bluuebunny/crossref_metadata_2025_split huggingface dataset:
RPA guides UNG to uracil in ssDNA to facilitate antibody class switching and repair of mutagenic uracil at the replication fork
Authors: Hayran Abdul B , Liabakk Nina B , Aas Per A , Kusnierczyk Anna , Vågbø Cathrine B , Sarno Antonio , Iveland Tobias S , Chawla Konika , Zahn Astrid , Di Noia Javier M , Slupphaug Geir , Kavli Bodil 
Published: November 2023

Abstract
Activation-induced cytidine deaminase (AID) interacts with replication protein A (RPA), the major ssDNA-binding protein, to promote deamination of cytosine to uracil in transcribed immunoglobulin (Ig) genes. Uracil-DNA glycosylase (UNG) acts in concert with AID during Ig diversification. In addition, UNG preserves genome integrity by base-excision repair (BER) in the overall genome. How UNG is regulated to support both mutagenic processing and error-free repair remains unknown. UNG is expressed as two isoforms, UNG1 and UNG2, which both contain an RPA-binding helix that facilitates uracil excision from RPA-coated ssDNA. However, the impact of this interaction in antibody diversification and genome maintenance has not been investigated. Here, we generated B-cell clones with targeted mutations in the UNG RPA-binding motif, and analysed class switch recombination (CSR), mutation frequency (5′ Ig Sμ), and genomic uracil in clones representing seven Ung genotypes. We show that the UNG:RPA interaction plays a crucial role in both CSR and repair of AID-induced uracil at the Ig loci. By contrast, the interaction had no significant impact on total genomic uracil levels. Thus, RPA coordinates UNG during CSR and pre-replicative repair of mutagenic uracil in ssDNA but is not essential in post-replicative and canonical BER of uracil in dsDNA.
Cyclic di-GMP inhibits nitrate assimilation by impairing the antitermination function of NasT in Pseudomonas putida
Authors: Nie Liang , Xiao Yujie , Zhou Tiantian , Feng Haoqi , He Meina , Liang Qingyuan , Mu Kexin , Nie Hailing , Huang Qiaoyun , Chen Wenli 
Published: November 2023

Abstract
The ubiquitous bacterial second messenger cyclic diguanylate (c-di-GMP) coordinates diverse cellular processes through its downstream receptors. However, whether c-di-GMP participates in regulating nitrate assimilation is unclear. Here, we found that NasT, an antiterminator involved in nitrate assimilation in Pseudomonas putida, specifically bound c-di-GMP. NasT was essential for expressing the nirBD operon encoding nitrite reductase during nitrate assimilation. High-level c-di-GMP inhibited the binding of NasT to the leading RNA of nirBD operon (NalA), thus attenuating the antitermination function of NasT, resulting in decreased nirBD expression and nitrite reductase activity, which in turn led to increased nitrite accumulation in cells and its export. Molecular docking and point mutation assays revealed five residues in NasT (R70, Q72, D123, K127 and R140) involved in c-di-GMP-binding, of which R140 was essential for both c-di-GMP-binding and NalA-binding. Three diguanylate cyclases (c-di-GMP synthetases) were found to interact with NasT and inhibited nirBD expression, including WspR, PP_2557, and PP_4405. Besides, the c-di-GMP-binding ability of NasT was conserved in the other three representative Pseudomonas species, including P. aeruginosa, P. fluorescens and P. syringae. Our findings provide new insights into nitrate assimilation regulation by revealing the mechanism by which c-di-GMP inhibits nitrate assimilation via NasT.
Co-transcriptional folding of the glmS ribozyme enables a rapid response to metabolite
Authors: Lou Yuan , Woodson Sarah A 
Published: November 2023

Abstract
The glmS ribozyme riboswitch, located in the 5′ untranslated region of the Bacillus subtilis glmS messenger RNA (mRNA), regulates cell wall biosynthesis through ligand-induced self-cleavage and decay of the glmS mRNA. Although self-cleavage of the refolded glmS ribozyme has been studied extensively, it is not known how early the ribozyme folds and self-cleaves during transcription. Here, we combine single-molecule fluorescence with kinetic modeling to show that self-cleavage can occur during transcription before the ribozyme is fully synthesized. Moreover, co-transcriptional folding of the RNA at a physiological elongation rate allows the ribozyme catalytic core to react without the downstream peripheral stability domain. Dimethyl sulfate footprinting further revealed how slow sequential folding favors formation of the native core structure through fraying of misfolded helices and nucleation of a native pseudoknot. Ribozyme self-cleavage at an early stage of transcription may benefit glmS regulation in B. subtilis, as it exposes the mRNA to exoribonuclease before translation of the open reading frame can begin. Our results emphasize the importance of co-transcriptional folding of RNA tertiary structure for cis-regulation of mRNA stability.
RNA-binding protein Nocte regulates Drosophila development by promoting translation reinitiation on mRNAs with long upstream open reading frames
Authors: Zhang Tianyi , Xue Yutong , Su Shuaikun , Altouma Valerie , Ho Katherine , Martindale Jennifer L , Lee Seung-Kyu , Shen Weiping , Park Aaron , Zhang Yongqing , De Supriyo , Gorospe Myriam , Wang Weidong 
Published: November 2023

Abstract
RNA-binding proteins (RBPs) with intrinsically disordered regions (IDRs) are linked to multiple human disorders, but their mechanisms of action remain unclear. Here, we report that one such protein, Nocte, is essential for Drosophila eye development by regulating a critical gene expression cascade at translational level. Knockout of nocte in flies leads to lethality, and its eye-specific depletion impairs eye size and morphology. Nocte preferentially enhances translation of mRNAs with long upstream open reading frames (uORFs). One of the key Nocte targets, glass mRNA, encodes a transcription factor critical for differentiation of photoreceptor neurons and accessory cells, and re-expression of Glass largely rescued the eye defects caused by Nocte depletion. Mechanistically, Nocte counteracts long uORF-mediated translational suppression by promoting translation reinitiation downstream of the uORF. Nocte interacts with translation factors eIF3 and Rack1 through its BAT2 domain, and a Nocte mutant lacking this domain fails to promote translation of glass mRNA. Notably, de novo mutations of human orthologs of Nocte have been detected in schizophrenia patients. Our data suggest that Nocte family of proteins can promote translation reinitiation to overcome long uORFs-mediated translational suppression, and disruption of this function can lead to developmental defects and neurological disorders.
Oxygen saturation in healthy-term neonates at high altitude: A multisite prospective study
Authors: Kannan Loganathan Prakash , Nettel-Aguirre Alberto , Lodha Abhay , Al Awad Essa , Fajardo Carlos , Nair Vrinda , Scotland Jeanne , Singhal Nalini , Young Marilyn , York Kristin , Rabi Yacov 
Published: November 2023

Abstract

Objectives
To determine oxygen saturation (SpO2) values and their variability in healthy-term neonates at high altitude.

Methods
In a prospective multisite, non-randomized blinded study, we performed SpO2 measurements in healthy neonates admitted to postnatal wards and followed up in Public Health Nurse Clinics (PHNC) in Calgary, Alberta, Canada. We recruited healthy-term neonates (≥37 weeks) between 6 and 24 h of age. Neonates underwent simultaneous pre- and post-ductal SpO2 recordings every 12 to 24 h until hospital discharge and again in the PHNC within a few days after discharge. Neonates were followed for 8 weeks to ascertain their health status.

Results
We included data for 252 neonates in hospital and 105 neonates presenting to the PHNC for follow-up. In hospital, the mean pre- and post-ductal SpO2 were 94.3% and 96.0%, respectively. In the PHNC, mean pre- and post-ductal SpO2 were 94.4% and 95.6%, respectively. Desaturation episodes occurred frequently at a median rate of once every 5 minutes. The median duration of pre-ductal desaturation episodes was longer in hospital than in the PHNC for all SpO2 thresholds (P &lt; 0.05).

Conclusion
SpO2 levels in healthy-term neonates at high altitude are approximately 94% and remained stable over the first few days after birth. Desaturation episodes are common in the immediate neonatal period, but their duration decreases over time, and they are not associated with clinical deterioration.
Clinic trials.org (NCT 02095041).
Improved super-resolution ribosome profiling reveals prevalent translation of upstream ORFs and small ORFs in Arabidopsis
Authors: Wu Hsin-Yen Larry , Ai Qiaoyun , Teixeira Rita Teresa , Nguyen Phong H T , Song Gaoyuan , Montes Christian , Elmore J Mitch , Walley Justin W , Hsu Polly Yingshan 
Published: November 2023

Abstract
A crucial step in functional genomics is identifying actively translated ORFs and linking them to biological functions. The challenge lies in identifying short ORFs, as their identification is greatly influenced by data quality and depth. Here, we improved the coverage of super-resolution Ribo-seq in Arabidopsis (Arabidopsis thaliana), revealing uncharacterized translation events for nuclear, chloroplastic, and mitochondrial genes. Assisted by a transcriptome assembly, we identified 7,751 unconventional translation events, comprising 6,996 upstream ORFs (uORFs) and 209 downstream ORFs on annotated protein-coding genes, as well as 546 ORFs in presumed noncoding RNAs. Proteomic data confirmed the production of stable proteins from some of these unannotated translation events. We present evidence of active translation from primary transcripts of trans-acting small interfering RNAs (TAS1–4) and microRNAs (pri-MIR163 and pri-MIR169) and periodic ribosome stalling supporting cotranslational decay. Additionally, we developed a method for identifying extremely short uORFs, including 370 minimum uORFs (AUG-stop), and 2,921 tiny uORFs (2 to 10 amino acids) and 681 uORFs that overlap with each other. Remarkably, these short uORFs exhibit strong translational repression as do longer uORFs. We also systematically discovered 594 uORFs regulated by alternative splicing, suggesting widespread isoform-specific translational control. Finally, these prevalent uORFs are associated with numerous important pathways. In summary, our improved Arabidopsis translational landscape provides valuable resources to study gene expression regulation.
Conservation of the moss RNA editing factor PPR78 despite the loss of its known cytidine-to-uridine editing sites is explained by a hidden extra target
Authors: Lesch Elena , Stempel Maike Simone , Dressnandt Vanessa , Oldenkott Bastian , Knoop Volker , Schallenberg-Rüdinger Mareike 
Published: November 2023

Abstract
Cytidine (C)-to-uridine (U) RNA editing in plant organelles relies on specific RNA-binding pentatricopeptide repeat (PPR) proteins. In the moss Physcomitrium patens, all such RNA editing factors feature a C-terminal DYW domain that acts as the cytidine deaminase for C-to-U conversion. PPR78 of Physcomitrium targets 2 mitochondrial editing sites, cox1eU755SL and rps14eU137SL. Remarkably, the latter is edited to highly variable degrees in different mosses. Here, we aimed to unravel the coevolution of PPR78 and its 2 target sites in mosses. Heterologous complementation in a Physcomitrium knockout line revealed that the variable editing of rps14eU137SL depends on the PPR arrays of different PPR78 orthologues but not their C-terminal domains. Intriguingly, PPR78 has remained conserved despite the simultaneous loss of editing at both known targets among Hypnales (feather mosses), suggesting it serves an additional function. Using a recently established RNA editing assay in Escherichia coli, we confirmed site-specific RNA editing by PPR78 in the bacterium and identified 4 additional off-targets in the bacterial transcriptome. Based on conservation profiles, we predicted ccmFNeU1465RC as a candidate editing target of PPR78 in moss mitochondrial transcriptomes. We confirmed editing at this site in several mosses and verified that PPR78 targets ccmFNeU1465RC in the bacterial editing system, explaining the conservation and functional adaptation of PPR78 during moss evolution.
Long-term outcomes of lupus nephritis with low-level proteinuria: a multicentre, retrospective study
Authors: Zoshima Takeshi , Hara Satoshi , Suzuki Kazuyuki , Yoshida Misaki , Konishi Masahiro , Hibino Shinya , Suda Takuya , Hoshiba Ryohei , Kawahara Hiroyuki , Horita Shigeto , Nuka Hiromi , Mizushima Ichiro , Kawano Mitsuhiro 
Published: November 2023

Abstract

Objectives
Reportedly, patients with LN and low-level proteinuria have favourable short-term renal outcomes. We aimed to clarify the long-term renal outcomes and overall survival of these patients, and the significance of renal biopsy in the early phase with low-level proteinuria.

Methods
We included 144 Japanese patients with biopsy-proven LN from 10 hospitals. Low-level proteinuria was defined by a urine protein:creatinine ratio (UPCR) of ≤1 g/gCr based on previous reports. The outcomes were end-stage renal disease (ESRD) and death.

Results
Compared with patients with high-level proteinuria (UPCR &gt;1 g/gCr), those with low-level proteinuria [n = 67 (46.5%)] had significantly improved renal function at the time of renal biopsy, and low activity index and chronicity index while the frequency of class III/IV was similar (79.1% vs 84.4%, P = 0.409). In patients with low-level proteinuria, CYC usage was less, and the incidences of ESRD (3.0% vs 13.0%, P = 0.036) and death (3.0% vs 16.9%, P = 0.006) during the total observation period (median, 72 months) were low. Kaplan–Meier analysis showed significant differences in the incidence of ESRD and death between the groups. Multivariate Cox regression analysis revealed that the significant risk factors for ESRD were high chronicity index and hypertension, whereas those for death were increased age and high-level proteinuria.

Conclusion
Patients with LN and low-level proteinuria had favourable long-term renal and life outcomes. As these patients have substantial active pathological lesions, renal biopsy in the early phase with low-level proteinuria could enable early diagnosis and treatment and thus improve prognosis.
Genetic testing of Behçet’s disease using next-generation sequencing to identify monogenic mimics and HLA-B*51
Authors: Burleigh Alice , Omoyinmi Ebun , Papadopoulou Charalampia , Al-Abadi Eslam , Hong Ying , Price-Kuehne Fiona , Moraitis Elena , Titheradge Hannah , Montesi Francesca , Xu Diane , Eleftheriou Despina , Brogan Paul 
Published: November 2023

Abstract

Objective
Several monogenic autoinflammatory disorders and primary immunodeficiencies can present early in life with features that may be mistaken for Behçet’s disease (BD). We aimed to develop a genetic analysis workflow to identify rare monogenic BD-like diseases and establish the contribution of HLA haplotype in a cohort of patients from the UK.

Methods
Patients with clinically suspected BD were recruited from four BD specialist care centres in the UK. All participants underwent whole-exome sequencing (WES), and genetic analysis thereafter by (i) examining genes known to cause monogenic immunodeficiency, autoinflammation or vasculitis by virtual panel application; (ii) scrutiny of variants prioritized by Exomiser using Human Phenotype Ontology (HPO); (iii) identification of copy number variants using ExomeDepth; and (iv) HLA-typing using OptiType.

Results
Thirty-one patients were recruited: median age 15 (4–52), and median disease onset age 5 (0–20). Nine/31 (29%) patients had monogenic disease mimicking BD: five cases of Haploinsufficiency of A20 with novel TNFAIP3 variants (p.T76I, p. M112Tfs*8, p. S548Dfs*128, p. C657Vfs*14, p. E661Nfs*36); one case of ISG15 deficiency with a novel nonsense variant (ISG15: p.Q16X) and 1p36.33 microdeletion; one case of common variable immune deficiency (TNFRSF13B: p.A181E); and two cases of TNF receptor-associated periodic syndrome (TNFRSF1A: p.R92Q). Of the remaining 22 patients, eight (36%) were HLA-B*51 positive.

Conclusion
We describe a novel genetic workflow for BD, which can efficiently detect known and potentially novel monogenic forms of BD, whilst additionally providing HLA-typing. Our results highlight the importance of genetic testing before BD diagnosis, as this has an impact on choice of therapy, prognosis and genetic counselling.
The saliency of the CEO pay ratio
Authors: Boone Audra , Starkweather Austin , White Joshua T 
Published: November 2023

Abstract
The US Securities and Exchange Commission’s mandated CEO pay ratio is a simple, but salient, metric that could resonate with employees given it focuses on their compensation. Reporting a relatively or surprisingly high ratio reduces employee perceptions of their pay, views of the CEO, and hampers productivity growth. Employee pay satisfaction drops after disclosing a high ratio even if their wages were previously disclosed and when the pay ratio disclosure adds little new information. Disclosures by firms with a high ratio contain more discretionary language to explain the ratio or portray employee relations positively and are more likely to be covered by the media. However, neither information source substantially alters the employee response to a salient ratio. Our work illustrates that requiring firms to disclose a salient metric can have unintended consequences on employees and suggests caution in requiring firms to report simplified Environmental, Social, and Governance (ESG) metrics that are inherently multifaceted.
Israel—estate planning for the unwary
Authors: Eyal Lyat 
Published: November 2023

Abstract
The importance of estate planning cannot be emphasized enough, so much more so where the relevant individuals have a connection to more than one jurisdiction. Said connection may be with respect to citizenship, residency, ownership of assets or the jurisdiction of residence of the heirs. This article considers each of these factors separately. As the world is global, more individuals are affected by the laws of foreign jurisdictions upon their demise and if no planning has been effected during their lifetime, the heirs are left to clean up the mess.
Implications of the COVID-19 trajectory for the evaluation of hand hygiene interventions: Secondary analysis of the Soapp trial
Authors: Baretta Dario , Inauen Jennifer 
Published: November 2023

Abstract
Hand hygiene behavior is crucial to counter the spread of infectious diseases. However, its adoption during the early stages of the Coronavirus disease (COVID-19) pandemic showed temporal fluctuations associated with the trajectory of the pandemic (e.g. new COVID-19 infections). Such associations can confound conclusions about the effectiveness of interventions aimed at promoting hand hygiene during a pandemic. In this study, we performed a secondary analysis of a dataset from the optimization phase of Soapp, an app to promote hand hygiene during the COVID-19 pandemic. We used a longitudinal study design to test whether the associations between the pandemic trajectory and hand hygiene behavior were still present one year after the outbreak (primary outcome) and whether they impacted conclusions about the effectiveness of Soapp (secondary outcome). Participants (N = 216) were randomized to different versions of Soapp and used an electronic diary to self-report their hand hygiene behavior multiple times during the study. We considered the following indicators of the COVID-19 pandemic from the country of Switzerland in the period between March and August 2021: total cases/deaths, increases in recent new cases/deaths, new cases/deaths, and number of administered doses of vaccine. Data were analyzed using a multilevel approach. Results suggested that there were no significant associations between hand hygiene and the indicators of the pandemic trajectory. However, models including total cases/deaths impacted the conclusions about Soapp’s effectiveness. Implications from this study are that the development and evaluation of hand hygiene interventions during a pandemic context should account for the trajectory indicators to maximize their effectiveness and control for confounding effects.
LINC02454 promotes thyroid carcinoma progression via upregulating HMGA2 through CREB1
Authors: Cao Yan , Li Jian , Du Yongliang , Sun Yuxuan , Liu Le , Fang Hao , Liang Yan , Mao Shanshan 
Published: November 2023

AbstractThyroid carcinoma (THCA) is the most common malignancy in the endocrine system. Long intergenic non‐coding RNA 2454 (LINC02454) exhibits an HMGA2‐like expression pattern, but their relationship and roles in THCA are largely unknown. The present purpose was to delineate the roles of LINC02454 in THCA progression and its molecular mechanisms. We collected THCA tissues from patients and monitored patient survival. THCA cell colony formation, migration, and invasion were evaluated. Metastasis was evaluated by examining EMT markers through Western blotting. Gene interaction was determined with ChIP, RIP, RNA pull‐down, and luciferase activity assays. A mouse model of a subcutaneous tumor was used to determine the activity of LINC02454 knockdown in vivo. We found that LINC02454 was highly expressed in THCA, and its upregulation was associated with poor survival. The knockdown of LINC02454 repressed colony formation, migration, and invasion. Moreover, loss of LINC02454 inhibited tumor growth and metastasis in mice. HMGA2 promoted LINC02454 transcription via binding to the LINC02454 promoter, and silencing of HMGA2 suppressed malignant behaviors through downregulation of LINC02454. HMGA2 was a novel functional target of LINC02454 in THCA cells, and knockdown of LINC02454‐mediated anti‐tumor effects was reversed by HMGA2 overexpression. Mechanically, LINC02454 promoted CREB1 phosphorylation and nuclear translocation, and CREB1 was subsequently bound to the HMGA2 promoter to facilitate its expression. LINC02454 cis‐regulates HMGA2 transcription via facilitating CREB1 phosphorylation and nuclear translocation, and, in turn, HMGA2 promotes LINC02454 expression, thus accelerating thyroid carcinoma progression. Our results support therapeutic targets of LINC02454 and HMGA2 for THCA.
Phase-amplitude coupling of NREM sleep oscillations is unaffected by pre-sleep learning but related to overnight memory gains depending on the declarative learning paradigm
Authors: Cross Nathan , O’Byrne Jordan , Weiner Oren M. , Giraud Julia , Perrault Aurore A. , Dang-Vu Thien Thanh 
Published: November 2023

AbstractThere is growing evidence in humans linking the temporal coupling between spindles and slow oscillations during NREM sleep with the overnight stabilization of memories encoded from daytime experiences in humans. However, whether the type and strength of learning influence that relationship is still unknown. Here we tested whether the amount or type of verbal word-pair learning prior to sleep affects subsequent phase-amplitude coupling (PAC) between spindles and slow oscillations (SO). We measured the strength and preferred timing of such coupling in the EEG of 41 healthy human participants over a post-learning and control night, to compare intra-individual changes with inter-individual differences. We leveraged learning paradigms of varying word-pair (WP) load: 40 WP learned to a minimum criterion of 60% correct (n=11); 40 WP presented twice (n=15); 120 WP presented twice (n=15). There were no significant differences in the preferred phase or strength between the control and post-learning nights, in all learning conditions. We observed an overnight consolidation effect (improved performance at delayed recall) for the criterion learning condition only, and only in this condition was the overnight change in memory performance significantly positively correlated with the phase of SO-spindle coupling. These results suggest that the coupling of brain oscillations during human NREM sleep are stable traits that are not modulated by the amount of pre-sleep learning, yet are implicated in the sleep-dependent consolidation of memory.