julilili42/papers huggingface dataset:
In Vivo Efficacy and Safety Evaluations of Therapeutic Splicing Correction Using U1 snRNA in the Mouse Retina
2023-03-21

Efficacy and safety considerations constitute essential steps during development of in vivo gene therapies. Herein, we evaluated efficacy and safety of splice factor-based treatments to correct mutation-induced splice defects in an Opa1 mutant mouse line. We applied adeno-associated viruses to the retina. The viruses transduced retinal cells with an engineered U1 snRNA splice factor designed to correct the Opa1 splice defect. We found the treatment to be efficient in increasing wild-type Opa1 transcripts. Correspondingly, Opa1 protein levels increased significantly in treated eyes. Measurements of retinal morphology and function did not reveal therapy-related side-effects supporting the short-term safety of the treatment. Alterations of potential off-target genes were not detected. Our data suggest that treatments of splice defects applying engineered U1 snRNAs represent a promising in vivo therapeutic approach. The therapy increased wild-type Opa1 transcripts and protein levels without detectable morphological, functional or genetic side-effects in the mouse eye. The U1 snRNA-based therapy can be tailored to specific disease gene mutations, hence, raising the possibility of a wider applicability of this promising technology towards treatment of different inherited retinal diseases.
Lipocalin 2 – mutation screen and serum levels in patients with anorexia nervosa or obesity and in lean individuals
2023-03-21

Context The bone-derived adipokine lipocalin-2 is relevant for body weight regulation by stimulating the leptin-melanocortin pathway. Objective We aimed to (i) detect variants in the lipocalin-2 gene ( LCN2 ) which are relevant for body weight regulation and/or anorexia nervosa (AN); (ii) describe and characterize the impact of LCN2 and MC4R variants on circulating lipocalin-2 level. Methods Sanger sequencing of the coding region of LCN2 in 284 children and adolescents with severe obesity or 287 patients with anorexia nervosa. In-silico analyses to evaluate functional implications of detected LCN2 variants. TaqMan assays for rare non-synonymous variants (NSVs) in additional independent study groups. Serum levels of lipocalin-2 were measured by ELISA in 35 females with NSVs in either LCN2 or MC4R , and 33 matched controls without NSVs in the two genes. Results Fourteen LCN2 -variants (five NSVs) were detected. LCN2 -p.Leu6Pro and p.Gly9Val located in the highly conserved signal peptide region may induce functional consequences. The secondary structure change of lipocalin-2 due to LCN 2-p.Val89Ile may decrease solubility and results in a low lipocalin-2 level in a heterozygotes carrier (female recovered from AN). Lean individuals had lower lipocalin-2 levels compared to patients with obesity ( p = 0.033). Conclusion Lipocalin-2 levels are positively associated with body mass index (BMI). Single LCN2 -variants might have a profound effect on lipocalin-2 levels.
Relevance of university dual career support services – student–athletes’ perspectives
2023-03-21

Rationale/Purpose Universities provide various services supporting athletes pursuing a dual career. This paper focuses on the preconditions of being simultaneously included in elite sport and educational system, aiming to analyse the assessment of such services from the student–athletes' perspective.Design/Methodology/Approach The data originate from an online survey of 1055 international student–athletes, who participated in the 2019 Winter and Summer Universiades. Based on exploratory factor analysis, support services were grouped into categories. Implementing probit models, the respondents' perceptions were regressed with their sporting and academic background by controlling for socio-demographic factors.Findings The study identifies three factors of dual career support services in the context of higher education and reveals statistically significant associations between socio-demographic, academic, and sporting career-related factors and the perceived relevance of support services.Practical Implications To get the university context functionalised in favour of student–athletes' dual careers, tailor-made support should particularly address differences regarding gender, university levels, and types of sport.Research Contribution The study enhances the understanding of dual career challenges, related to the student–athletes' conflicting roles. It provides evidence that adequate dual career support services at the interfaces of elite sport and higher education need to be individualised according to the athletes' needs.
Repeated Lung Ultrasound versus Chest X-ray—Which One Predicts Better Clinical Outcome in COVID-19?
2023-03-21

The purpose of this study was to evaluate whether changes in repeated lung ultrasound (LUS) or chest X-ray (CXR) of coronavirus disease 2019 (COVID-19) patients can predict the development of severe disease and the need for treatment in the intensive care unit (ICU). In this prospective monocentric study, COVID-19 patients received standardized LUS and CXR at day 1, 3 and 5. Scores for changes in LUS (LUS score) and CXR (RALE and M-RALE) were calculated and compared. Intra-class correlation was calculated for two readers of CXR and ROC analysis to evaluate the best discriminator for the need for ICU treatment. A total of 30 patients were analyzed, 26 patients with follow-up LUS and CXR. Increase in M-RALE between baseline and follow-up 1 was significantly higher in patients with need for ICU treatment in the further hospital stay (p = 0.008). Both RALE and M-RALE significantly correlated with LUS score (r = 0.5, p &lt; 0.0001). ROC curves with need for ICU treatment as separator were not significantly different for changes in M-RALE (AUC: 0.87) and LUS score (AUC: 0.79), both being good discriminators. ICC was moderate for RALE (0.56) and substantial for M-RALE (0.74). The present study demonstrates that both follow-up LUS and CXR are powerful tools to track the evolution of COVID-19, and can be used equally as predictors for the need for ICU treatment.
Deep Annotation of Donated Chemical Probes (DCP) in Organotypic Human Liver Cultures and Patient-Derived Organoids from Tumor and Normal Colorectum
2023-03-21

Well-characterized small molecules are essential tools for studying the biology and therapeutic relevance of a target protein. However, many compounds reported in the literature and routinely studied in biomedical research lack the potency and selectivity required for mechanistic cellular studies on the function of a given protein. Furthermore, commercially available compounds often do not include useful tools developed by industry as part of their research and development efforts, as they frequently remain proprietary. The freely available donated chemical probe (DCP) library, fueled by generous donations of compounds from industry and academia, enables easy access to a steadily growing collection of these valuable and well-characterized tools. Here, we provide a systematic description of the current DCP library collection and their associated comprehensive characterization data, including a variety of <i>in vitro</i> and cellular assays. Of note, we characterized the set in relevant human primary models by employing hepatotoxicity screening in primary human liver spheroids and viability screening in patient-derived colorectal cancer organoids and matched normal-adjacent epithelium. Taken together, the DCP library represents a well-annotated, openly available collection of tool compounds for studying a wide range of targets, including kinases, G-protein-coupled receptors, and ion channels. As such, it represents a unique resource for the biomedical research community.
China’s Twitter Diplomacy in Germany: Practices, Reactions, and Discrepancies
2023-03-21

China’s digital public diplomacy on social media and the ways in which Chinese diplomats communicate have received international attention and generated academic interest. As the first study to conduct country-specific investigation on how Chinese diplomats in Germany practice digital public diplomacy on Twitter, this article examines their communication strategies based on Twitter data collected from verified accounts of Chinese diplomats in Germany during the part of the pandemic from January 2020 to February 2021. The study also identifies discrepancies between the actual practices of China’s Twitter diplomacy in Germany and media perception of China’s Twitter diplomacy represented by relevant news articles from two German mainstream newspapers, Frankfurter Allgemeine Zeitung and the Süddeutsche Zeitung in 2020. The discrepancies, the author claims, can be attributed to the process of othering China, i.e. framing China as the other, that eventually compromises the effectiveness of China’s communication strategies. Seeing China’s Twitter diplomacy as network-centric public diplomacy with Chinese characteristics, this article depicts the ways in which the case of Germany contributes to the understanding of the global communication network of China’s public diplomacy on Twitter by showing its country-specific communication strategies.
Comment on cp-2023-2
2023-03-21

<strong class="journal-contentHeaderColor">Abstract.</strong> Changes in tropical precipitation over the past millennia have usually been associated with latitudinal displacements of the Intertropical Convergence Zone (ITCZ). Recent studies provide new evidence that contraction and expansion of the tropical rainbelt may also have contributed to ITCZ variability on centennial time scales. Over tropical South America few records point to a similar interpretation, which prevents a clear diagnosis of ITCZ changes in the region. In order to improve our understanding of the equatorial rainbelt variability, our study presents a reconstruction of precipitation for the last 3200 years from the Northeast Brazil (NEB) region, an area solely influenced by ITCZ precipitation. We analyze oxygen isotopes in speleothems that serve as a faithful proxy for the past location of the southern margin of the ITCZ. Our results, in comparison with other ITCZ proxies, indicate that the range of seasonal migration, contraction and expansion of the ITCZ was not symmetrical around the equator. A new NEB ITCZ pattern emerged based on the comparison between two distinct proxies that characterize the ITCZ behavior during the last 2500 years, with an ITCZ zonal pattern between NEB and the eastern Amazon. In NEB, the period related to the Medieval Climate Anomaly (MCA) was characterized by an abrupt transition from wet to dry conditions. These drier conditions persisted until the onset of the period corresponding to the Little Ice Age (LIA), representing the longest dry period over the last 3200 years in NEB. The ITCZ was apparently forced by teleconnections between Atlantic Multidecadal Variability and Pacific Decadal Variability that controlled the position, intensity and width of Walker cell over South America changing the ITCZ zonally, and sea surface temperature changes in both the Pacific and Atlantic, stretching/weaking the ITCZ-related rainfall meridionally over NEB. Wetter conditions started around 1500 CE in NEB. During the last 500 years, our speleothems document the occurrence of some of the strongest drought events for the last millennia, which drastically affected population and environment of NEB during the Portuguese colonial period. The historical droughts were able to affect the karst system, and led to significant impacts over the entire NEB region.
S3-CIMA: Supervised spatial single-cell image analysis for the identification of disease-associated cell type compositions in tissue
2023-03-21

Abstract The spatial organization of various cell types within the tissue microenvironment is a key element for the formation of physiological and pathological processes, including cancer and autoimmune diseases. Here, we present S 3 -CIMA, a weakly supervised convolutional neural network model that enables the detection of disease-specific microenvironment compositions from high-dimensional proteomic imaging data. We demonstrate the utility of this approach by determining cancer outcome- and cellular signaling-specific spatial cell state compositions in highly multiplexed fluorescence microscopy data of the tumor microenvironment in colorectal cancer. Moreover, we use S 3 -CIMA to identify disease onset-specific changes of the pancreatic tissue microenvironment in type 1 diabetes using imaging mass cytometry data. We evaluated S 3 -CIMA as a powerful tool to discover novel disease-associated spatial cellular interactions from currently available and future spatial biology datasets.
Titanium-catalysed deoxygenation of benzylic alcohols and lignin model compounds
2023-03-21

We report a catalytic system for direct deoxygenation of benzylic alcohols by using non-precious precatalyst Cp2TiCl2 and 2 MeTHF as solvent. Mechanistic studies showed that the used silane Me(EtO)2SiH acts both as H-donor and regenerating agent of the active catalytic species. This method tolerates a wide variety of functional and protecting groups and enables sequential deoxygenation-dehalogenation and deoxygenation-hydrogenation reactions. The procedure was successfully applied in the exhaustive reduction of lignin model substrates into value-added compounds.
A novel miR-99b-5p-Zbp1pathway in microglia contributes to the pathogenesis of schizophrenia
2023-03-21

Abstract Schizophrenia is a psychiatric disorder that is still not readily treatable. Pharmaceutical advances in the treatment of schizophrenia have mainly focused on the protein coding part of the human genome. However, the vast majority of the human transcriptome consists of non-coding RNAs. MicroRNAs are small non-coding RNAs that control the transcriptome at the systems level. In the present study we analyzed the microRNAome in blood and postmortem brains of controls and schizophrenia patients and found that miR-99b-5p was downregulated in both the prefrontal cortex and blood of patients. At the mechanistic level we show that inhibition of miR-99b-5p leads to schizophrenia-like phenotypes in mice and induced inflammatory processes in microglia linked to synaptic pruning. The miR-99b-5p-mediated inflammatory response in microglia depended on Z-DNA binding protein 1 ( Zbp1 ) which we identified as a novel miR-99b-5p target. Antisense oligos (ASOs) against Zbp1 ameliorated the pathological phenotypes caused by miR-99b-5p inhibition. In conclusion, we report a novel miR-99b-5p- Zbp1 pathway in microglia that contributes to the pathogenesis of schizophrenia. Our data suggest that strategies to increase the levels of miR-99b-5p or inhibit Zbp1 could become a novel therapeutic strategy.
High-quality digital distance teaching during COVID-19 school closures: Does familiarity with technology matter?
2023-03-22

During the COVID-19-related school closures teachers and students were challenged to suddenly switch to digital teaching at a distance. In particular, the challenge was to organize high-quality teaching in which students stay on task. Familiarity with technology may have helped to master the situation. However, only few studies so far have examined the quality of digital distance teaching (e.g., cognitive activation) during school closures and its relation to students' learning (e.g., effort investment). Moreover, systematic research concerning the role of familiarity with technology-enhanced teaching and learning acquired during face-to-face teaching is yet lacking. In our study, we used data from 729 ninth graders to investigate how student-observed learning activities when using technology at a distance were related to students' effort in learning in two subjects (mathematics, German). In addition, we examined whether student-perceived cognitive activation mediated this relation. Finally, the sample provides the unique opportunity to examine the role of familiarity, as some of the classes had been randomly equipped with tablet computers one year before the school closures and thus had the opportunity to gain familiarity with using technology in the classroom. Results from structural equation models showed that student-observed learning activities were associated with students' learning effort in both subjects. Student-perceived cognitive activation mediated this association. Familiarity with face-to-face technology-enhanced teaching gained before the COVID-19 pandemic appeared to be less important for high-quality digital distance teaching. Thus, infrastructural measures, such as equipping schools with digital devices so that teachers and students can familiarize themselves with technology, do not seem to be decisive for high-quality digital (distance) teaching-at least in the case of short-term change from face-to-face to digital distance teaching, as was necessary during the COVID-19 pandemic.
p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study
2023-03-22

Abstract Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high‐grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi‐institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36–3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11–2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.
Women directors, board attendance, and corporate financial performance
2023-03-22

Abstract Research Question/Issue Using insights from an in‐depth qualitative interview study, we propose an input‐process‐output model where the link between women directors (input) and corporate financial performance (output) is mediated by board attendance and where board attendance serves as a proxy of several intermediate but latent board processes. Further, we dig deeper into the nonlinearities of female boardroom representation by analyzing in how far the postulated mediation depends on the number of women in the boardroom. Research Findings/Insights Analyzing quantitative data from German supervisory boards over an 11‐year period, we find the link between women directors and corporate financial performance to be partially mediated by board attendance, and we find the mediation to depend on whether there is more than just one “token” woman in the boardroom. When there is only one woman in the boardroom, her presence is positively linked to board attendance, but the higher board attendance does not to translate into a better corporate financial performance. Theoretical/Academic Implications Our study contributes to theory, by inductively enriching our understanding of how and when women directors and corporate financial performance are linked. Practitioner/Policy Implications Our study encourages firms to appoint more than one woman to the boardroom to profit from an enhanced board attendance that will then also translate into a better corporate financial performance.
The transcriptional regulator JAZ8 interacts with the C2 protein from geminiviruses and limits the geminiviral infection in Arabidopsis
2023-03-22

ABSTRACT Jasmonates (JAs) are phytohormones that finely regulate critical biological processes, including plant development and defense. JASMONATE ZIM‐DOMAIN (JAZ) proteins are crucial transcriptional regulators that keep JA‐responsive genes in a repressed state. In the presence of JA‐Ile, JAZ repressors are ubiquitinated and targeted for degradation by the ubiquitin/proteasome system, allowing the activation of downstream transcription factors and, consequently, the induction of JA‐responsive genes. A growing body of evidence has shown that JA signaling is crucial in defending against plant viruses and their insect vectors. Here, we describe the interaction of C2 proteins from two tomato‐infecting geminiviruses from the genus Begomovirus, tomato yellow leaf curl virus (TYLCV) and tomato yellow curl Sardinia virus (TYLCSaV), with the transcriptional repressor JAZ8 from Arabidopsis thaliana and its closest orthologue in tomato, SlJAZ9. Both JAZ and C2 proteins colocalize in the nucleus, forming discrete nuclear speckles. Overexpression of JAZ8 did not lead to altered responses to TYLCV infection in Arabidopsis ; however, knock‐down of JAZ8 favors geminiviral infection. Low levels of JAZ8 likely affect the viral infection specifically, since JAZ8 ‐silenced plants neither display obvious developmental phenotypes nor present differences in their interaction with the viral insect vector. In summary, our results show that the geminivirus‐encoded C2 interacts with JAZ8 in the nucleus, and suggest that this plant protein exerts an anti‐geminiviral effect.
Discovery of the linear energy dependence of the spectral lag of X-ray bursts from SGR J1935+2154
2023-03-22

ABSTRACT Spectral lag of the low-energy photons with respect to the high-energy ones is a common astrophysical phenomenon (such as gamma-ray bursts and the Crab Pulsar) and may serve as a key probe to the underlying radiation mechanism. However, spectral lag in keV range of the magnetar bursts has not been systematically studied yet. In this work, we perform a detailed spectral lag analysis with the Li et al.’s Cross-Correlation Function (Li-CCF) method for SGR J1935+2154 bursts observed by Insight-Hard X-ray Modulation Telescope (HXMT), Gravitational Wave High-energy Electromagnetic Counterpart All-sky Monitor (GECAM), and Fermi/Gamma-ray Burst Monitor (GBM) from 2014 July to 2022 January. We discover that the spectral lags of about 61 per cent (non-zero significance &amp;gt;1σ) bursts from SGR J1935+2154 are linearly dependent on the photon energy (E) with tlag(E) = α(E/keV) + C, which may be explained by a linear change of the temperature of the blackbody-emitting plasma with time. The distribution of the slope (α) approximately follows a Gaussian function with mean and standard deviation of 0.02 ms keV−1 (i.e. high-energy photons arrive earlier) and 0.02 ms keV−1, respectively. We also find that the distribution can be well fitted with three Gaussians with mean values of ∼−10.009, 0.013, and 0.039 ms keV−1, which may correspond to different origins of the bursts. These spectral lag features may have important implications on the magnetar bursts.