bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel, rapid and sensitive flow cytometry method reveals degradation of promoter proximal paused RNAPII in the presence and absence of UV
Authors: Bay Lilli T E , Syljuåsen Randi G , Landsverk Helga B 
Published: June 2022

Abstract
RNA polymerase II (RNAPII) is emerging as an important factor in DNA damage responses, but how it responds to genotoxic stress is not fully understood. We have developed a rapid and sensitive flow cytometry method to study chromatin binding of RNAPII in individual human cells through the cell cycle. Indicating enhanced transcription initiation at early timepoints, levels of RNAPII were increased at 15–30min after UV-induced DNA damage. This was particularly evident for the S5 phosphorylated form of RNAPII (pRNAPII S5), which is typically associated with promoter proximal pausing. Furthermore, degradation of pRNAPII S5 frequently occurs, as its levels on chromatin were strongly enhanced by the proteasome inhibitor MG132 with and without UV. Remarkably, inhibiting pause release with 5,6-dichloro-1-beta-ribo-furanosyl benzimidazole (DRB) further promoted UV-induced degradation of pRNAPII S5, suggesting enhanced initiation may lead to a phenomenon of ‘promoter proximal crowding’ resulting in premature termination via degradation of RNAPII. Moreover, pRNAPII S2 levels on chromatin were more stable in S phase of the cell cycle 2h after UV, indicating cell cycle specific effects. Altogether our results demonstrate a useful new method and suggest that degradation of promoter proximal RNAPII plays an unanticipated large role both during normal transcription and after UV.
NetSurfP-3.0: accurate and fast prediction of protein structural features by protein language models and deep learning
Authors: Høie Magnus Haraldson , Kiehl Erik Nicolas , Petersen Bent , Nielsen Morten , Winther Ole , Nielsen Henrik , Hallgren Jeppe , Marcatili Paolo 
Published: June 2022

Abstract
Recent advances in machine learning and natural language processing have made it possible to profoundly advance our ability to accurately predict protein structures and their functions. While such improvements are significantly impacting the fields of biology and biotechnology at large, such methods have the downside of high demands in terms of computing power and runtime, hampering their applicability to large datasets. Here, we present NetSurfP-3.0, a tool for predicting solvent accessibility, secondary structure, structural disorder and backbone dihedral angles for each residue of an amino acid sequence. This NetSurfP update exploits recent advances in pre-trained protein language models to drastically improve the runtime of its predecessor by two orders of magnitude, while displaying similar prediction performance. We assessed the accuracy of NetSurfP-3.0 on several independent test datasets and found it to consistently produce state-of-the-art predictions for each of its output features, with a runtime that is up to to 600 times faster than the most commonly available methods performing the same tasks. The tool is freely available as a web server with a user-friendly interface to navigate the results, as well as a standalone downloadable package.
Enhanced nucleosome assembly at CpG sites containing an extended 5-methylcytosine analogue
Authors: Tomkuvienė Miglė , Meier Markus , Ikasalaitė Diana , Wildenauer Julia , Kairys Visvaldas , Klimašauskas Saulius , Manelytė Laura 
Published: June 2022

Abstract
Methylation of cytosine to 5-methylcytosine (mC) at CpG sites is a prevalent reversible epigenetic mark in vertebrates established by DNA methyltransferases (MTases); the attached methyl groups can alter local structure of DNA and chromatin as well as binding of dedicated proteins. Nucleosome assembly on methylated DNA has been studied extensively, however little is known how the chromatin structure is affected by larger chemical variations in the major groove of DNA. Here, we studied the nucleosome formation in vitro on DNA containing an extended 5mC analog, 5-(6-azidohex-2-ynyl)cytosine (ahyC) installed at biological relevant CpG sites. We found that multiple ahyC residues on 80-Widom and Hsp70 promoter DNA fragments proved compatible with nucleosome assembly. Moreover, unlike mC, ahyC increases the affinity of histones to the DNA, partially altering nucleosome positioning, stability, and the action of chromatin remodelers. Based on molecular dynamics calculations, we suggest that these new features are due to increased DNA flexibility at ahyC-modified sites. Our findings provide new insights into the biophysical behavior of modified DNA and open new ways for directed design of synthetic nucleosomes.
Utilizing RNA origami scaffolds in Saccharomyces cerevisiae for dCas9-mediated transcriptional control
Authors: Pothoulakis Georgios , Nguyen Michael T A , Andersen Ebbe S 
Published: June 2022

Abstract
Designer RNA scaffolds constitute a promising tool for synthetic biology, as they can be genetically expressed to perform specific functions in vivo such as scaffolding enzymatic cascades and regulating gene expression through CRISPR-dCas9 applications. RNA origami is a recently developed RNA design approach that allows construction of large RNA nanostructures that can position aptamer motifs to spatially organize other molecules, including proteins. However, it is still not fully understood how positioning multiple aptamers on a scaffold and the orientation of a scaffold affects functional properties. Here, we investigate fusions of single-guide RNAs and RNA origami scaffolds (termed sgRNAO) capable of recruiting activating domains for control of gene expression in yeast. Using MS2 and PP7 as orthogonal protein-binding aptamers, we observe a gradual increase in transcriptional activation for up to four aptamers. We demonstrate that different aptamer positions on a scaffold and scaffold orientation affect transcriptional activation. Finally, sgRNAOs are used to regulate expression of enzymes of the violacein biosynthesis pathway to control metabolic flux. The integration of RNA origami nanostructures at promoter sites achieved here, can in the future be expanded by the addition of functional motifs such as riboswitches, ribozymes and sensor elements to allow for complex gene regulation.
The legacy effect of a home walking exercise programme in kidney failure patients on dialysis
Authors: Manfredini Fabio , D'arrigo Graziella , Lamberti Nicola , Torino Claudia , Tripepi Giovanni , Mallamaci Francesca , Zoccali Carmine 
Published: June 2022

ABSTRACTBackgroundThe EXerCise Introduction To Enhance performance (EXCITE) trial (J Am Soc Nephrol 28: 1259–1268, 2017) in dialysis patients showed that a 6-month home walking exercise programme improves physical function and two dimensions of the Kidney Disease Quality of Life Short Form (KDQOLSF-SF™) questionnaire. Whether improvements in physical function achieved by exercise interventions are maintained in the long term has never been tested in the dialysis population.MethodsIn this post-trial study embedded in the EXCITE trial, we tested the response to the 6 min walking test (6MWT) and the 5-time Sit-To-Stand (5STS) tests and the KDQOLSF-SF™ from the 6th month (end of the trial) to the 36th month.ResultsAmong the 227 patients of the EXCITE trial cohort, 162 underwent at least three out of four testing visits (baseline, 6, 18 and/or 36 months) contemplated by the study protocol and 89 during all four testing visits. In the primary analysis by the linear mixed model, the gain in walking distance achieved in the 6th month in the exercise group [between-arms difference: +36 m, 95% confidence interval (CI): 22–51, P &lt; .001] was maintained at the 18th month (between-arms difference: +37 m, 95% CI: 19–57, P &lt; .001) and reduced to 23 m (95% CI: −4 to 49 meters, P = .10) at the 36th month. Overall, the post-trial difference in walking distance trajectories between the two study arms was highly significant (P = .004). Furthermore, the walking distance changes at the 6th (r = 0.34, P = .018) and 18th month (r = 0.30, P = .043) were directly related to the number of structured exercise sessions completed during the trial (i.e. the first 6 month). No such effect was registered in the response to the 5STS or in quality of life as measured by the KDQOLSF-SF™.ConclusionsIn dialysis patients, the benefits of a 6-month structured walking programme outlast the duration of the intervention and postpone the loss of walking performance which naturally occurs in this population, but does not affect the quality of life (QoL) and the response to the STS test.
Inhibit progression of coronary artery calcification with vitamin K in hemodialysis patients (the iPACK-HD study): a randomized, placebo-controlled multi-center, pilot trial
Authors: Holden Rachel M , Booth Sarah L , Zimmerman Deborah , Moist Louise , Norman Patrick A , Day Andrew G , Menard Alex , Fu Xueyan , Shea M Kyla , Babiolakis Corinne S , Nolan Robert , Turner Mandy E , Ward Emilie , Kaufmann Martin , Adams Michael A , Heyland Daren K 
Published: June 2022

ABSTRACT

Background
Vitamin K activates matrix Gla protein (MGP), a key inhibitor of vascular calcification. There is a high prevalence of sub-clinical vitamin K deficiency in patients with end-stage kidney disease.

Methods
A parallel randomized placebo-controlled pilot trial was designed to determine whether 10 mg of phylloquinone thrice weekly versus placebo modifies coronary artery calcification progression over 12 months in patients requiring hemodialysis with a coronary artery calcium score (CAC) ≥30 Agatston Units (ClinicalTrials.gov identifier NCT01528800). The primary outcome was feasibility (recruitment rate, compliance with study medication, study completion and adherence overall to study protocol). CAC score was used to assess calcification at baseline and 12 months. Secondary objectives were to explore the impact of phylloquinone on vitamin K-related biomarkers (phylloquinone, dephospho-uncarboxylated MGP and the Gla-osteocalcin to Glu-osteocalcin ratio) and events of clinical interest.

Results
A total of 86 patients with a CAC score ≥30 Agatston Units were randomized to either 10 mg of phylloquinone or a matching placebo three times per week. In all, 69 participants (80%) completed the trial. Recruitment rate (4.4 participants/month) and medication compliance (96%) met pre-defined feasibility criteria of ≥4.17 and ≥90%, respectively. Patients randomized to phylloquinone for 12 months had significantly reduced levels of dephospho-uncarboxylated MGP (86% reduction) and increased levels of phylloquinone and Gla-osteocalcin to Glu-osteocalcin ratio compared with placebo. There was no difference in the absolute or relative progression of coronary artery calcification between groups.

Conclusion
We demonstrated that phylloquinone treatment improves vitamin K status and that a fully powered randomized trial may be feasible.
Hippocampal avoidance prophylactic cranial irradiation (HA-PCI) for small cell lung cancer reduces hippocampal atrophy compared to conventional PCI
Authors: de Ruiter Michiel B , Groot Paul F C , Deprez Sabine , Pullens Pim , Sunaert Stefan , de Ruysscher Dirk , Schagen Sanne B , Belderbos José 
Published: June 2022

Abstract

Background
Reducing radiation dose to the hippocampus with hippocampal avoidance prophylactic cranial irradiation (HA-PCI) is proposed to prevent cognitive decline. It has, however, not been investigated whether hippocampal atrophy is actually mitigated by this approach. Here, we determined whether HA-PCI reduces hippocampal atrophy. Additionally, we evaluated neurotoxicity of (HA-)PCI to other brain regions. Finally, we evaluated associations of hippocampal atrophy and brain neurotoxicity with memory decline.

Methods
High-quality research MRI scans were acquired in the multicenter, randomized phase 3 trial NCT01780675. Hippocampal atrophy was evaluated for 4 months (57 HA-PCI patients and 46 PCI patients) and 12 months (28 HA-PCI patients and 27 PCI patients) after (HA-)PCI. We additionally studied multimodal indices of brain injury. Memory was assessed with the Hopkins Verbal Learning Test–Revised (HVLT-R).

Results
HA-PCI reduced hippocampal atrophy at 4 months (1.8% for HA-PCI and 3.0% for PCI) and at 12 months (3.0% for HA-PCI and 5.8% for PCI). Both HA-PCI and PCI were associated with considerable reductions in gray matter and normal-appearing white matter, increases in white matter hyperintensities, and brain aging. There were no significant associations between hippocampal atrophy and memory.

Conclusions
HA-PCI reduces hippocampal atrophy at 4 and 12 months compared to regular PCI. Both types of radiotherapy are associated with considerable brain injury. We did not find evidence for excessive brain injury after HA-PCI relative to PCI. Hippocampal atrophy was not associated with memory decline in this population as measured with HVLT-R. The usefulness of HA-PCI is still subject to debate.
Differential seasonal avoidance of anthropogenic features and woody vegetation by Lesser Prairie-Chickens
Authors: Lawrence Andrew J , Boggie Matthew A , Gould William R , Carleton Scott A , Nichols Clay T 
Published: June 2022

Abstract
The influence of seasonal variation on animal behavior is a critical component of habitat selection analyses. To examine this relationship, we conducted multi-scale analyses of Lesser Prairie-Chicken (Tympanuchus pallidicinctus) habitat selection in relation to anthropogenic infrastructure associated with oil and gas development, mesquite, and trees during the spring and summer at home range and lek area scales. We tracked 159 Lesser Prairie-Chickens using VHF radiotelemetry or PTT-GPS transmitters in the sand shinnery oak prairie region of eastern New Mexico, USA. We used discrete choice models and logistic regression to assess seasonal patterns of habitat selection at home range and lek area scales, respectively. The static habitat features we examined allowed us to observe differential patterns of habitat selection between the two seasons, revealing an overall increase in the degree of avoidance following the spring season. Results of our home range scale analysis indicate that utility pole density, mesquite cover, and proximity to active well pads, private roads, and mesquite have significant negative effects on habitat selection during both seasons. Avoidance of high utility pole densities was significantly greater during the summer compared to spring. Lek area habitat selection results were similar, but differences in sensitivity to features between seasons were stronger. Avoidance of high mesquite cover and utility pole and tree densities, in particular, was significantly greater in the summer. The effects of density and cover of these features, which have previously been understudied in Lesser Prairie-Chicken research, provide critical information for future conservation practices. Furthermore, our study highlights the importance of accounting for potential seasonal patterns of study species to best examine habitat selection.
Determination of sampling time interval for investigating ecological trends of tintinnids
Authors: Baek Sang-Soo , Kim Young Ok , Choi Jungmin , Cho Hong Yeon , Jang Min-Chul 
Published: June 2022

Abstract
Tintinnids are a major group of planktonic ciliates. To determine a desirable sampling interval for analyzing the temporal dynamics of tintinnids, intensive monitoring was conducted on the southern coast of Korea. The mean sampling interval was 1.5 days. The abundance of tintinnids were analyzed by microscopy. The high- frequency temporal pattern showed detailed changes in concentrations and a distinct seasonality in the abundance of tintinnids. An optimal monitoring interval for tintinnid abundance estimations was determined by polynomial interpolation and statistical analysis, involving three steps, namely, interpolation by increasing the number of sampling intervals, graphical analysis with interpolated data and determination of the changepoint depending on the interpolated results. The value of changepoint was 7 days, indicating the optimal monitoring interval. Therefore, data collection at weekly intervals is sufficient and desirable for tracing the temporal signals of tintinnid ecology and its long-term trends.
Plant–microbe interactions that have impacted plant terrestrializations
Authors: Puginier Camille , Keller Jean , Delaux Pierre-Marc 
Published: June 2022

Abstract
Plants display a tremendous diversity of developmental and physiological features, resulting from gains and losses of functional innovations across the plant phylogeny. Among those, the most impactful have been undoubtedly the ones that allowed plant terrestrializations, the transitions from an aquatic to a terrestrial environment. Although the embryophyte terrestrialization has been particularly scrutinized, others occurred across the plant phylogeny with the involvement of mutualistic symbioses as a common theme. Here, we review the current pieces of evidence supporting that the repeated colonization of land by plants has been facilitated by interactions with mutualistic symbionts. In that context, we detail two of these mutualistic symbioses: the arbuscular mycorrhizal symbiosis in embryophytes and the lichen symbiosis in chlorophyte algae. We suggest that associations with bacteria should be revisited in that context, and we propose that overlooked symbioses might have facilitated the emergence of other land plant clades.
The Incidence of Student Loan Subsidies: Evidence from the PLUS Program
Authors: Kargar Mahyar , Mann William 
Published: June 2022

AbstractHow much do students benefit from student loan subsidies? We investigate this question, exploiting a natural experiment: a demand shock due to the 2011 tightening of credit standards in the PLUS program. We first establish that the Bennett hypothesis is best explained by colleges charging large markups over their marginal costs, rather than by advantageous selection. Then we use our results to estimate that students plausibly capture less than 60 cents of each dollar of resources expended on loan subsidies. We discuss alternative approaches that would more directly benefit students.
Horizon Bias and the Term Structure of Equity Returns
Authors: Cassella Stefano , Golez Benjamin , Gulen Huseyin , Kelly Peter 
Published: June 2022

AbstractWe label the degree to which individuals are more optimistic at long horizons relative to short horizons as the horizon bias. We examine whether time-series variation in the horizon bias can explain the time-series variation in the equity term structure. We use analyst earnings forecasts to measure the degree of the horizon bias in the stock market. Consistent with the intuition from a stylized present value model, we find that periods of above-average horizon bias are associated with negative term premiums, whereas periods of below-average horizon bias are associated with positive term premiums.Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Impact of lung function and baseline clinical characteristics on patient-reported outcome measures in systemic sclerosis-associated interstitial lung disease
Authors: Kreuter Michael , Hoffmann-Vold Anna-Maria , Matucci-Cerinic Marco , Saketkoo Lesley Ann , Highland Kristin B , Wilson Hilary , Alves Margarida , Erhardt Elvira , Schoof Nils , Maher Toby M 
Published: June 2022

Abstract

Objective
The SENSCIS® trial demonstrated a significant reduction of lung function decline in patients with SSc-associated interstitial lung disease (SSc-ILD) treated with nintedanib, but no significant effect on health-related quality of life (HRQoL). To assess whether SSc/SSc-ILD severity and large changes in lung function correlate with HRQoL, a post-hoc analysis of SENSCIS®, aggregating treatment arms, was undertaken.

Methods
Patient-reported outcome (PRO) measures [St. George’s Respiratory Questionnaire (SGRQ), Functional Assessment of Chronic Illness Therapy (FACIT)-Dyspnoea, and HAQ–Disability Index (HAQ-DI), incorporating the Scleroderma HAQ visual analogue scale (SHAQ VAS)] at baseline and week 52 were assessed for associations to SSc-ILD severity.

Results
At baseline and at week 52, forced vital capacity (FVC) &lt;70% predicted was associated with worse PRO measure scores compared with FVC ≥70% predicted [week 52: SGRQ 45.1 vs 34.0 (P &lt; 0.0001); FACIT-Dyspnoea 48.9 vs 44.5 (P &lt; 0.0001); HAQ-DI 0.7 vs 0.6 (P &lt; 0.0228); SHAQ VAS breathing problems 3.6 vs 2.6 (P &lt; 0.0001)]. Patients with diffuse cutaneous SSc and other characteristics associated with SSc-ILD severity had worse PRO measure scores. Patients requiring oxygen or with &gt;30% fibrosis on high-resolution computed tomography at baseline demonstrated worse PRO measure scores at week 52. After 1 year, patients with a major (&gt;10%) improvement/worsening in FVC demonstrated corresponding improvement/worsening in SGRQ and other PRO measures, significant for the SGRQ symptom domain (P &lt; 0.001).

Conclusion
Severe SSc-ILD and major deteriorations in lung function have important impacts on HRQoL. Treatments that slow lung function decline and prevent severe SSc-ILD are important to preserve HRQoL.

Trial registration
clinicaltrials.gov, www.clinicaltrials.gov, NCT02597933
Private Company Valuations by Mutual Funds
Authors: Agarwal Vikas , Barber Brad , Cheng Si , Hameed Allaudeen , Yasuda Ayako 
Published: June 2022

AbstractMutual fund families set and report values of their private startup holdings, which affect the fund net asset value (NAV) at which investors buy/sell fund shares. We test three hypotheses related to the valuation practice: (i) information cost/access, (ii) litigation risk, and (iii) strategic NAV management. Consistent with (i), families with larger PE holdings and/or stronger information access update valuations more frequently in the absence of public information releases, their updates co-move less with other families, and their fund returns jump less at follow-on financings. We find no support for hypotheses (ii) or (iii). We also find that high-PE-exposure funds are subject to greater financial fragility.
Psychosocial Impact of Sickle Cell Disease and Diabetes Mellitus on Affected Children and Their Parents in Khartoum State, Sudan
Authors: Yousif Magda , Abdelrahman Abdalla , Al Jamea Lamiaa H , Al-Yami Fatimah S , Woodman Alexander 
Published: June 2022

AbstractThis study aimed to assess the psychosocial impact of sickle cell disease (SCD) and diabetes mellitus on children and their parents in Sudan, and the relationship between socioeconomic status and psychosocial issues. A descriptive, cross-sectional study was conducted among n = 320 children aged 6–12 years, of whom n = 170 were diagnosed with SCD, n = 150 children with diabetes mellitus and their parents. The strengths and difficulties questionnaire (SDQ scale) was used to assess the psychosocial aspect of children. Depression, Anxiety, Stress Scale -21 Items (DASS 21) was used to assess the psychological well-being of the caregivers. Data on psychological problems of children with SCD showed that 66.5% had emotional symptoms, 18.2% had conduct problems and 19.4% hyperactivity. Data of parents showed that 45.9% of parents did not experience depression; 27.9% were moderately depressed group. Data on psychological problems among children with diabetes showed that 57.3% experienced emotional symptoms, conduct problems were close to the average among 66%. Data on psychological problems among parents of children with diabetes showed that 45.3% of parents did not experience depression; 22.7% belonged to the moderately depressed group. Psychosocial problems were common both among children and parents. More research is needed in the context of caring for a child with chronic diseases and the role of health care providers in adapting and mitigating psychological problems among both parents and children.