bluuebunny/crossref_metadata_2025_split huggingface dataset:
Depletion of the RNA-binding protein PURA triggers changes in posttranscriptional gene regulation and loss of P-bodies
Authors: Molitor Lena , Klostermann Melina , Bacher Sabrina , Merl-Pham Juliane , Spranger Nadine , Burczyk Sandra , Ketteler Carolin , Rusha Ejona , Tews Daniel , Pertek Anna , Proske Marcel , Busch Anke , Reschke Sarah , Feederle Regina , Hauck Stefanie M , Blum Helmut , Drukker Micha , Fischer-Posovszky Pamela , König Julian , Zarnack Kathi , Niessing Dierk 
Published: January 2023

AbstractThe RNA-binding protein PURA has been implicated in the rare, monogenetic, neurodevelopmental disorder PURA Syndrome. PURA binds both DNA and RNA and has been associated with various cellular functions. Only little is known about its main cellular roles and the molecular pathways affected upon PURA depletion. Here, we show that PURA is predominantly located in the cytoplasm, where it binds to thousands of mRNAs. Many of these transcripts change abundance in response to PURA depletion. The encoded proteins suggest a role for PURA in immune responses, mitochondrial function, autophagy and processing (P)-body activity. Intriguingly, reduced PURA levels decrease the expression of the integral P-body components LSM14A and DDX6 and strongly affect P-body formation in human cells. Furthermore, PURA knockdown results in stabilization of P-body-enriched transcripts, whereas other mRNAs are not affected. Hence, reduced PURA levels, as reported in patients with PURA Syndrome, influence the formation and composition of this phase-separated RNA processing machinery. Our study proposes PURA Syndrome as a new model to study the tight connection between P-body-associated RNA regulation and neurodevelopmental disorders.
8-Oxoguanine targeted by 8-oxoguanine DNA glycosylase 1 (OGG1) is central to fibrogenic gene activation upon lung injury
Authors: Pan Lang , Hao Wenjing , Xue Yaoyao , Wang Ke , Zheng Xu , Luo Jixian , Ba Xueqing , Xiang Yang , Qin Xiaoqun , Bergwik Jesper , Tanner Lloyd , Egesten Arne , Brasier Allan R , Boldogh Istvan 
Published: January 2023

AbstractReactive oxygen species (ROS) are implicated in epithelial cell-state transition and deposition of extracellular matrix upon airway injury. Of the many cellular targets of ROS, oxidative DNA modification is a major driving signal. However, the role of oxidative DNA damage in modulation profibrotic processes has not been fully delineated. Herein, we report that oxidative DNA base lesions, 8-oxoG, complexed with 8-oxoguanine DNA glycosylase 1 (OGG1) functions as a pioneer factor, contributing to transcriptional reprogramming within airway epithelial cells. We show that TGFβ1-induced ROS increased 8-oxoG levels in open chromatin, dynamically reconfigure the chromatin state. OGG1 complexed with 8-oxoG recruits transcription factors, including phosphorylated SMAD3, to pro-fibrotic gene promoters thereby facilitating gene activation. Moreover, 8-oxoG levels are elevated in lungs of mice subjected to TGFβ1-induced injury. Pharmacologic targeting of OGG1 with the selective small molecule inhibitor of 8-oxoG binding, TH5487, abrogates fibrotic gene expression and remodeling in this model. Collectively, our study implicates that 8-oxoG substrate-specific binding by OGG1 is a central modulator of transcriptional regulation in response to tissue repair.
Annotation of uORFs in the OMIM genes allows to reveal pathogenic variants in 5′UTRs
Authors: Filatova Alexandra , Reveguk Ivan , Piatkova Maria , Bessonova Daria , Kuziakova Olga , Demakova Victoria , Romanishin Alexander , Fishman Veniamin , Imanmalik Yerzhan , Chekanov Nikolay , Skitchenko Rostislav , Barbitoff Yury , Kardymon Olga , Skoblov Mikhail 
Published: January 2023

AbstractAn increasing number of studies emphasize the role of non-coding variants in the development of hereditary diseases. However, the interpretation of such variants in clinical genetic testing still remains a critical challenge due to poor knowledge of their pathogenicity mechanisms. It was previously shown that variants in 5′-untranslated regions (5′UTRs) can lead to hereditary diseases due to disruption of upstream open reading frames (uORFs). Here, we performed a manual annotation of upstream translation initiation sites (TISs) in human disease-associated genes from the OMIM database and revealed ∼4.7 thousand of TISs related to uORFs. We compared our TISs with the previous studies and provided a list of ‘high confidence’ uORFs. Using a luciferase assay, we experimentally validated the translation of uORFs in the ETFDH, PAX9, MAST1, HTT, TTN,GLI2 and COL2A1 genes, as well as existence of N-terminal CDS extension in the ZIC2 gene. Besides, we created a tool to annotate the effects of genetic variants located in uORFs. We revealed the variants from the HGMD and ClinVar databases that disrupt uORFs and thereby could lead to Mendelian disorders. We also showed that the distribution of uORFs-affecting variants differs between pathogenic and population variants. Finally, drawing on manually curated data, we developed a machine-learning algorithm that allows us to predict the TISs in other human genes.
Trans-cisisomerization kinetics of cyanine dyes reports on the folding states of exogeneous RNA G-quadruplexes in live cells
Authors: Kitamura Akira , Tornmalm Johan , Demirbay Baris , Piguet Joachim , Kinjo Masataka , Widengren Jerker 
Published: January 2023

AbstractGuanine (G)-rich nucleic acids are prone to assemble into four-stranded structures, so-called G-quadruplexes. Abnormal GGGGCC repeat elongations, and in particular their folding states, are associated with amyotrophic lateral sclerosis and frontotemporal dementia. Due to methodological constraints however, most studies of G quadruplex structures are restricted to in vitro conditions. Evidence of how GGGGCC repeats form into G-quadruplexes in vivo is sparse. We devised a readout strategy, exploiting the sensitivity of trans-cis isomerization of cyanine dyes to local viscosity and sterical constraints. Thereby, folding states of cyanine-labeled RNA, and in particular G-quadruplexes, can be identified in a sensitive manner. The isomerization kinetics, monitored via fluorescence blinking generated upon transitions between a fluorescent trans isomer and a non-fluorescent cis isomer, was first characterized for RNA with GGGGCC repeats in aqueous solution using fluorescence correlation spectroscopy and transient state (TRAST) monitoring. With TRAST, monitoring the isomerization kinetics from how the average fluorescence intensity varies with laser excitation modulation characteristics, we could then detect folding states of fluorescently tagged RNA introduced into live cells.
Dynamic states of eIF6 and SDS variants modulate interactions with uL14 of the 60S ribosomal subunit
Authors: Elliff Jonah , Biswas Aparna , Roshan Poonam , Kuppa Sahiti , Patterson Angela , Mattice Jenna , Chinnaraj Mathivanan , Burd Ryan , Walker Sarah E , Pozzi Nicola , Antony Edwin , Bothner Brian , Origanti Sofia 
Published: January 2023

AbstractAssembly of ribosomal subunits into active ribosomal complexes is integral to protein synthesis. Release of eIF6 from the 60S ribosomal subunit primes 60S to associate with the 40S subunit and engage in translation. The dynamics of eIF6 interaction with the uL14 (RPL23) interface of 60S and its perturbation by somatic mutations acquired in Shwachman–Diamond Syndrome (SDS) is yet to be clearly understood. Here, by using a modified strategy to obtain high yields of recombinant human eIF6 we have uncovered the critical interface entailing eight key residues in the C-tail of uL14 that is essential for physical interactions between 60S and eIF6. Disruption of the complementary binding interface by conformational changes in eIF6 disease variants provide a mechanism for weakened interactions of variants with the 60S. Hydrogen–deuterium exchange mass spectrometry (HDX-MS) analyses uncovered dynamic configurational rearrangements in eIF6 induced by binding to uL14 and exposed an allosteric interface regulated by the C-tail of eIF6. Disrupting key residues in the eIF6–60S binding interface markedly limits proliferation of cancer cells, which highlights the significance of therapeutically targeting this interface. Establishing these key interfaces thus provide a therapeutic framework for targeting eIF6 in cancers and SDS.
CRISPR-associated type V proteins as a tool for controlling mRNA stability inS. cerevisiaesynthetic gene circuits
Authors: Yu Lifang , Marchisio Mario Andrea 
Published: January 2023

AbstractType V-A CRISPR-(d)Cas system has been used in multiplex genome editing and transcription regulation in both eukaryotes and prokaryotes. However, mRNA degradation through the endonuclease activity of Cas12a has never been studied. In this work, we present an efficient and powerful tool to induce mRNA degradation in the yeast Saccharomyces cerevisiae via the catalytic activity of (d)Cas12a on pre-crRNA structure. Our results point out that dFnCas12a, (d)LbCas12a, denAsCas12a and two variants (which carry either NLSs or NESs) perform significant mRNA degradation upon insertion of pre-crRNA fragments into the 5′- or 3′ UTR of the target mRNA. The tool worked well with two more Cas12 proteins—(d)MbCas12a and Casϕ2—whereas failed by using type VI LwaCas13a, which further highlights the great potential of type V-A Cas proteins in yeast. We applied our tool to the construction of Boolean NOT, NAND, and IMPLY gates, whose logic operations are fully based on the control of the degradation of the mRNA encoding for a reporter protein. Compared to other methods for the regulation of mRNA stability in yeast synthetic gene circuits (such as RNAi and riboswitches/ribozymes), our system is far easier to engineer and ensure very high performance.
Systemic structural analysis of alterations reveals a common structural basis of driver mutations in cancer
Authors: Meirson Tomer , Bomze David , Schueler-Furman Ora , Stemmer Salomon M , Markel Gal 
Published: January 2023

Abstract
A major effort in cancer research is to organize the complexities of the disease into fundamental traits. Despite conceptual progress in the last decades and the synthesis of hallmark features, no organizing principles governing cancer beyond cellular features exist. We analyzed experimentally determined structures harboring the most significant and prevalent driver missense mutations in human cancer, covering 73% (n = 168178) of the Catalog of Somatic Mutation in Cancer tumor samples (COSMIC). The results reveal that a single structural element—κ-helix (polyproline II helix)—lies at the core of driver point mutations, with significant enrichment in all major anatomical sites, suggesting that a small number of molecular traits are shared by most and perhaps all types of cancer. Thus, we uncovered the lowest possible level of organization at which carcinogenesis takes place at the protein level. This framework provides an initial scheme for a mechanistic understanding underlying the development of tumors and pinpoints key vulnerabilities.
EEPD1 promotes repair of oxidatively-stressed replication forks
Authors: Jaiswal Aruna S , Kim Hyun-Suk , Schärer Orlando D , Sharma Neelam , Williamson Elizabeth A , Srinivasan Gayathri , Phillips Linda , Kong Kimi , Arya Shailee , Misra Anurag , Dutta Arijit , Gupta Yogesh , Walter Christi A , Burma Sandeep , Narayan Satya , Sung Patrick , Nickoloff Jac A , Hromas Robert 
Published: January 2023

Abstract
Unrepaired oxidatively-stressed replication forks can lead to chromosomal instability and neoplastic transformation or cell death. To meet these challenges cells have evolved a robust mechanism to repair oxidative genomic DNA damage through the base excision repair (BER) pathway, but less is known about repair of oxidative damage at replication forks. We found that depletion or genetic deletion of EEPD1 decreases clonogenic cell survival after oxidative DNA damage. We demonstrate that EEPD1 is recruited to replication forks stressed by oxidative damage induced by H2O2 and that EEPD1 promotes replication fork repair and restart and decreases chromosomal abnormalities after such damage. EEPD1 binds to abasic DNA structures and promotes resolution of genomic abasic sites after oxidative stress. We further observed that restoration of expression of EEPD1 via expression vector transfection restores cell survival and suppresses chromosomal abnormalities induced by oxidative stress in EEPD1-depleted cells. Consistent with this, we found that EEPD1 preserves replication fork integrity by preventing oxidatively-stressed unrepaired fork fusion, thereby decreasing chromosome instability and mitotic abnormalities. Our results indicate a novel role for EEPD1 in replication fork preservation and maintenance of chromosomal stability during oxidative stress.
Longitudinal evaluation of serum microRNAs as biomarkers for neuroblastoma burden and therapeutic p53 reactivation
Authors: Van Goethem Alan , Deleu Jill , Yigit Nurten , Everaert Celine , Moreno-Smith Myrthala , Vasudevan Sanjeev A , Zeka Fjoralba , Demuynck Fleur , Barbieri Eveline , Speleman Frank , Mestdagh Pieter , Shohet Jason , Vandesompele Jo , Van Maerken Tom 
Published: January 2023

Abstract
Accurate assessment of treatment response and residual disease is indispensable for the evaluation of cancer treatment efficacy. However, performing tissue biopsies for longitudinal follow-up poses a major challenge in the management of solid tumours like neuroblastoma. In the present study, we evaluated whether circulating miRNAs are suitable to monitor neuroblastoma tumour burden and whether treatment-induced changes of miRNA abundance in the tumour are detectable in serum. We performed small RNA sequencing on longitudinally collected serum samples from mice carrying orthotopic neuroblastoma xenografts that were exposed to treatment with idasanutlin or temsirolimus. We identified 57 serum miRNAs to be differentially expressed upon xenograft tumour manifestation, out of which 21 were also found specifically expressed in the serum of human high-risk neuroblastoma patients. The murine serum levels of these 57 miRNAs correlated with tumour tissue expression and tumour volume, suggesting potential utility for monitoring tumour burden. In addition, we describe serum miRNAs that dynamically respond to p53 activation following treatment of engrafted mice with idasanutlin. We identified idasanutlin-induced serum miRNA expression changes upon one day and 11 days of treatment. By limiting to miRNAs with a tumour-related induction, we put forward hsa-miR-34a-5p as a potential pharmacodynamic biomarker of p53 activation in serum.
Effectiveness of cold HD for the prevention of HD hypotension and mortality in the general HD population
Authors: Zoccali Carmine , Tripepi Giovanni , Neri Luca , Savoia Matteo , Baró Salvador Maria Eva , Ponce Pedro , Hymes Jeffrey , Maddux Frank , Mallamaci Francesca , Stuard Stefano 
Published: January 2023

ABSTRACTBackgroundCold hemodialysis (HD) prevented intradialysis hypotension (IDH) in small, short-term, randomized trials in selected patients with IDH. Whether this treatments prevents IDH and mortality in the HD population at large is unknown.MethodsWe investigated the relationship between dialysate temperature and the risk of IDH, i.e. nadir blood pressure &lt;90 mmHg (generalized estimating equation model) and all-cause mortality (Cox's regression) in an incident cohort of HD patients (n = 8071). To control for confounding by bias by indication and other factors we applied instrumental variables adjusting for case mix at facility level.ResultsTwenty-seven percent of patients in the study cohort were systematically treated with a dialysate temperature ≤35.5°C. Over a median follow-up of 13.6 months (interquartile range 5.2–26.1 months), a 0.5°C reduction of the dialysate temperature was associated with a small (–2.4%) reduction of the risk of IDH [odds ratio (OR) 0.976, 95% confidence interval (CI) 0.957–0.995, P = .013]. In case-mix, facility-level adjusted analysis, the association became much stronger (OR 0.67, 95% CI 0.63–0.72, risk reduction = 33%, P &lt; .001). In contrast, colder dialysate temperature had no effect on mortality both in the unadjusted [hazard ratio (HR) (0.5°C decrease) 1.074, 95% CI 0.972–1.187, P = .16] and case-mix-adjusted analysis at facility level (HR 1.01, 95% CI 0.88–1.16, P = .84). Similar results were registered in additional analyses by instrumental variables applying the median dialysate temperature or the facility percentage of patients prescribed a dialysate temperature &lt;36°C. Further analyses restricted to patients with recurrent IDH fully confirmed these findings.ConclusionsCold HD was associated with IDH in the HD population but had no association with all-cause mortality.
Kidney outcome after mild to moderate COVID-19
Authors: Schmidt-Lauber Christian , Hänzelmann Sonja , Schunk Stefan , Petersen Elina L , Alabdo Ammar , Lindenmeyer Maja , Hausmann Fabian , Kuta Piotr , Renné Thomas , Twerenbold Raphael , Zeller Tanja , Blankenberg Stefan , Fliser Danilo , Huber Tobias B 
Published: January 2023

ABSTRACT

Background
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a remarkable kidney tropism. While kidney effects are common in severe coronavirus disease 2019 (COVID-19), data on non-severe courses are limited. Here we provide a multilevel analysis of kidney outcomes after non-severe COVID-19 to test for eventual kidney sequela.

Methods
This cross-sectional study investigates individuals after COVID-19 and matched controls recruited from the Hamburg City Health Study (HCHS) and its COVID-19 program. The HCHS is a prospective population-based cohort study within the city of Hamburg, Germany. During the COVID-19 pandemic the study additionally recruited subjects after polymerase chain reaction–confirmed SARS-CoV-2 infections. Matching was performed by age, sex and education. Main outcomes were estimated glomerular filtration rate (eGFR), albuminuria, Dickkopf3, haematuria and pyuria.

Results
A total of 443 subjects in a median of 9 months after non-severe COVID-19 were compared with 1328 non-COVID-19 subjects. The mean eGFR was mildly lower in post-COVID-19 than non-COVID-19 subjects, even after adjusting for known risk factors {β = −1.84 [95% confidence interval (CI) −3.16 to −0.52]}. However, chronic kidney disease [odds ratio (OR) 0.90 (95% CI 0.48–1.66)] or severely increased albuminuria [OR 0.76 (95% CI 0.49–1.09)] equally occurred in post-COVID-19 and non-COVID-19 subjects. Haematuria, pyuria and proteinuria were also similar between the two cohorts, suggesting no ongoing kidney injury after non-severe COVID-19. Further, Dickkopf3 was not increased in the post-COVID-19 cohort, indicating no systematic risk for ongoing GFR decline [β = −72.19 (95% CI −130.0 to −14.4)].

Conclusion
While mean eGFR was slightly lower in subjects after non-severe COVID-19, there was no evidence for ongoing or progressive kidney sequela.
The rationale, design and baseline data of FLOW, a kidney outcomes trial with once-weekly semaglutide in people with type 2 diabetes and chronic kidney disease
Authors: Rossing Peter , Baeres Florian M M , Bakris George , Bosch-Traberg Heidrun , Gislum Mette , Gough Stephen C L , Idorn Thomas , Lawson Jack , Mahaffey Kenneth W , Mann Johannes F E , Mersebach Henriette , Perkovic Vlado , Tuttle Katherine , Pratley Richard 
Published: January 2023

ABSTRACT

Background
Chronic kidney disease (CKD) is a common complication of type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and lower body weight in people with T2D, and some reduce the risk of cardiovascular (CV) events in those with high CV risk. GLP-1RAs might also have kidney-protective effects. We report the design and baseline data for FLOW (NCT03819153), a trial investigating the effects of semaglutide, a once-weekly (OW) GLP-1RA, on kidney outcomes in participants with CKD and T2D.

Methods
FLOW is a randomised, double-blind, parallel-group, multinational, phase 3b trial. Participants with T2D, estimated glomerular filtration rate (eGFR) ≥50‒≤75 ml/min/1.73 m2 and urine albumin:creatinine ratio (UACR) &gt;300‒&lt;5000 mg/g or eGFR ≥25‒&lt;50 ml/min/1.73 m2 and UACR &gt;100‒&lt;5000 mg/g were randomised 1:1 to OW semaglutide 1.0 mg or matched placebo, with renin–angiotensin–aldosterone system blockade (unless not tolerated/contraindicated). The composite primary endpoint is time to first kidney failure (persistent eGFR &lt;15 ml/min/1.73 m2 or initiation of chronic kidney replacement therapy), persistent ≥50% reduction in eGFR or death from kidney or CV causes.

Results
Enrolled participants (N = 3534) had a baseline mean age of 66.6 years [standard deviation (SD) 9.0], haemoglobin A1c of 7.8% (SD 1.3), diabetes duration of 17.4 years (SD 9.3), eGFR of 47.0 ml/min/1.73 m2 (SD 15.2) and median UACR of 568 mg/g (range 2‒11 852). According to Kidney Disease: Improving Global Outcomes guidelines categorisation, 68.2% were at very high risk for CKD progression.

Conclusion
FLOW will evaluate the effect of semaglutide on kidney outcomes in participants with CKD and T2D, and is expected to be completed in late 2024.
Safety
Authors: Barling Julian 
Published: January 2023

Abstract
Although not at the forefront of the public imagination, workplace injuries and fatalities remain a daily reality in many workplaces across the world, a concern made worse with more than three thousand health care workers who died from COVID-19 during the first year of the pandemic. There is very little research to guide a discussion on the benefits that might accrue when workplace safety is assured. In sharp contrast, we know that workplace attitudes and employee well-being suffer following safety infractions. Special features of this chapter include a discussion of the extensive financial costs borne by injured workers, their families, and their organizations following workplace injuries and fatalities; and a consideration the disproportionate safety risks faced by foreign correspondents and young workers.
Toward productive, healthy, and safe workplaces
Authors: Barling Julian 
Published: January 2023

Abstract
Fulfilling people’s needs for high-quality leadership, autonomy, belonging, fairness, growth and development, meaningful work, and safety are key to providing productive, healthy, and safe work. As we emerge from the COVID-19 pandemic, the breadth and pace of social change already evident will likely intensify. Internal pressures within organizations for innovations involving remote or hybrid work, as well as the four-day workweek, are already upon us. Social forces promoting gender equity, racial equality, and indigeneity will continue to create tremendous pressure on organizations to adapt, and at the same time organizations will need to provide decisive leadership in responding to the climate crisis. All these internal and external forces will shape the nature of work and organizations in the future. Successful organizations in the future will be those which choose to “build back fairer,” and develop productive, healthy, and safe workplaces.
Questions
Authors: Rufai Sohaib R. 
Published: January 2023

Abstract
This paper covers the full range of core subjects tested in the FRCOphth Part 1 examination: optics, anatomy, physiology, pathology, pharmacology, genetics, investigations, and miscellaneous (biostatistics and evidence-based medicine). As well as ophthalmic subjects, this paper covers general physiology, general pathology, microbiology, biochemistry, and immunology. Several high-yield topics are covered. An anatomical diagram displays the contents of the cavernous sinus. The normal electrocardiogram is explained in a helpful schematic. Histopathological slides are included for temporal arteritis and basal cell carcinoma. Anterior segment optical coherence tomography images of the cornea and iridocorneal angle are included, displaying key anatomical landmarks.