julilili42/papers huggingface dataset:
BCR::ABL1 tyrosine kinase inhibitors hamper the therapeutic efficacy of blinatumomab in vitro
2022-05-13

Abstract Purpose Acute B-lymphoblastic leukemia (B-ALL) is a malignant disease characterized by accumulation of clonal immature lymphocytes in the bone marrow and peripheral blood. The approval of BCR::ABL1 tyrosine kinase inhibitors (TKI) such as imatinib, dasatinib, nilotinib and ponatinib marked a milestone in targeted therapy only for a subset of patients carrying the translocation t(9;22)(q34;q11). Immunotherapy with the bispecific antibody (bsAb) blinatumomab targeting CD19xCD3 revolutionized treatment of all B-ALL cases. The combination of both TKI and bsAb, so-called “dual targeting”, is currently under clinical investigation, although TKI might influence T cell effects. Methods We here investigated the combination of different TKI and blinatumomab in BCR::ABL1 + and BCR::ABL1 − B-ALL cell lines and primary samples regarding T cell proliferation, differentiation, cytokine release and killing of tumor cells. Results In vitro analysis revealed profound reduction of T cell proliferation, differentiation, cytokine release and killing of tumor cells upon application of BCR::ABL1 TKI with blinatumomab. Inhibition was more pronounced with dasatinib and ponatinib compared to nilotinib and imatinib. T cell signalling after CD3 stimulation was impaired by TKI mirrored by inhibition of LCK phosphorylation. This known off-target effect might influence the efficacy of bsAb therapy when combined with BCR::ABL1 TKI. Conclusion In conclusion, we propose that nilotinib and imatinib might also be suitable substances for combination with blinatumomab and suggest evaluation in clinical trials.
Genome-Wide Association Study Suggests the Variant rs7551288*A within the DHCR24 Gene Is Associated with Poor Overall Survival in Melanoma Patients
2022-05-13

Melanoma incidence rates are high among individuals with fair skin and multiple naevi. Established prognostic factors are tumour specific, and less is known about prognostic host factors. A total of 556 stage I to stage IV melanoma patients from Germany with phenotypic and disease-specific data were analysed; 64 of these patients died of melanoma after a median follow-up time of 8 years. Germline DNA was assessed by the HumanCoreExome BeadChip and data of 356,384 common polymorphisms distributed over all 23 chromosomes were used for a genome-wide analysis. A suggestive genome-wide significant association of the intronic allele rs7551288*A with diminished melanoma-specific survival was detected (p = 2 × 10−6). The frequency of rs7551288*A was 0.43 and was not associated with melanoma risk, hair and eye colour, tanning and total naevus count. Cox regression multivariate analyses revealed a 5.31-fold increased risk of melanoma-specific death for patients with the rs7551288 A/A genotype, independent of tumour thickness, ulceration and stage of disease at diagnoses. The variant rs7551288 belongs to the DHCR24 gene, which encodes Seladin-1, an enzyme involved in the biosynthesis of cholesterol. Further investigations are needed to confirm this genetic variant as a novel prognostic biomarker and to explore whether specific treatment strategies for melanoma patients might be derived from it.
The targeted deletion of genes responsible for expression of the Mth60 fimbriae leads to loss of cell-cell connections in M. thermautotrophicus ΔH
2022-05-13

Abstract This study was continued by the Environmental Biotechnology Group of the University of Tübingen in memoriam to Reinhard Wirth, who initiated the work on Mth60 fimbriae at the University of Regensburg. Growth in biofilms or biofilm-like structures is the prevailing lifestyle for most microbes in nature. The first step to initiate biofilms is the adherence of microbes to biotic and abiotic surfaces. Therefore, it is important to elucidate the initial step of biofilm formation, which is generally established through cell-surface structures ( i.e ., cell appendages), such as fimbriae or pili, that adhere to surfaces. The Mth60 fimbriae of Methanothermobacter thermautotrophicus ΔH are one of only few known archaeal cell appendages that do not assemble via the type-IV assembly mechanism. Here, we report the constitutive expression of Mth60 fimbriae-encoding genes from a shuttle-vector construct, as well as the deletion of the Mth60 fimbriae-encoding genes from the genomic DNA of M. thermautotrophicus ΔH. We expanded our system for genetic modification of M. thermautotrophicus ΔH by an allelic-exchange method. While overexpression of the respective genes resulted in an increase of the Mth60 fimbriae, deletion of the Mth60 fimbriae-encoding genes led to a loss of Mth60 fimbriae in planktonic cells of M. thermautotrophicus ΔH. This either increased or decreased number of Mth60 fimbriae correlated with a significant increase or decrease of biotic cell-cell connections in the respective M. thermautotrophicus ΔH strains compared to the wild-type strain. Originality-Significance Statement Methanothermobacter spp. have been studied for the biochemistry of hydrogenotrophic methanogenesis for many years. However, due to the lack of genetic tools, the detailed investigation of certain aspects, such as regulatory processes, was not possible. Here, we amend our genetic toolbox for M. thermautotrophicus ΔH with an allelic exchange method. We report the deletion of genes that encode for the Mth60 fimbriae. Our findings provide a first insight into the regulation of the expression of these genes and reveal a role of the Mth60 fimbriae in the formation of cell-cell connections of M. thermautotrophicus ΔH.
A Highly Integrated Ambient Light Robust Eye-Tracking Sensor for Retinal Projection AR Glasses Based on Laser Feedback Interferometry
2022-05-13

Robust and highly integrated eye-tracking is a key technology to improve resolution of near-eye-display technologies for augmented reality (AR) glasses such as focus-free retinal projection as it enables display enhancements like foveated rendering. Furthermore, eye-tracking sensors enables novel ways to interact with user interfaces of AR glasses, improving thus the user experience compared to other wearables. In this work, we present a novel approach to track the user's eye by scanned laser feedback interferometry sensing. The main advantages over modern video-oculography (VOG) systems are the seamless integration of the eye-tracking sensor and the excellent robustness to ambient light with significantly lower power consumption. We further present an algorithm to track the bright pupil signal captured by our sensor with a significantly lower computational effort compared to VOG systems. We evaluate a prototype to prove the high robustness against ambient light and achieve a gaze accuracy of 1.62\\, , which is comparable to other state-of-the-art scanned laser eye-tracking sensors. The outstanding robustness and high integrability of the proposed sensor will pave the way for everyday eye-tracking in consumer AR glasses.
Antibiotic acyldepsipeptides stimulate theStreptomycesClp-ATPase/ClpP complex for accelerated proteolysis
2022-05-13

Abstract Clp proteases consist of a proteolytic, tetradecameric core ClpP and AAA+ Clp-ATPases. Streptomycetes, producers of a plethora of secondary metabolites, encode up to five different ClpP homologs and the composition of their unusually complex Clp protease machinery has remained unsolved. Here, we report on the composition of the house-keeping Clp protease in Streptomyces , consisting of a hetero-tetradecameric core built of ClpP1, ClpP2 and the cognate Clp-ATPases ClpX, ClpC1 or ClpC2, all interacting with ClpP2 only. ADEP antibiotics dysregulate the Clp protease for unregulated proteolysis. We observed that ADEP binds Streptomyces ClpP1, but not ClpP2, thereby not only triggering the degradation of non-native protein substrates but also accelerating Clp-ATPase-dependent proteolysis. The explanation is the concomitant binding of ADEP and Clp-ATPases to opposite sides of the ClpP1P2 barrel, hence revealing a third, so far unknown mechanism of ADEP action, i.e., the accelerated proteolysis of native protein substrates by the Clp protease. Significance Clp proteases are antibiotic and anti-cancer drug targets. Composed of the proteolytic core ClpP and a regulatory Clp-ATPase, the protease machinery is important for protein homeostasis and regulatory proteolysis. The acyldepsipeptide antibiotic ADEP targets ClpP and has shown promise for treating multi-resistant and persistent bacterial infections. The molecular mechanism of ADEP is multi-layered. Here, we present a new way how ADEP can deregulate the Clp protease system. Clp-ATPases and ADEP bind to opposite sides of Streptomyces ClpP, accelerating the degradation of natural Clp protease substrates. We also demonstrate the composition of the major Streptomyces Clp protease complex, a heteromeric ClpP1P2 core with the Clp-ATPases ClpX, ClpC1 or ClpC2 exclusively bound to ClpP2, and the killing mechanism of ADEP in Streptomyces .
Changes of oscillatory and aperiodic neuronal activity in working memory following anaesthesia: a prospective observational study
2022-05-13

Abstract Background Anaesthesia and surgery can lead to cognitive decline, especially in the elderly. However, to date, the neurophysiological underpinnings of perioperative cognitive decline remain unknown. Methods We included male patients, who were 60 years or older scheduled for elective radical prostatectomy under general anaesthesia. We obtained neuropsychological (NP) tests as well as a visual match-to-sample working memory (WM) task with concomitant 62-channel scalp electroencephalography (EEG) before and after surgery. Results A total number of 26 patients completed neuropsychological assessments and EEG pre- and postoperatively. Behavioural performance declined in the neuropsychological assessment after anaesthesia (total recall; t-tests: t 25 = -3.25, Bonferroni-corrected p = 0.015 d = -0.902), while WM performance showed a dissociation between match and mis-match accuracy ( rmANOVA : match*session F 1,25 = 3.866, p = 0.060). Distinct EEG signatures tracked behavioural performance: Better performance in the NP assessment was correlated with an increase of non-oscillatory (aperiodic) activity, reflecting increased cortical activity ( cluster permutation tests: total recall r = 0.66, p = 0.029, learning slope r = 0.66, p = 0.015), while WM accuracy was tracked by distinct temporally-structured oscillatory theta/alpha (7 – 9 Hz), low beta (14 – 18 Hz) and high beta/gamma (34 – 38 Hz) activity ( cluster permutation tests: matches: p &lt; 0.001, mis-matches: p = 0.022). Conclusions Oscillatory and non-oscillatory (aperiodic) activity in perioperative scalp EEG recordings track distinct features of perioperative cognition. Aperiodic activity provides a novel electrophysiological biomarker to identify patients at risk for developing perioperative neurocognitive decline.
Cold Atmospheric Plasma Reduces Vessel Density and Increases Vascular Permeability and Apoptotic Cell Death in Solid Tumors
2022-05-14

Cold atmospheric plasma (CAP) has demonstrated promising anti-cancer effects in numerous in vitro and in vivo studies. Despite their relevance for the treatment of solid tumors, effects of CAP on tumor vasculature and microcirculation have only rarely been investigated. Here, we report the reduction of vessel density and an increase in vascular permeability and tumor cell apoptosis after CAP application. Solid tumors in the chorioallantoic membrane of chicken embryos were treated with CAP and evaluated with respect to effects of CAP on embryo survival, tumor size, and tumor morphology. Furthermore, intratumoral blood vessel density, apoptotic cell death and the tumor-associated microcirculation were investigated and compared to sham treatment. Treatment with CAP significantly reduced intratumoral vessel density while increasing the rate of intratumoral apoptosis in solid tumors. Furthermore, CAP treatment increased vascular permeability and attenuated the microcirculation by causing vessel occlusions in the tumor-associated vasculature. These effects point out the potential of CAP as a promising and yet underrated therapeutic modality for addressing the tumor vasculature in the treatment of solid tumors.
Alpha-synuclein overexpression induces epigenomic dysregulation of glutamate signaling and locomotor pathways
2022-05-14

Abstract Parkinson’s disease (PD) is a neurological disorder with complex interindividual etiology that is becoming increasingly prevalent worldwide. Elevated alpha-synuclein levels can increase risk of PD and may influence epigenetic regulation of PD pathways. Here, we report genome-wide DNA methylation and hydroxymethylation alterations associated with overexpression of two PD-linked alpha-synuclein variants (wild-type and A30P) in LUHMES cells differentiated to dopaminergic neurons. Alpha-synuclein altered DNA methylation at thousands of CpGs and DNA hydroxymethylation at hundreds of CpGs in both genotypes, primarily in locomotor behavior and glutamate signaling pathway genes. In some cases, epigenetic changes were associated with transcription. SMITE network analysis incorporating H3K4me1 ChIP-seq to score DNA methylation and hydroxymethylation changes across promoters, enhancers, and gene bodies confirmed epigenetic and transcriptional deregulation of glutamate signaling modules in both genotypes. Our results identify distinct and shared impacts of alpha-synuclein variants on the epigenome, and associate alpha-synuclein with the epigenetic etiology of PD.
Generation, expansion, and drug treatment of hematopoietic progenitor cells derived from human iPSCs
2022-05-14

Severe congenital neutropenia (CN) is a pre-leukemic bone marrow failure syndrome that can progress to acute myeloid leukemia (CN/AML). Patient material to study leukemogenesis, especially hematopoietic progenitor cells (HPCs) is limited and hard to access. We have established a protocol for generation of HPCs from iPSCs followed by HPC expansion on Sl/Sl feeder cells expressing FLT3L. We performed drug treatment of iPSC-derived HPCs on feeder cells or under feeder-free conditions. Our protocol is also suitable for primary leukemia blasts. For complete details on the use and execution of this protocol, please refer to Dannenmann et al. (2021), (2020), and (2019).
Open Access Repository-Scale Propagated Nearest Neighbor Suspect Spectral Library for Untargeted Metabolomics
2022-05-15

Abstract Despite the increasing availability of tandem mass spectrometry (MS/MS) community spectral libraries for untargeted metabolomics over the past decade, the majority of acquired MS/MS spectra remain uninterpreted. To further aid in interpreting unannotated spectra, we created a nearest neighbor suspect spectral library, consisting of 87,916 annotated MS/MS spectra derived from hundreds of millions of public MS/MS spectra. Annotations were propagated based on structural relationships to reference molecules using MS/MS-based spectrum alignment. We demonstrate the broad relevance of the nearest neighbor suspect spectral library through representative examples of propagation-based annotation of acylcarnitines, bacterial and plant natural products, and drug metabolism. Our results also highlight how the library can help to better understand an Alzheimer’s brain phenotype. The nearest neighbor suspect spectral library is openly available through the GNPS platform to help investigators hypothesize candidate structures for unknown MS/MS spectra in untargeted metabolomics data.
Seasonal phytoplankton and geochemical shifts in the subsurface chlorophyll maximum layer of a dimictic ferruginous lake
2022-05-15

Abstract Subsurface chlorophyll maxima layers (SCML) are ubiquitous features of stratified aquatic systems. Availability of the micronutrient iron is known to influence marine SCML, but iron has not been explored in detail as a factor in the development of freshwater SCML. This study investigates the relationship between dissolved iron and the SCML within the dimictic, ferruginous lake Grosses Heiliges Meer in northern Germany. The occurrence of the SCML under nonferruginous conditions in the spring and ferruginous conditions in the fall are context to explore temporal changes in the phytoplankton community and indicators of primary productivity. Results indicate that despite more abundant chlorophyll in the spring, the SCML sits below a likely primary productivity maximum within the epilimnion, inferred based on colocated dissolved oxygen, δ 13 C DIC , and pH maxima. The peak amount of chlorophyll in the SCML is lower in the fall than in the spring, but in the fall the SCML is colocated with elevated dissolved iron concentrations and a local δ 13 C DIC maximum. Cyanobacteria and Chlorophyta have elevated abundances within the SCML in the fall. Further investigation of the relationship of iron to primary productivity within ferruginous SCML may help to understand the environmental controls on primary productivity in past ferruginous oceans.
Posthuman / Cyber-Gothic: An Interview with Anya Heise-Von Der Lippe
2022-05-15

Anya Heise-von der Lippe is assistant lecturer with the chair of Anglophone Literatures and teaches English Literature and Culture at the University of Tübingen, Germany. After completing her PhD with a dissertation on Monstrous Textualities (published by UWP in June 2021), she has recently started a new research project on Romanticism and Climate Change. Her publications include various chapters and articles on monsters, hypertext, zombies, dystopias and cyberpunk, as well as the edited collection Posthuman Gothic (2017), and co-edited collections Literaturwissenschaften in der Krise (2018) and Kinship and Collective Action in Literature and Culture (2020). She is one of the series editors of the book series CHALLENGES for the Humanities with Narr, Tübingen.
Between Skepticism and Identification: A Systematic Mapping of Adolescents’ Persuasion Knowledge of Influencer Marketing
2022-05-16

How well are adolescents prepared to competently cope with sponsored influencer content? This article provides a systematic mapping of influencer-specific dispositional persuasion knowledge in the five dimensions proposed by the persuasion knowledge model (PKM). In twenty-three focus groups with 132 German adolescents between eleven and fifteen years of age, the author found that adolescents are well aware of sponsored influencer posts, even if they might overestimate their knowledge. Specifically, the author observed a tension in adolescents between their knowledge that sponsored content is advertising and should be scrutinized skeptically and their identification with particular influencers.
All roads lead to Rome? Talent narratives of elite athletes, musicians, and mathematicians
2022-05-16

Public accounts about world-class athletes, musicians, and mathematicians often include notions of the highly talented child that then develops into a successful performer in a more or less straightforward manner. However, a large corpus of scientific literature indicates that talent development trajectories are highly diverse and idiosyncratic. Analysing the experiences of the high-achieving individuals themselves might add an additional perspective to our understanding of how talent develops over time. In this regard, the stories that individuals tell about their talent development can provide in-depth accounts of their experiences but also of individual and societal beliefs about talent and its development. The current study intends to examine the talent development stories of athletes, musicians, and mathematicians. Cross-domain talent research might help to culturally contextualise developmental processes. In this regard, our aims are twofold. First, we aim to examine how high-achieving individuals story their talent development pathways. Second, we aim to identify cultural ideas about talent in the individual stories. In total, we interviewed ten elite athletes, ten professional musicians, and ten elite mathematicians. We employed a thematic narrative analysis and a structural narrative analysis. We identified five types of talent narratives on developmental pathways: searching for the spotlight, straightforward career, overcoming obstacles, riding the waves, and applying effort. These types of narratives were observable across performance domains. Despite the idiosyncratic nature of developmental pathways, athletes, musicians, and mathematicians appeared to be impacted by similar sociocultural narratives about talent and its development when constructing their personal talent development stories.
Chronic Stroke Sensorimotor Impairment Is Related to Smaller Hippocampal Volumes: An ENIGMA Analysis
2022-05-16

Background Persistent sensorimotor impairments after stroke can negatively impact quality of life. The hippocampus is vulnerable to poststroke secondary degeneration and is involved in sensorimotor behavior but has not been widely studied within the context of poststroke upper‐limb sensorimotor impairment. We investigated associations between non‐lesioned hippocampal volume and upper limb sensorimotor impairment in people with chronic stroke, hypothesizing that smaller ipsilesional hippocampal volumes would be associated with greater sensorimotor impairment. Methods and Results Cross‐sectional T1‐weighted magnetic resonance images of the brain were pooled from 357 participants with chronic stroke from 18 research cohorts of the ENIGMA (Enhancing NeuoImaging Genetics through Meta‐Analysis) Stroke Recovery Working Group. Sensorimotor impairment was estimated from the FMA‐UE (Fugl‐Meyer Assessment of Upper Extremity). Robust mixed‐effects linear models were used to test associations between poststroke sensorimotor impairment and hippocampal volumes (ipsilesional and contralesional separately; Bonferroni‐corrected, P &lt;0.025), controlling for age, sex, lesion volume, and lesioned hemisphere. In exploratory analyses, we tested for a sensorimotor impairment and sex interaction and relationships between lesion volume, sensorimotor damage, and hippocampal volume. Greater sensorimotor impairment was significantly associated with ipsilesional ( P =0.005; β=0.16) but not contralesional ( P =0.96; β=0.003) hippocampal volume, independent of lesion volume and other covariates ( P =0.001; β=0.26). Women showed progressively worsening sensorimotor impairment with smaller ipsilesional ( P =0.008; β=−0.26) and contralesional ( P =0.006; β=−0.27) hippocampal volumes compared with men. Hippocampal volume was associated with lesion size ( P &lt;0.001; β=−0.21) and extent of sensorimotor damage ( P =0.003; β=−0.15). Conclusions The present study identifies novel associations between chronic poststroke sensorimotor impairment and ipsilesional hippocampal volume that are not caused by lesion size and may be stronger in women.
A Novel Proxy for Tracking the Provenance of Dust Based on Paired E1’‐Peroxy Paramagnetic Defect Centers in Fine‐Grained Quartz
2022-05-16

Abstract Crystal lattice defects in quartz have long been exploited for age determination, yet also show potential for sediment provenance studies. Here, we introduce a novel method for tracking aeolian dust provenance by utilizing the natural accumulation of E 1 ’ and peroxy defect centers in quartz. Our approach is based on the previously observed premise that E 1 ’ and peroxy centers arise from Frenkel defect pairs, and that their concentration increases with the age of the quartz‐bearing source rock. We propose that these defect centers can be utilized as a characteristic feature of the source rock and consequently, for fingerprinting sediments derived from it. We successfully apply our new protocol to distinguish fine‐grained quartz extracted from loess deposits from two regions in Central Asia which are known to derive from different source material of differing age. Our method offers strong potential for identifying variability in source, both spatially and through time down sedimentary sequences.