julilili42/papers huggingface dataset:
Inhibition of the MAPK/c-Jun-EGR1 Pathway Decreases Photoreceptor Cell Death in the rd1 Mouse Model for Inherited Retinal Degeneration
2022-11-23

Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies that typically results in photoreceptor cell death and vision loss. Here, we explored the effect of early growth response-1 (EGR1) expression on photoreceptor cell death in Pde6brd1 (rd1) mice and its mechanism of action. To this end, single-cell RNA-seq (scRNA-seq) was used to identify differentially expressed genes in rd1 and congenic wild-type (WT) mice. Chromatin immunoprecipitation (ChIP), the dual-luciferase reporter gene assay, and western blotting were used to verify the relationship between EGR1 and poly (ADP-ribose) polymerase-1 (PARP1). Immunofluorescence staining was used to assess PARP1 expression after silencing or overexpression of EGR1. Photoreceptor cell death was assessed using the TUNEL assay following silencing/overexpression of EGR1 or administration of MAPK/c-Jun pathway inhibitors tanzisertib and PD98059. Our results showed differential expression of ERG1 in rd1 and WT mice via scRNA-seq analysis. The ChIP assay demonstrated EGR1 binding to the PARP1 promoter region. The dual-luciferase reporter gene assay and western blotting results revealed that EGR1 upregulated PARP1 expression. Additionally, the TUNEL assay showed that silencing EGR1 effectively reduced photoreceptor cell death. Similarly, the addition of tanzisertib and PD98059 reduced the expression of c-Jun and EGR1 and decreased photoreceptor cell death. Our study revealed that inhibition of the MAPK/c-Jun pathway reduced the expression of EGR1 and PARP1 and prevented photoreceptor cell death. These results highlight the importance of EGR1 for photoreceptor cell death and identify a new avenue for therapeutic interventions in RP.
Intronic enhancers of the human SNCA gene predominantly regulate its expression in brain in vivo
2022-11-23

Evidence from patients with Parkinson’s disease (PD) and our previously reported α-synuclein (SNCA) transgenic rat model support the idea that increased SNCA protein is a substantial risk factor of PD pathogenesis. However, little is known about the transcription control of the human SNCA gene in the brain in vivo. Here, we identified that the DYT6 gene product THAP1 (THAP domain-containing apoptosis-associated protein 1) and its interaction partner CTCF (CCCTC-binding factor) act as transcription regulators of SNCA . THAP1 controls SNCA intronic enhancers’ activities, while CTCF regulates its enhancer-promoter loop formation. The SNCA intronic enhancers present neurodevelopment-dependent activities and form enhancer clusters similar to “super-enhancers” in the brain, in which the PD-associated single-nucleotide polymorphisms are enriched. Deletion of the SNCA intronic enhancer clusters prevents the release of paused RNA polymerase II from its promoter and subsequently reduces its expression drastically in the brain, which may provide new therapeutic approaches to prevent its accumulation and thus related neurodegenerative diseases defined as synucleinopathies.
Detection and Characterization of a De Novo Alu Retrotransposition Event Causing NKX2‐1‐Related Disorder
2022-11-23

Abstract Background Heterozygous NKX2‐1 loss‐of‐function variants cause combinations of hyperkinetic movement disorders (MDs, particularly childhood‐onset chorea), pulmonary dysfunction, and hypothyroidism. Mobile element insertions (MEIs) are potential disease‐causing structural variants whose detection in routine diagnostics remains challenging. Objective To establish the molecular diagnosis of two first‐degree relatives with clinically suspected NKX2‐1 ‐related disorder who had negative NKX2‐1 Sanger (SS), whole‐exome (WES), and whole‐genome (WGS) sequencing. Methods The proband's WES was analyzed for MEIs. A candidate MEI in NKX2‐1 underwent optimized SS after plasmid cloning. Functional studies exploring NKX2‐1 haploinsufficiency at RNA and protein levels were performed. Results A 347‐bp Alu Ya5 insertion with a 65‐bp poly‐A tail followed by a 16‐bp duplication of the pre‐insertion wild‐type sequence in exon 3 of NKX2‐1 (ENST00000354822.7:c.556_557ins Alu 541_556dup) segregated with the disease phenotype. Conclusions We identified a de novo exonic Alu Ya5 insertion causing NKX2‐1 ‐related disorder in SS/WES/WGS‐negative cases, suggesting that MEI analysis of short‐read sequencing data or targeted long‐read sequencing could unmask the molecular diagnosis of unsolved MD cases. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Immunophenotyping of Circulating and Intratumoral Myeloid and T Cells in Glioblastoma Patients
2022-11-23

Glioblastoma is the most common and lethal primary brain malignancy that almost inevitably recurs as therapy-refractory cancer. While the success of immune checkpoint blockade (ICB) revealed the immense potential of immune-targeted therapies in several types of cancers outside the central nervous system, it failed to show objective responses in glioblastoma patients as of now. The ability of glioblastoma cells to drive multiple modes of T cell dysfunction while exhibiting low-quality neoepitopes, low-mutational load, and poor antigen priming limits anti-tumor immunity and efficacy of antigen-unspecific immunotherapies such as ICB. An in-depth understanding of the GBM immune landscape is essential to delineate and reprogram such immunosuppressive circuits during disease progression. In this view, the present study aimed to characterize the peripheral and intratumoral immune compartments of 35 glioblastoma patients compared to age- and sex-matched healthy control probands, particularly focusing on exhaustion signatures on myeloid and T cell subsets. Compared to healthy control participants, different immune signatures were already found in the peripheral circulation, partially related to the steroid medication the patients received. Intratumoral CD4+ and CD8+ TEM cells (CD62Llow/CD45ROhigh) revealed a high expression of PD1, which was also increased on intratumoral, pro-tumorigenic macrophages/microglia. Histopathological analysis further identified high PSGL-1 expression levels of the latter, which has recently been linked to increased metastasis in melanoma and colon cancer via P-selectin-mediated platelet activation. Overall, the present study comprises immunophenotyping of a patient cohort to give implications for eligible immunotherapeutic targets in neurooncology in the future.
The influence of sedimentary heterogeneity on the diffusion of radionuclides in the sandy facies of Opalinus Clay at the field scale
2022-11-23

Abstract. Radionuclide migration in clay-rich formations is typically dominated by diffusion considering the low permeability of these formations. An accurate estimation of radionuclide migration in host rocks using numerical tools plays a key role in the safety assessment of disposal concepts for nuclear waste. In the sandy facies of the Opalinus Clay (SF-OPA), the spatial variability of the pore space network and compositional heterogeneity at the pore scale (nm to μm) cause heterogeneous diffusion at the core scale (cm to dm). Such heterogeneous diffusion patterns affect the migration of radionuclides in various sedimentary layers even above the core scale (m). In this work, we study the heterogeneous diffusion of cations based on a two-dimensional (2D) structural model at the m-scale. As key parameters for the diffusive transport calculation, the effective diffusion coefficients in different sedimentary layers are quantified based on our previous developed up-scaling workflow from pore- to core-scale simulation combined with the multi-scale digital rock models. The heterogeneous effective diffusivities are then implemented into the large-scale structural model for diffusive transport simulation using the FEM-based OpenGeoSys-6 simulator. The sensitivity analysis focuses on the effects of the SF-OPA bedding angle and the effect of different layer-succession layout with different canister emplacement on the spatio-temporal evolution of radionuclide diffusion front line. Results show that the moving distance of the diffusion front is farther away from the canister center, along the direction with the neighboring layer having lower diffusion coefficient within the total simulation time of 2000 years. When the bedding angle increases, the diffusion front moves farther in in vertical upward direction direction, which has less retardation effect for the radionuclide from the ground surface point. For different layer-succession layout with different canister emplacement, the smallest migration distance of the diffusion front line is 1.65 m. Within 2000 years, for the conceptual model 2B that the canister is emplaced in the layer with the highest diffusivity coefficient, the diffusion front can migrate 0.19 m farther along vertical downward direction due to the influence of the neighboring layer. The numerical results provide insight into the effects of rocks heterogeneity on diffusion of radionuclides, contributing to enhanced long-term predictability of radionuclide migration in SF-OPA as potential host rock for a deep geological repository.
Synthesis of Nε‐acetyl‐L‐homolysine by the Lossen rearrangement and its application for probing deacetylases and binding modules of acetyl‐lysine
2022-11-23

Lysine acetylation is a posttranslational protein modification mediating protein–protein interactions by recruitment of bromodomains. Investigations of bromodomains have focused so far on the sequence context of the modification site and acyl‐modifications installed at lysine side chains. In contrast, there is only little information about the impact of the lysine residue that carries the modification on bromodomain binding. Here, we report a synthesis strategy for L‐acetyl‐homolysine from L‐2‐aminosuberic acid by the Lossen rearrangement. Peptide probes containing acetylated homolysine, lysine, and ornithine were generated and used for probing the binding preferences of four bromodomains from three different families. Tested bromodomains showed distinct binding patterns, and one of them bound acetylated homolysine with similar efficiency as the native substrate containing acetyl‐lysine. Deacetylation assays with a bacterial sirtuin showed a strong preference for acetylated lysine, despite a broad specificity for N‐acyl modifications.
Parameters of Optokinetic Nystagmus Are Influenced by the Nature of a Visual Stimulus
2022-11-23

Studies on contrast sensitivity (CS) testing using optokinetic nystagmus (OKN) proposed adjusting the stimulus presentation duration based on its contrast, to increase the time efficiency of such measurement. Furthermore, stimulus-specific limits of the least OKN gain might reduce false negatives in OKN detection procedures. Therefore, we aimed to test the effects of various stimulus characteristics on OKN and to propose the stimulus-specific limits for the OKN gain and stimulus presentation duration. We tested the effect of contrast (C), spatial frequency (SF), and color on selected parameters of robust OKN response, namely its onset and offset time, amplitude, and gain. The right eyes of fifteen emmetropes were tracked with an infrared eye tracker during monocular observations of sinusoidal gratings moving over the horizontal plane with a velocity of (21∘/s). The available contrast levels were C: 0.5%, 2.0%, 8.2%, 16.5%, 33.0%, and 55.5% presented in a random order for ten times in all measurements of SF: 0.12, 0.25, 0.5, and 1.00 cycles per degree and grating type: luminance, red-green, and blue-yellow. This study showed a significant effect of the stimulus characteristics on the OKN onset, offset and gain. The effect of SF was insignificant in OKN amplitude; however, it indicated significance for the C and grating type. Furthermore, the OKN gain and offset limits were proposed as functions of contrast for the luminance and chromatic gratings. This study concludes the characteristics of a visual stimulus have an effect on the OKN gain and onset and offset time, yet do not affect the eye-movement amplitude considerably. Moreover, the proposed limits are expected to improve the time efficiency and eye-movement detection in OKN-based contrast sensitivity measurements.
Verbal Irony in Translation: LXX Amos 4:4–5, Isaiah 47:12–13, Ezekiel 28:3–5
2022-11-23

Abstract This study explores the use of verbal irony in three case studies across the Septuagint Prophets: Amos 4:4–5, Isa 47:12–13, and Ezek 28:3–5. In the MT, all three of these passages make use of verbal irony to express criticism. The prophets’ critiques remain in the LXX versions, but do not contain verbal irony in some cases. This paper aims to discern how each translator has approached rendering the verbal irony of the Hebrew parent text by describing the observable results of the translation process on linguistic and rhetorical levels.
Grazing and ecosystem service delivery in global drylands
2022-11-24

Grazing represents the most extensive use of land worldwide. Yet its impacts on ecosystem services remain uncertain because pervasive interactions between grazing pressure, climate, soil properties, and biodiversity may occur but have never been addressed simultaneously. Using a standardized survey at 98 sites across six continents, we show that interactions between grazing pressure, climate, soil, and biodiversity are critical to explain the delivery of fundamental ecosystem services across drylands worldwide. Increasing grazing pressure reduced ecosystem service delivery in warmer and species-poor drylands, whereas positive effects of grazing were observed in colder and species-rich areas. Considering interactions between grazing and local abiotic and biotic factors is key for understanding the fate of dryland ecosystems under climate change and increasing human pressure.
Heavy metalla vinyl-cations show metal–Lewis acid cooperativity in reaction with small molecules (NH3, N2H4, H2O, H2)
2022-11-24

Tetrylidinium–iridium cations [ArE = IrHL 3 ] + (E = Ge, Sn) show a vinyl-cation type bonding situation and are highly reactive electrophiles acting as a cooperative metal–ligand Lewis acid enabling 1,2-addition of NH 3 , N 2 H 4 , H 2 O, HCl and H 2 .
Mechanistic modeling indicates rapid glyphosate dissipation and sorption‐driven persistence of its metabolite AMPA in soil
2022-11-24

Abstract Residual concentrations of glyphosate and its main transformation product aminomethylphosphonic acid (AMPA) are often observed in soils. The factors controlling their biodegradation are currently not well understood. We analyzed sorption‐limited biodegradation of glyphosate and AMPA in soil with a set of microcosm experiments. A mechanistic model that accounts for equilibrium and kinetic sorption facilitated interpretation of the experimental results. Both compounds showed a biphasic dissipation with an initial fast (up to Days 7–10) and subsequent slower transformation rate, pointing to sorption‐limited degradation. Glyphosate transformation was well described by considering only equilibrium sorption. Model simulations suggested that only 0.02–0.13% of total glyphosate was present in the soil solution and thus bioavailable. Glyphosate transformation was rapid in solution (time required for 50 % dissipation of the total initially added chemical [DT 50 ] = 3.9 min), and, despite strong equilibrium sorption, total glyphosate in soil dissipated quickly (DT 50 = 2.4 d). Aminomethylphosphonic acid dissipation kinetics could only be described when considering both equilibrium and kinetic sorption. In comparison to glyphosate, the model simulations showed that a higher proportion of total AMPA was dissolved and directly bioavailable (0.27–3.32%), but biodegradation of dissolved AMPA was slower (DT 50 = 1.9 h). The model‐based data interpretation suggests that kinetic sorption strongly reduces AMPA bioavailability, leading to increased AMPA persistence in soil (DT 50 = 12 d). Thus, strong sorption combined with rapid degradation points to low risks of glyphosate leaching by vertical transport through soil in the absence of preferential flow. Ecotoxicological effects on soil microorganisms might be reduced. In contrast, AMPA persists, rendering these risks more likely.
The eROSITA Final Equatorial-Depth Survey (eFEDS)
2022-11-24

Context. We present the results of a systematic X-ray analysis of optically rich galaxy clusters detected by the Subaru Hyper Suprime-Cam (HSC) survey in the eROSITA Final Equatorial-Depth Survey (eFEDS) field. Aims. Through a joint analysis of the SRG (Spectrum Roentgen Gamma)/eROSITA and Subaru/HSC surveys, we aim to investigate the dynamical status of the optically selected clusters and to derive the cluster scaling relations. Methods. The sample consists of 43 optically selected galaxy clusters with a richness &gt;40 in the redshift range of 0.16–0.89. We systematically analyzed the X-ray images and emission spectra using the eROSITA data. We identified the brightest cluster galaxy (BCG) using the optical and far-infrared databases. We evaluated the cluster’s dynamical status by measuring three quantities: offset between the X-ray peak and BCG position, the gas concentration parameter, and the number of galaxy-density peaks. We investigated the luminosity–temperature and mass–luminosity relations based on eROSITA X-ray spectra and HSC weak-lensing data analyses. Results. Based on these three measurements, we estimated the fraction of relaxed clusters to be 2(&lt; 39)%, which is smaller than that of the X-ray-selected cluster samples. After correcting for a selection bias due to the richness cut, we obtained a shallow L − T slope of 2.1 ± 0.5, which is consistent with the predictions of the self-similar model and the baseline model incorporating a mass–concentration relation. The L − M slope of 1.5 ± 0.3 is in agreement with the above-cited theoretical models as well as the data on the shear-selected clusters in the eFEDs field. Conclusions. Our analysis of high-richness optical clusters yields a small fraction of relaxed clusters and a shallow slope for the luminosity–temperature relation. This suggests that the average X-ray properties of the optical clusters are likely to be different from those observed in the X-ray samples. Thus, the joint eROSITA and HSC observations are a powerful tool in extending the analysis to a larger sample and understanding the selection effect with a view to establish cluster scaling relations.
Success rate and duration of orotracheal intubation of premature infants by healthcare providers with different levels of experience using a video laryngoscope as compared to direct laryngoscopy in a simulation-based setting
2022-11-24

Background Endotracheal intubation of very low birth weight infants (VLBWI) is an essential procedure in NICUs, but intubation experience is often limited. Video laryngoscopy (VL) has been described as a tool to improve intubation skills, but studies in high-risk neonatal populations are limited. Objective The aim of this study was to investigate whether VL is a useful tool to support airway management in high-risk premature infants with inexperienced operators. Methods In this crossover study predominantly inexperienced participants were exposed in random sequence to VL and conventional direct laryngoscopy (DL) for endotracheal intubation of a VLBWI simulation manikin to measure total time, number of attempts, success rate on first attempt, view of the vocal cords and perceived subjective safety until successful intubation. Results In our study group of 94 participants there was no significant difference in the total time (mean VL: 34 s (±24 s); DL: 37 s (±28 s), p = 0.246), while the number of intubation attempts using VL was significantly lower (mean VL: 1.22 (±0.53); DL: 1.37 (±0.60), p = 0.023). Success rate of VL during the first attempt was significantly higher (VL: 84%; DL 69%, p = 0.016), view of the vocal cords was significantly better and perceived subjective safety was increased using VL. Conclusions Our study results suggest that with rather inexperienced operators, VL can be a useful tool to increase rate of successful endotracheal intubation of VLBWI and to improve their perceived safety during the procedure, which may have an impact on mortality and/or morbidity.
Nudging digital physical activity breaks for home studying of university students—A randomized controlled trial during the COVID-19 pandemic with daily activity measures
2022-11-24

University students are of particular public health interest because they are at high risk for physical inactivity and sedentary behaviors. In conjunction with the COVID-19 pandemic, sedentariness and physical inactivity were reinforced, as the pandemic led to an increase in home studying. Physical activity (PA) breaks have been identified as promoting factors for university students' physical and mental health. Therefore, the present study explored an approach to nudge students to take PA breaks at home while studying. The purpose was to test the effectiveness of digital nudging for PA breaks for 10 days using a randomized intervention design during the COVID-19 pandemic. It included an intervention group who received daily digital motivational prompts for PA break videos and a minimal intervention control group who got low-level access to PA break videos via a one-time link sent to the media library. Using a sample of university students in the southwest of Germany ( n = 57), two-level binary logistic regression models were calculated to predict daily participation in PA breaks during the intervention period depending on the nudging intervention, as well as previous participation in PA breaks, the general PA level of the subjects before the intervention, the time spent on PA and on home studying in a day, the kind of day during the intervention (weekday vs. weekend), and the students' age. Results revealed that the digital nudging intervention did not show any significant effect on the likelihood to participate in PA breaks on a given day (0.69 ≤ β ≤ 0.75, p &amp;gt; 0.3). Instead, an individual-level effect revealed that the longer a student studied at home over the course of a day, the more likely he or she was to take a PA break (1.07 ≤ β ≤ 1.11, p &amp;lt; 0.001). Current findings show that individual characteristics such as daily time spent on home studying, which can change over the course of the intervention phase, are relevant considerations within nudging intervention in university setting. This provides initial insights especially for digital PA breaks for students during home studying.
Prediction of Drug–Drug–Gene Interaction Scenarios of (E)-Clomiphene and Its Metabolites Using Physiologically Based Pharmacokinetic Modeling
2022-11-25

Clomiphene, a selective estrogen receptor modulator (SERM), has been used for the treatment of anovulation for more than 50 years. However, since (E)-clomiphene ((E)-Clom) and its metabolites are eliminated primarily via Cytochrome P450 (CYP) 2D6 and CYP3A4, exposure can be affected by CYP2D6 polymorphisms and concomitant use with CYP inhibitors. Thus, clomiphene therapy may be susceptible to drug–gene interactions (DGIs), drug–drug interactions (DDIs) and drug–drug–gene interactions (DDGIs). Physiologically based pharmacokinetic (PBPK) modeling is a tool to quantify such DGI and DD(G)I scenarios. This study aimed to develop a whole-body PBPK model of (E)-Clom including three important metabolites to describe and predict DGI and DD(G)I effects. Model performance was evaluated both graphically and by calculating quantitative measures. Here, 90% of predicted Cmax and 80% of AUClast values were within two-fold of the corresponding observed value for DGIs and DD(G)Is with clarithromycin and paroxetine. The model also revealed quantitative contributions of different CYP enzymes to the involved metabolic pathways of (E)-Clom and its metabolites. The developed PBPK model can be employed to assess the exposure of (E)-Clom and its active metabolites in as-yet unexplored DD(G)I scenarios in future studies.