations produce among West African youth, the mechanisms through which such precarious experiences develop remain loosely articulated. This paper fills this gap. The findings revealed that precarious experiences emanate from an overbearing athletic identity, a disconnect between imagined mobility through football and actual opportunity, institutional failures, and corruption and exploitation. The policy implications include a need for a framework for dual career and life after football programme in amateur and semi-professional clubs, centred around information, health education and skills training, as well as institutional and regulatory reforms for better governance of the sector.
Translational symmetry in convolutions with localized kernels causes an implicit bias toward high frequency adversarial examples
2024-06-20

Adversarial attacks are still a significant challenge for neural networks. Recent efforts have shown that adversarial perturbations typically contain high-frequency features, but the root cause of this phenomenon remains unknown. Inspired by theoretical work on linear convolutional models, we hypothesize that translational symmetry in convolutional operations together with localized kernels implicitly bias the learning of high-frequency features , and that this is one of the main causes of high frequency adversarial examples . To test this hypothesis, we analyzed the impact of different choices of linear and non-linear architectures on the implicit bias of the learned features and adversarial perturbations, in spatial and frequency domains. We find that, independently of the training dataset, convolutional operations have higher frequency adversarial attacks compared to other architectural parameterizations, and that this phenomenon is exacerbated with stronger locality of the kernel (kernel size) end depth of the model. The explanation for the kernel size dependence involves the Fourier Uncertainty Principle: a spatially-limited filter (local kernel in the space domain) cannot also be frequency-limited (local in the frequency domain). Using larger convolution kernel sizes or avoiding convolutions (e.g., by using Vision Transformers or MLP-style architectures) significantly reduces this high-frequency bias. Looking forward, our work strongly suggests that understanding and controlling the implicit bias of architectures will be essential for achieving adversarial robustness.
Ex vivo Study of Partial Bladder Resection in a Porcine Model
2024-06-20

Introduction: Partial cystectomy aims to preserve bladder function, yet its urodynamic impacts remain unclear. We investigate these effects using an ex vivo porcine model, evaluating bladder volume, compliance, and wall thickness, alongside with thermal damage after bi- and monopolar resection. Methods: Within an artificial human pelvis, we conducted partial bladder wall resections (5 cm2, 10 cm2). Urodynamic tests and sonography assessed volume, compliance, and thickness changes. Traction force for catheter retrieval and thermal collagen destruction were measured. Results: Bladder compliance decreased by 1.12 and 1.5 after 5 cm2 and 10 cm2 resections, respectively, with volume reductions of 3–6% and 10–18%. Wall thickness decreased by 20% and 30% post-resection. Comparable thermal damage was observed with mono- and bipolar resection methods. Conclusion: Our study outlines urodynamic impacts and technical considerations of partial cystectomy, affirming its endoscopic feasibility while highlighting potential bladder dysfunction risks.
Filamin protects myofibrils from contractile damage through changes in its mechanosensory region
2024-06-21

Filamins are mechanosensitive actin crosslinking proteins that organize the actin cytoskeleton in a variety of shapes and tissues. In muscles, filamin crosslinks actin filaments from opposing sarcomeres, the smallest contractile units of muscles. This happens at the Z-disc, the actin-organizing center of sarcomeres. In flies and vertebrates, filamin mutations lead to fragile muscles that appear ruptured, suggesting filamin helps counteract muscle rupturing during muscle contractions by providing elastic support and/or through signaling. An elastic region at the C-terminus of filamin is called the mechanosensitive region and has been proposed to sense and counteract contractile damage. Here we use molecularly defined mutants and microscopy analysis of the Drosophila indirect flight muscles to investigate the molecular details by which filamin provides cohesion to the Z-disc. We made novel filamin mutations affecting the C-terminal region to interrogate the mechanosensitive region and detected three Z-disc phenotypes: dissociation of actin filaments, Z-disc rupture, and Z-disc enlargement. We tested a constitutively closed filamin mutant, which prevents the elastic changes in the mechanosensitive region and results in ruptured Z-discs, and a constitutively open mutant which has the opposite elastic effect on the mechanosensitive region and gives rise to enlarged Z-discs. Finally, we show that muscle contraction is required for Z-disc rupture. We propose that filamin senses myofibril damage by elastic changes in its mechanosensory region, stabilizes the Z-disc, and counteracts contractile damage at the Z-disc.
Cataclysmic variables around the period-bounce: An eROSITA-enhanced multiwavelength catalog
2024-06-21

Context. Cataclysmic variables (CVs) with degenerate donors that have evolved past the period minimum are predicted to make up a great portion of the CV population, namely, between 40% and 80%. However, either due to shortcomings in the models or the intrinsic faintness of these strongly evolved systems, only a few of these so-called “period-bouncers” have been confidently identified thus far. Aims. We compiled a multiwavelength catalog of period-bouncers and CVs around the period minimum from the literature to provide an in-depth characterization of the elusive subclass of period-bounce CVs that will support the identification of new candidates. Methods. We combined recently published or archival multiwavelength data with new X-ray observations from the all-sky surveys carried out with the extended ROentgen Survey with an Imaging Telescope Array (eROSITA) on board the Spektrum-Roentgen-Gamma spacecraft (SRG). Our catalog comprises 192 CVs around the period minimum, chosen as likely period-bounce candidates based on reported short orbital periods and low donor mass. This sample helped us establish specific selection parameters, which were used to compile a “scorecard” that rates the likelihood that a particular system is a period-bouncer. Results. Our “scorecard” correctly assigns high scores to the already confirmed period-bouncers in our literature catalog. It has also identified 103 additional strong period-bounce candidates in the literature that had not previously been classified as such. We established two selection cuts based on the X-ray-to-optical flux ratio (−1.21 ≤ log( F x / F opt ) ≤ 0) and the typical X-ray luminosity (log( L x,bol ) ≤ 30.4 [erg s −1 ]) observed from the eight period-bouncers that have already been confirmed with eROSITA data. These X-ray selection cuts led to the updated categorization of seven systems as new period-bouncers, increasing their known population to 24 systems in total. Conclusions. Our multiwavelength catalog of CVs around the period minimum drawn from the literature, together with X-ray data from eROSITA, has resulted in a ~40% increase in the population of period-bouncers. Both the catalog and “scorecard” we constructed will aid in future searches for new period-bounce candidates. These tools will contribute to the goal of resolving the discrepancy between the predicted high number of period-bouncers and the low number of these systems successfully observed to date.
Genomic insights into the evolution of secondary metabolism of Escovopsis and its allies, specialized fungal symbionts of fungus-farming ants
2024-06-21

ABSTRACT The metabolic intimacy of symbiosis often demands the work of specialists. Natural products and defensive secondary metabolites can drive specificity by ensuring infection and propagation across host generations. But in contrast to bacteria, little is known about the diversity and distribution of natural product biosynthetic pathways among fungi and how they evolve to facilitate symbiosis and adaptation to their host environment. In this study, we define the secondary metabolism of Escovopsis and closely related genera, symbionts in the gardens of fungus-farming ants. We ask how the gain and loss of various biosynthetic pathways correspond to divergent lifestyles. Long-read sequencing allowed us to define the chromosomal features of representative Escovopsis strains, revealing highly reduced genomes composed of seven to eight chromosomes. The genomes are highly syntenic with macrosynteny decreasing with increasing phylogenetic distance, while maintaining a high degree of mesosynteny. An ancestral state reconstruction analysis of biosynthetic pathways revealed that, while many secondary metabolites are shared with non-ant-associated Sordariomycetes , 56 pathways are unique to the symbiotic genera. Reflecting adaptation to diverging ant agricultural systems, we observe that the stepwise acquisition of these pathways mirrors the ecological radiations of attine ants and the dynamic recruitment and replacement of their fungal cultivars. As different clades encode characteristic combinations of biosynthetic gene clusters, these delineating profiles provide important insights into the possible mechanisms underlying specificity between these symbionts and their fungal hosts. Collectively, our findings shed light on the evolutionary dynamic nature of secondary metabolism in Escovopsis and its allies, reflecting adaptation of the symbionts to an ancient agricultural system. IMPORTANCE Microbial symbionts interact with their hosts and competitors through a remarkable array of secondary metabolites and natural products. Here, we highlight the highly streamlined genomic features of attine-associated fungal symbionts. The genomes of Escovopsis species, as well as species from other symbiont genera, many of which are common with the gardens of fungus-growing ants, are defined by seven chromosomes. Despite a high degree of metabolic conservation, we observe some variation in the symbionts’ potential to produce secondary metabolites. As the phylogenetic distribution of the encoding biosynthetic gene clusters coincides with attine transitions in agricultural systems, we highlight the likely role of these metabolites in mediating adaptation by a group of highly specialized symbionts.
Limitations in next-generation sequencing-based genotyping of breast cancer polygenic risk score loci
2024-06-21

Abstract Considering polygenic risk scores (PRSs) in individual risk prediction is increasingly implemented in genetic testing for hereditary breast cancer (BC) based on next-generation sequencing (NGS). To calculate individual BC risks, the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) with the inclusion of the BCAC 313 or the BRIDGES 306 BC PRS is commonly used. The PRS calculation depends on accurately reproducing the variant allele frequencies (AFs) and, consequently, the distribution of PRS values anticipated by the algorithm. Here, the 324 loci of the BCAC 313 and the BRIDGES 306 BC PRS were examined in population-specific database gnomAD and in real-world data sets of five centers of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), to determine whether these expected AFs can be reproduced by NGS-based genotyping. Four PRS loci were non-existent in gnomAD v3.1.2 non-Finnish Europeans, further 24 loci showed noticeably deviating AFs. In real-world data, between 11 and 23 loci were reported with noticeably deviating AFs, and were shown to have effects on final risk prediction. Deviations depended on the sequencing approach, variant caller and calling mode (forced versus unforced) employed. Therefore, this study demonstrates the necessity to apply quality assurance not only in terms of sequencing coverage but also observed AFs in a sufficiently large cohort, when implementing PRSs in a routine diagnostic setting. Furthermore, future PRS design should be guided by the technical reproducibility of expected AFs across commonly used genotyping methods, especially NGS, in addition to the observed effect sizes.
Organomagnesia: Reversibly High Carbon Dioxide Uptake by Magnesium Pyrazolates
2024-06-21

Abstract A series of new pyrazolate and mixed pyrazolate/pyrazole magnesium complexes is described and their reactivity toward carbon dioxide is examined. The dimeric complex [Mg(pz t Bu, t Bu ) 2 ] 2 inserts CO 2 instantly and quantitatively forming the tetrameric complex [Mg(CO 2 ·pz t Bu, t Bu ) 2 ] 4 and monomeric donor‐stabilized [Mg(CO 2 ·pz t Bu, t Bu ) 2 (thf) 2 ]. Complexes of the type [Mg x (pz R,R ) 2 x (Hpz R,R ) y ] n (R = i Pr, t Bu) engage in similar insertion reactions involving dissociation of the carbamic acid HOOCpz R,R . Even solid polymeric derivatives [Mg(pz R,R ) 2 ] n (R = Me, H) react instantaneously and exhaustively with CO 2 , the resulting [Mg(CO 2 ·pz) 2 ] m featuring a CO 2 capacity of 35.7 wt% (8.2 mmol g −1 ). All described magnesium pyrazolates display completely reversible CO 2 uptake in solution and in the solid state, respectively, as monitored via VT 1 H NMR and in situ FTIR spectroscopy as well as thermogravimetric analysis. Fluorinated [Mg 2 (pz CF3,CF3 ) 4 (thf) 3 ] does not yield any isolable CO 2 insertion product but exhibits the highest activity in the catalytic transformation of epoxides and CO 2 to cyclic carbonates.
Vaccine-associated axillary lymphadenopathy with a focus on COVID-19 vaccines
2024-06-21

Abstract Axillary lymphadenopathy (LA) after COVID-19 vaccination is now known to be a common side effect. In these cases, malignancy cannot always be excluded on the basis of morphological imaging criteria. Narrative review for decision-making regarding control and follow-up intervals for axillary LA according to currently published research. This article provides a practical overview of the management of vaccine-associated LA using image examples and a flowchart and provides recommendations for follow-up intervals. A particular focus is on patients presenting for diagnostic breast imaging. The diagnostic criteria for pathological lymph nodes (LN) are explained. Axillary LA is a common adverse effect after COVID-19 vaccination (0.3–53%). The average duration of LA is more than 100 days. LA is also known to occur after other vaccinations, such as the seasonal influenza vaccine. Systematic studies on this topic are missing. Other causes of LA after vaccination (infections, autoimmune diseases, malignancies) should be considered for the differential diagnosis. If the LA persists for more than 3 months after COVID-19 vaccination, a primarily sonographic follow-up examination is recommended after another 3 months. A minimally invasive biopsy of the LA is recommended if a clinically suspicious LN persists or progresses. In the case of histologically confirmed breast cancer, a core biopsy without a follow-up interval is recommended regardless of the vaccination, as treatment appropriate to the stage should not be influenced by follow-up intervals. For follow-up after breast cancer, the procedure depends on the duration of the LA and the woman’s individual risk of recurrence. Vaccination history should be well documented and taken into account when evaluating suspicious LN. Biopsy of abnormal, persistent, or progressive LNs is recommended. Preoperative staging of breast cancer should not be delayed by follow-up. The risk of false-positive findings is accepted, and the suspicious LNs are histologically examined in a minimally invasive procedure.
Looking in the Mirror: Vocal Arousal and Affective Reactions during Mirror Exposure in Women with Anorexia Nervosa and Bulimia Nervosa
2024-06-21

Objectives : Although mirror exposure improves treatment outcomes in women with eating disorders, it remains uncertain how the cognitive, emotional, and physiological reactions evoked by this technique differ between women with anorexia nervosa and women with bulimia nervosa. Moreover, it is unclear whether vocal arousal is a psychophysiological correlate of these reactions and how the specific emotions elicited by looking at one’s body change during mirror exposure. Methods : Thus, a total of N = 136 women ( n = 39 with anorexia nervosa, n = 24 with bulimia nervosa, and n = 73 healthy controls) first underwent a non-activating baseline, followed by a mirror exposure condition with the task to freely describe aloud arising thoughts and feelings towards their body. Self-reported arousal, emotional valence, and specific emotions were assessed before, in the middle of, and after each condition. Furthermore, we analyzed fundamental frequency ( f 0 ) as a marker of vocally encoded emotional arousal. Results : Women with both forms of eating disorder showed stronger increases in self-reported arousal and equally high levels of f 0 in contrast to women without eating disorders. Fear increased in all women, while guilt, hostility, and sadness only increased in women with eating disorders. Conclusion : In sum, findings suggest heightened emotional activation and vocal arousal evoked by mirror exposure, particularly in women with eating disorders. In mirror exposure therapy, addressing varied body-related emotions alongside fear might enhance therapeutic success.
A study on interoperability between two Personal Health Train infrastructures in leukodystrophy data analysis
2024-06-22

Abstract The development of platforms for distributed analytics has been driven by a growing need to comply with various governance-related or legal constraints. Among these platforms, the so-called Personal Health Train (PHT) is one representative that has emerged over the recent years. However, in projects that require data from sites featuring different PHT infrastructures, institutions are facing challenges emerging from the combination of multiple PHT ecosystems, including data governance, regulatory compliance, or the modification of existing workflows. In these scenarios, the interoperability of the platforms is preferable. In this work, we introduce a conceptual framework for the technical interoperability of the PHT covering five essential requirements: Data integration, unified station identifiers, mutual metadata, aligned security protocols, and business logic. We evaluated our concept in a feasibility study that involves two distinct PHT infrastructures: PHT-meDIC and PADME. We analyzed data on leukodystrophy from patients in the University Hospitals of Tübingen and Leipzig, and patients with differential diagnoses at the University Hospital Aachen. The results of our study demonstrate the technical interoperability between these two PHT infrastructures, allowing researchers to perform analyses across the participating institutions. Our method is more space-efficient compared to the multi-homing strategy, and it shows only a minimal time overhead.
Clinical and Genetic Findings in a Cohort of Patients with PRPF31-Associated Retinal Dystrophy
2024-06-22

Our study confirms high phenotypic variability in disease onset and age at which legal blindness is reached in PRPF31-associated RP. Non-penetrance is commonly documented in family history, although poorly represented in our study, possibly indicating that true asymptomatic mutation carriers are rare if followed-up over lifetime with thorough ophthalmologic workup.