bluuebunny/crossref_metadata_2025_split huggingface dataset:
The THO complex counteracts TERRA R-loop-mediated telomere fragility in telomerase+ cells and telomeric recombination in ALT+ cells
Authors: Fernandes Rita Valador , Lingner Joachim 
Published: May 2023

Abstract
Telomeres are the nucleoprotein structures at the ends of linear chromosomes. Telomeres are transcribed into long non-coding Telomeric Repeat-Containing RNA (TERRA), whose functions rely on its ability to associate with telomeric chromatin. The conserved THO complex (THOC) was previously identified at human telomeres. It links transcription with RNA processing, decreasing the accumulation of co-transcriptional DNA:RNA hybrids throughout the genome. Here, we explore the role of THOC at human telomeres, as a regulator of TERRA localization to chromosome ends. We show that THOC counteracts TERRA association with telomeres via R-loops formed co-transcriptionally and also post-transcriptionally, in trans. We demonstrate that THOC binds nucleoplasmic TERRA, and that RNaseH1 loss, which increases telomeric R-loops, promotes THOC occupancy at telomeres. Additionally, we show that THOC counteracts lagging and mainly leading strand telomere fragility, suggesting that TERRA R-loops can interfere with replication fork progression. Finally, we observed that THOC suppresses telomeric sister-chromatid exchange and C-circle accumulation in ALT cancer cells, which maintain telomeres by recombination. Altogether, our findings reveal crucial roles of THOC in telomeric homeostasis through the co- and post-transcriptional regulation of TERRA R-loops.
Gene knockout inference with variational graph autoencoder learning single-cell gene regulatory networks
Authors: Yang Yongjian , Li Guanxun , Zhong Yan , Xu Qian , Chen Bo-Jia , Lin Yu-Te , Chapkin Robert S , Cai James J 
Published: May 2023

AbstractIn this paper, we introduce Gene Knockout Inference (GenKI), a virtual knockout (KO) tool for gene function prediction using single-cell RNA sequencing (scRNA-seq) data in the absence of KO samples when only wild-type (WT) samples are available. Without using any information from real KO samples, GenKI is designed to capture shifting patterns in gene regulation caused by the KO perturbation in an unsupervised manner and provide a robust and scalable framework for gene function studies. To achieve this goal, GenKI adapts a variational graph autoencoder (VGAE) model to learn latent representations of genes and interactions between genes from the input WT scRNA-seq data and a derived single-cell gene regulatory network (scGRN). The virtual KO data is then generated by computationally removing all edges of the KO gene—the gene to be knocked out for functional study—from the scGRN. The differences between WT and virtual KO data are discerned by using their corresponding latent parameters derived from the trained VGAE model. Our simulations show that GenKI accurately approximates the perturbation profiles upon gene KO and outperforms the state-of-the-art under a series of evaluation conditions. Using publicly available scRNA-seq data sets, we demonstrate that GenKI recapitulates discoveries of real-animal KO experiments and accurately predicts cell type-specific functions of KO genes. Thus, GenKI provides an in-silico alternative to KO experiments that may partially replace the need for genetically modified animals or other genetically perturbed systems.
eEF2 diphthamide modification restrains spurious frameshifting to maintain translational fidelity
Authors: Shin Byung-Sik , Ivanov Ivaylo P , Kim Joo-Ran , Cao Chune , Kinzy Terri G , Dever Thomas E 
Published: May 2023

Abstract
Diphthamide (DPH), a conserved amino acid modification on eukaryotic translation elongation factor eEF2, is synthesized via a complex, multi-enzyme pathway. While DPH is non-essential for cell viability and its function has not been resolved, diphtheria and other bacterial toxins ADP-ribosylate DPH to inhibit translation. Characterizing Saccharomyces cerevisiae mutants that lack DPH or show synthetic growth defects in the absence of DPH, we show that loss of DPH increases resistance to the fungal translation inhibitor sordarin and increases –1 ribosomal frameshifting at non-programmed sites during normal translation elongation and at viral programmed frameshifting sites. Ribosome profiling of yeast and mammalian cells lacking DPH reveals increased ribosomal drop-off during elongation, and removal of out-of-frame stop codons restores ribosomal processivity on the ultralong yeast MDN1 mRNA. Finally, we show that ADP-ribosylation of DPH impairs the productive binding of eEF2 to elongating ribosomes. Our results reveal that loss of DPH impairs the fidelity of translocation during translation elongation resulting in increased rates of ribosomal frameshifting throughout elongation and leading to premature termination at out-of-frame stop codons. We propose that the costly, yet non-essential, DPH modification has been conserved through evolution to maintain translational fidelity despite being a target for inactivation by bacterial toxins.
NOVA1 prevents overactivation of the unfolded protein response and facilitates chromatin access during human white adipogenesis
Authors: Yang Zhigang , Dong Ping , Cao Jiankun , Lin Na , Ma Shize , Cao Rui , Cai Lei , Wang Lei , Cao Changchang , Xue Yuanchao , Pan Jing , Li Xiu , Wang Kang , Liu Qiwei , Li Chen , Gong Fuxing , Fu Xin , Xiao Ran 
Published: May 2023

Abstract
The molecular mechanism underlying white adipogenesis in humans has not been fully elucidated beyond the transcriptional level. Here, we found that the RNA-binding protein NOVA1 is required for the adipogenic differentiation of human mesenchymal stem cells. By thoroughly exploring the interactions between NOVA1 and its binding RNA, we proved that NOVA1 deficiency resulted in the aberrant splicing of DNAJC10 with an in-frame premature stop codon, reduced DNAJC10 expression at the protein level and hyperactivation of the unfolded protein response (UPR). Moreover, NOVA1 knockdown abrogated the down-regulation of NCOR2 during adipogenesis and up-regulated the 47b+ splicing isoform, which led to decreased chromatin accessibility at the loci of lipid metabolism genes. Interestingly, these effects on human adipogenesis could not be recapitulated in mice. Further analysis of multispecies genomes and transcriptomes indicated that NOVA1-targeted RNA splicing is evolutionarily regulated. Our findings provide evidence for human-specific roles of NOVA1 in coordinating splicing and cell organelle functions during white adipogenesis.
The prognostic impact of subclonal IDH1 mutation in grade 2–4 astrocytomas
Authors: Vij Meenakshi , Yokoda Raquel T , Rashidipour Omid , Tran Ivy , Vasudevaraja Varshini , Snuderl Matija , Yong Raymund L , Cobb William S , Umphlett Melissa , Walker Jamie M , Tsankova Nadejda M , Richardson Timothy E 
Published: May 2023

Abstract

Background
Isocitrate dehydrogenase (IDH) mutations are thought to represent an early oncogenic event in glioma evolution, found with high penetrance across tumor cells; however, in rare cases, IDH mutation may exist only in a small subset of the total tumor cells (subclonal IDH mutation).

Methods
We present 2 institutional cases with subclonal IDH1 R132H mutation. In addition, 2 large publicly available cohorts of IDH-mutant astrocytomas were mined for cases harboring subclonal IDH mutations (defined as tumor cell fraction with IDH mutation ≤0.67) and the clinical and molecular features of these subclonal cases were compared to clonal IDH-mutant astrocytomas.

Results
Immunohistochemistry (IHC) performed on 2 institutional World Health Organization grade 4 IDH-mutant astrocytomas revealed only a minority of tumor cells in each case with IDH1 R132H mutant protein, and next-generation sequencing (NGS) revealed remarkably low IDH1 variant allele frequencies compared to other pathogenic mutations, including TP53 and/or ATRX. DNA methylation classified the first tumor as high-grade IDH-mutant astrocytoma with high confidence (0.98 scores). In the publicly available datasets, subclonal IDH mutation was present in 3.9% of IDH-mutant astrocytomas (18/466 tumors). Compared to clonal IDH-mutant astrocytomas (n = 156), subclonal cases demonstrated worse overall survival in grades 3 (P = .0106) and 4 (P = .0184).

Conclusions
While rare, subclonal IDH1 mutations are present in a subset of IDH-mutant astrocytomas of all grades, which may lead to a mismatch between IHC results and genetic/epigenetic classification. These findings suggest a possible prognostic role of IDH mutation subclonality, and highlight the potential clinical utility of quantitative IDH1 mutation evaluation by IHC and NGS.
Derivation and External Validation of a Clinical Prediction Model for Viral Diarrhea Etiology in Bangladesh
Authors: Garbern Stephanie Chow , Islam Md Taufiqul , Islam Kamrul , Ahmed Sharia M , Brintz Ben J , Khan Ashraful Islam , Taniuchi Mami , Platts-Mills James A , Qadri Firdausi , Leung Daniel T 
Published: May 2023

Abstract

Background
Antibiotics are commonly overused for diarrheal illness in many low- and middle-income countries, partly due to a lack of diagnostics to identify viral cases, in which antibiotics are not beneficial. This study aimed to develop clinical prediction models to predict risk of viral-only diarrhea across all ages, using routinely collected demographic and clinical variables.

Methods
We used a derivation dataset from 10 hospitals across Bangladesh and a separate validation dataset from the icddr,b Dhaka Hospital. The primary outcome was viral-only etiology determined by stool quantitative polymerase chain reaction. Multivariable logistic regression models were fit and externally validated; discrimination was quantified using area under the receiver operating characteristic curve (AUC) and calibration assessed using calibration plots.

Results
Viral-only diarrhea was common in all age groups (&lt;1 year, 41.4%; 18–55 years, 17.7%). A forward stepwise model had AUC of 0.82 (95% confidence interval [CI], .80–.84) while a simplified model with age, abdominal pain, and bloody stool had AUC of 0.81 (95% CI, .78–.82). In external validation, the models performed adequately although less robustly (AUC, 0.72 [95% CI, .70–.74]).

Conclusions
Prediction models consisting of 3 routinely collected variables can accurately predict viral-only diarrhea in patients of all ages in Bangladesh and may help support efforts to reduce inappropriate antibiotic use.
Humans feel too special for machines to score their morals
Authors: Purcell Zoe A , Bonnefon Jean-François 
Published: May 2023

Abstract
Artificial intelligence (AI) can be harnessed to create sophisticated social and moral scoring systems—enabling people and organizations to form judgments of others at scale. However, it also poses significant ethical challenges and is, subsequently, the subject of wide debate. As these technologies are developed and governing bodies face regulatory decisions, it is crucial that we understand the attraction or resistance that people have for AI moral scoring. Across four experiments, we show that the acceptability of moral scoring by AI is related to expectations about the quality of those scores, but that expectations about quality are compromised by people's tendency to see themselves as morally peculiar. We demonstrate that people overestimate the peculiarity of their moral profile, believe that AI will neglect this peculiarity, and resist for this reason the introduction of moral scoring by AI.
Toward the remote monitoring of armed conflicts
Authors: Sticher Valerie , Wegner Jan D , Pfeifle Birke 
Published: May 2023

AbstractThe war in Ukraine has pushed the role of satellite imagery in armed conflicts into the spotlight. For a long time, satellite images were primarily used for military and intelligence purposes, but today they permeate every aspect of armed conflicts. Their importance in influencing the course of armed conflicts will further grow as progress in deep learning makes automated analysis progressively possible. This article assesses the state of the research working toward the remote monitoring of armed conflicts and highlights opportunities to increase the positive societal impact of future research efforts. First, we map the existing literature, categorizing studies in terms of conflict events that are covered, conflict context and scope, techniques, and types of satellite imagery used to identify conflict events. Second, we discuss how these choices affect opportunities to develop applications for human rights, humanitarian, and peacekeeping actors. Third, we provide an outlook, assessing promising paths forward. While much focus has been on high spatial resolution imagery, we demonstrate why research on freely available satellite images with moderate spatial but high temporal resolution can lead to more scalable and transferable options. We argue that research on such images should be prioritized, as it will have a greater positive impact on society, and we discuss what types of applications may soon become feasible through such research. We call for concerted efforts to compile a large dataset of nonsensitive conflict events to accelerate research toward the remote monitoring of armed conflicts and for interdisciplinary collaboration to ensure conflict-sensitive monitoring solutions.
Attribution and Explanation in Relativism
Authors: Rattan Gurpreet 
Published: May 2023

Abstract
Is relativism a coherent thesis? The paper argues for a new view of relativism that opposes both classic and contemporary views. On this view, the thesis of relativism is coherent even if the key notions in the standard apparatus of relativism—of alternative conceptual schemes, relative truth, perspectival content—are all incoherent. The view defended here highlights issues about attitude attribution and explanation in formulating the thesis of relativism and it proposes a surprising connection between relativism and nonsense. The paper argues further that the thesis of relativism, so understood, is coherent, by considering different accounts of the semantics of attitude attributions in their application to the attribution of nonsensical thinking.
Role of the Inspiratory Muscles on Functional Performance From Critical Care to Hospital Discharge and Beyond in Patients With COVID-19
Authors: Formiga Magno F , Dosbaba Filip , Hartman Martin , Batalik Ladislav , Senkyr Vojtech , Radkovcova Ivana , Richter Svatopluk , Brat Kristian , Cahalin Lawrence P 
Published: May 2023

AbstractObjectiveThe role of inspiratory muscle performance in functional performance in patients with coronavirus disease 2019 (COVID-19) is poorly understood. The purpose of this study was to perform a longitudinal examination of inspiratory and functional performance from intensive care unit (ICU) discharge (ICUD) to hospital discharge (HD) and symptoms at HD and 1 month after HD in patients with COVID-19.MethodsThirty patients (19 men, 11 women) with COVID-19 were included. Examination of inspiratory muscle performance at ICUD and HD was performed with an electronic manometer, which provided the maximal inspiratory pressure (MIP) and several other inspiratory measures. Examination of dyspnea and functional performance was performed at ICUD and HD with the Modified Borg Dyspnea Scale and the 1-minute sit-to-stand test (1MSST), respectively.ResultsThe mean age was 71 (SD = 11) years, the mean length of ICU stay was 9 (SD = 6) days, and the mean length of hospital stay was 26 (SD = 16) days. Most of the patients were diagnosed with severe COVID-19 (76.7%) and had a mean Charlson Comorbidity Index of 4.4 (SD = 1.9), reflecting high comorbidity. The mean MIP of the entire cohort increased minimally from ICUD to HD (from 36 [SD = 21] to 40 [SD = 20] cm H2O), reflecting predicted values for men and women at ICUD and HD of 46 (25%) to 51 (23%) and 37 (24%) to 37 (20%), respectively. The 1MSTS score increased significantly from ICUD to HD (9.9 [SD = 7.1] vs 17.7 [SD = 11.1]) for the entire cohort but remained far below population-based reference values (2.5th percentile) for the majority of patients at ICUD and HD. At ICUD, MIP was found to be a significant predictor of a favorable change in 1MSTS performance (β = 0.308; odds ratio = 1.36) at HD.ConclusionA significant reduction in inspiratory and functional performance exists in patients with COVID-19 at both ICUD and HD, with a greater MIP at ICUD being a significant predictor of a greater 1MSTS score at HD.ImpactThis study shows that inspiratory muscle training may be an important adjunct after COVID-19.
Radioiodine therapy during the COVID-19 pandemic in a public reference hospital in Brazil: an experience report
Authors: Fontes Lídia F , Pujatti Priscilla B , da Silva Jorge W E , Costa Célia H , Palhota Cláudia , de Oliveira Antônio P , de Mello Rossana C R 
Published: May 2023

Abstract
COVID-2019 has resulted in an emerging respiratory infection that has spread as a pandemic since January 2020. Nuclear Medicine Services and its workers experienced a dramatic change in their clinical routine. They were required to adjust protocols for this new health condition. Regarding radioiodine therapy (RIT), initial orientations were to postpone treatments. In Brazil, National Nuclear Energy Commission prepared guidelines. It authorized RIT to employ activities over 1850 MBq in an outpatient setting on an exceptional basis. This study reports the RIT experience of a Brazilian hospital during the COVID-19 pandemic, intending to evaluate the applicability of outpatient treatment employing over 1850 MBq of I-131 on a large scale. During referred period, 106 patients at our service had an indication for RIT, of which 58 agreed to participate in the research and provided informed consent. Majority of patients did not meet the minimum requirements for outpatient treatment using doses &gt; 1850 MBq.
Comparison of male and female perspective in couples involved in sexual relationships and facing endometriosis
Authors: Helfenstein Fabienne , Kohl Schwartz Alexandra S , Imesch Patrick , Rauchfuss Martina , Wölfler Monika M , Haeberlin Felix , von Orelli Stefanie , Leeners Brigitte 
Published: May 2023

Abstract

Background
While the sexuality of patients with endometriosis is an established topic in research, the possible effect of endometriosis on partnership sexuality has come to the fore only recently. To improve counseling, more information is needed on how both partners experience sexuality in the context of endometriosis.

Aim
Previous research regarding endometriosis and sexuality normally focused on one partner to explore couples’ intimate relations, whereas this study provides a comparison on both partners’ perspectives on their common sexuality.

Methods
An overall 302 couples received a questionnaire based on the Brief Index of Sexual Functioning and Sexual History Form, which was modified by endometriosis specialists to better focus on endometriosis-specific aspects. To detect different perspectives on common sexuality within the couple, the Wilcoxon test and the Pearson chi-square test were performed.

Outcomes
Various aspects of couple sexuality were assessed by both partners to investigate divergent perspectives between the man and the woman within a couple.

Results
On one hand, male and female partners seem to have divergent perspectives on sexual satisfaction in general, desired frequency of sexual contacts, and the question of the female partner engaging in sexual activity despite discomfort. On the other, they have similar perspectives on who takes initiative in sexual contacts, satisfaction with variety in the sexual relationship, and the impact of sexual limitations on their satisfaction within the partnership.

Clinical implications
Endometriosis research addressing issues related to sexuality should include male partners; the same applies to consulting women with endometriosis in the context of their relationships rather than as individuals.

Strengths and Limitations
This is the first analysis conducted on a larger scale of data from both partners in couples dealing with endometriosis. As it provides quantitative information only, some qualitative information remains unexplored.

Conclusion
As both partners showed tendencies to overestimate their partners’ sexual satisfaction and had different perspectives on sensitive topics in sexuality, such as the female partner engaging in sexual activity despite discomfort, addressing sexual communication could be a starting point in counseling couples dealing with endometriosis.
Effects of tadalafil on sexual behavior of male rats induced by chronic unpredictable mild stress
Authors: Wang Heng , Liu Xue , Zhang Ziheng , Han Ziyang , Jiang Yongsheng , Qiao Yu , Liu Tao , Chen Jianhuai , Chen Yun 
Published: May 2023

Abstract

Background
Few studies have investigated psychogenic sexual dysfunction including psychogenic erectile dysfunction (pED); the effect of tadalafil on sexual behavior of male rats induced by chronic unpredictable mild stress (CUMS) remains unclear.

Aim
The aim was to explore the influence of CUMS on sexual behavior of male rats and the effects of tadalafil on that.

Methods
Adult male rats were divided into 3 groups, including the normal group without CUMS, the model group with 6 weeks’ CUMS, and the tadalafil group with treatment of tadalafil during CUMS. CUMS consists of water deprivation, food deprivation, stroboscopic lightning, white noise, cage tilting, weeding packing, and housing 2 unfamiliar rats. The apomorphine test and vaginal smear test were conducted with the aim to screen out male rats with good erectile function and make preparation for the sexual behavior test, respectively.

Outcomes
At the end of the study period, the level of anhedonia and sexual function were evaluated by the sucrose preference test, sexual behavior test, and measurement of serum testosterone, dopamine, and 5-HT.

Results
Sucrose preference showed significant decrease in rats after CUMS. The intromission ratio and total intromission frequency decreased significantly, while the mount latency and ejaculation latency prolonged significantly in CUMS-induced rats when compared with normal rats. Meanwhile, the treatment of tadalafil reversed the level of anhedonia and sexual function in CUMS-induced rats. However, there were no statistical differences in the levels of serum testosterone, dopamine, and 5-HT among groups.

Clinical Implications
The study constructed an animal model that can provide clinical insights into the mechanism of psychogenic sexual dysfunction and supports the application of tadalafil in pED therapy.

Strengths and Limitations
We found that CUMS-induced rats exhibited anhedonia and poor sexual function that could be prevented by tadalafil administration. Future research needs to construct the standard of pED model and explore the mechanism of tadalafil on central nervous system.

Conclusion
Tadalafil could prevent the changes of depression and poor sexual function in rats induced by CUMS, and the method of CUMS and the sexual behavior test should be used in the future for pED modeling.