bluuebunny/crossref_metadata_2025_split huggingface dataset:
Approximate Bayesian Computation Untangles Signatures of Contemporary and Historical Hybridization between Two Endangered Species
Authors: Dittberner Hannes , Tellier Aurelien , de Meaux Juliette 
Published: January 2022

AbstractContemporary gene flow, when resumed after a period of isolation, can have crucial consequences for endangered species, as it can both increase the supply of adaptive alleles and erode local adaptation. Determining the history of gene flow and thus the importance of contemporary hybridization, however, is notoriously difficult. Here, we focus on two endangered plant species, Arabis nemorensis and A. sagittata, which hybridize naturally in a sympatric population located on the banks of the Rhine. Using reduced genome sequencing, we determined the phylogeography of the two taxa but report only a unique sympatric population. Molecular variation in chloroplast DNA indicated that A. sagittata is the principal receiver of gene flow. Applying classical D-statistics and its derivatives to whole-genome data of 35 accessions, we detect gene flow not only in the sympatric population but also among allopatric populations. Using an Approximate Bayesian computation approach, we identify the model that best describes the history of gene flow between these taxa. This model shows that low levels of gene flow have persisted long after speciation. Around 10 000 years ago, gene flow stopped and a period of complete isolation began. Eventually, a hotspot of contemporary hybridization was formed in the unique sympatric population. Occasional sympatry may have helped protect these lineages from extinction in spite of their extremely low diversity.
Loss of histone methyltransferase SETD1B in oogenesis results in the redistribution of genomic histone 3 lysine 4 trimethylation
Authors: Hanna Courtney W , Huang Jiahao , Belton Christian , Reinhardt Susanne , Dahl Andreas , Andrews Simon , Stewart A Francis , Kranz Andrea , Kelsey Gavin 
Published: January 2022

Abstract
Histone 3 lysine 4 trimethylation (H3K4me3) is an epigenetic mark found at gene promoters and CpG islands. H3K4me3 is essential for mammalian development, yet mechanisms underlying its genomic targeting are poorly understood. H3K4me3 methyltransferases SETD1B and MLL2 (KMT2B) are essential for oogenesis. We investigated changes in H3K4me3 in Setd1b conditional knockout (cKO) oocytes using ultra-low input ChIP-seq, with comparisons to DNA methylation and gene expression analyses. H3K4me3 was redistributed in Setd1b cKO oocytes showing losses at active gene promoters associated with downregulated gene expression. Remarkably, many regions also gained H3K4me3, in particular those that were DNA hypomethylated, transcriptionally inactive and CpG-rich, which are hallmarks of MLL2 targets. Consequently, loss of SETD1B disrupts the balance between MLL2 and de novo DNA methyltransferases in determining the epigenetic landscape during oogenesis. Our work reveals two distinct, complementary mechanisms of genomic targeting of H3K4me3 in oogenesis, with SETD1B linked to gene expression and MLL2 to CpG content.
RBFOX2 is required for establishing RNA regulatory networks essential for heart development
Authors: Verma Sunil K , Deshmukh Vaibhav , Thatcher Kaitlyn , Belanger KarryAnne K , Rhyner Alexander M , Meng Shu , Holcomb Richard Joshua , Bressan Michael , Martin James F , Cooke John P , Wythe Joshua D , Widen Steven G , Lincoln Joy , Kuyumcu-Martinez Muge N 
Published: January 2022

Abstract
Human genetic studies identified a strong association between loss of function mutations in RBFOX2 and hypoplastic left heart syndrome (HLHS). There are currently no Rbfox2 mouse models that recapitulate HLHS. Therefore, it is still unknown how RBFOX2 as an RNA binding protein contributes to heart development. To address this, we conditionally deleted Rbfox2 in embryonic mouse hearts and found profound defects in cardiac chamber and yolk sac vasculature formation. Importantly, our Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS. To determine the molecular drivers of these cardiac defects, we performed RNA-sequencing in Rbfox2 mutant hearts and identified dysregulated alternative splicing (AS) networks that affect cell adhesion to extracellular matrix (ECM) mediated by Rho GTPases. We identified two Rho GTPase cycling genes as targets of RBFOX2. Modulating AS of these two genes using antisense oligos led to cell cycle and cell-ECM adhesion defects. Consistently, Rbfox2 mutant hearts displayed cell cycle defects and inability to undergo endocardial-mesenchymal transition, processes dependent on cell-ECM adhesion and that are seen in HLHS. Overall, our work not only revealed that loss of Rbfox2 leads to heart development defects resembling HLHS, but also identified RBFOX2-regulated AS networks that influence cell-ECM communication vital for heart development.
Commonality and diversity in tRNA substrate recognition in t6A biogenesis by eukaryotic KEOPSs
Authors: Wang Jin-Tao , Zhou Jing-Bo , Mao Xue-Ling , Zhou Li , Chen Meirong , Zhang Wenhua , Wang En-Duo , Zhou Xiao-Long 
Published: January 2022

Abstract
N 6-Threonylcarbamoyladenosine (t6A) is a universal and pivotal tRNA modification. KEOPS in eukaryotes participates in its biogenesis, whose mutations are connected with Galloway-Mowat syndrome. However, the tRNA substrate selection mechanism by KEOPS and t6A modification function in mammalian cells remain unclear. Here, we confirmed that all ANN-decoding human cytoplasmic tRNAs harbor a t6A moiety. Using t6A modification systems from various eukaryotes, we proposed the possible coevolution of position 33 of initiator tRNAMet and modification enzymes. The role of the universal CCA end in t6A biogenesis varied among species. However, all KEOPSs critically depended on C32 and two base pairs in the D-stem. Knockdown of the catalytic subunit OSGEP in HEK293T cells had no effect on the steady-state abundance of cytoplasmic tRNAs but selectively inhibited tRNAIle aminoacylation. Combined with in vitro aminoacylation assays, we revealed that t6A functions as a tRNAIle isoacceptor-specific positive determinant for human cytoplasmic isoleucyl-tRNA synthetase (IARS1). t6A deficiency had divergent effects on decoding efficiency at ANN codons and promoted +1 frameshifting. Altogether, our results shed light on the tRNA recognition mechanism, revealing both commonality and diversity in substrate recognition by eukaryotic KEOPSs, and elucidated the critical role of t6A in tRNAIle aminoacylation and codon decoding in human cells.
Does rapid sequence divergence preclude RNA structure conservation in vertebrates?
Authors: Seemann Stefan E , Mirza Aashiq H , Bang-Berthelsen Claus H , Garde Christian , Christensen-Dalsgaard Mikkel , Workman Christopher T , Pociot Flemming , Tommerup Niels , Gorodkin Jan , Ruzzo Walter L 
Published: January 2022

Abstract
Accelerated evolution of any portion of the genome is of significant interest, potentially signaling positive selection of phenotypic traits and adaptation. Accelerated evolution remains understudied for structured RNAs, despite the fact that an RNA’s structure is often key to its function. RNA structures are typically characterized by compensatory (structure-preserving) basepair changes that are unexpected given the underlying sequence variation, i.e., they have evolved through negative selection on structure. We address the question of how fast the primary sequence of an RNA can change through evolution while conserving its structure. Specifically, we consider predicted and known structures in vertebrate genomes. After careful control of false discovery rates, we obtain 13 de novo structures (and three known Rfam structures) that we predict to have rapidly evolving sequences—defined as structures where the primary sequences of human and mouse have diverged at least twice as fast (1.5 times for Rfam) as nearby neutrally evolving sequences. Two of the three known structures function in translation inhibition related to infection and immune response. We conclude that rapid sequence divergence does not preclude RNA structure conservation in vertebrates, although these events are relatively rare.
Genome-wide RNAi screen identifies novel players in human 60S subunit biogenesis including key enzymes of polyamine metabolism
Authors: Dörner Kerstin , Badertscher Lukas , Horváth Bianka , Hollandi Réka , Molnár Csaba , Fuhrer Tobias , Meier Roger , Sárazová Marie , van den Heuvel Jasmin , Zamboni Nicola , Horvath Peter , Kutay Ulrike 
Published: January 2022

Abstract
Ribosome assembly is an essential process that is linked to human congenital diseases and tumorigenesis. While great progress has been made in deciphering mechanisms governing ribosome biogenesis in eukaryotes, an inventory of factors that support ribosome synthesis in human cells is still missing, in particular regarding the maturation of the large 60S subunit. Here, we performed a genome-wide RNAi screen using an imaging-based, single cell assay to unravel the cellular machinery promoting 60S subunit assembly in human cells. Our screen identified a group of 310 high confidence factors. These highlight the conservation of the process across eukaryotes and reveal the intricate connectivity of 60S subunit maturation with other key cellular processes, including splicing, translation, protein degradation, chromatin organization and transcription. Intriguingly, we also identified a cluster of hits comprising metabolic enzymes of the polyamine synthesis pathway. We demonstrate that polyamines, which have long been used as buffer additives to support ribosome assembly in vitro, are required for 60S maturation in living cells. Perturbation of polyamine metabolism results in early defects in 60S but not 40S subunit maturation. Collectively, our data reveal a novel function for polyamines in living cells and provide a rich source for future studies on ribosome synthesis.
RAD51 protects against nonconservative DNA double-strand break repair through a nonenzymatic function
Authors: So Ayeong , Dardillac Elodie , Muhammad Ali , Chailleux Catherine , Sesma-Sanz Laura , Ragu Sandrine , Le Cam Eric , Canitrot Yvan , Masson Jean Yves , Dupaigne Pauline , Lopez Bernard S , Guirouilh-Barbat Josée 
Published: January 2022

Abstract
Selection of the appropriate DNA double-strand break (DSB) repair pathway is decisive for genetic stability. It is proposed to act according to two steps: 1-canonical nonhomologous end-joining (C-NHEJ) versus resection that generates single-stranded DNA (ssDNA) stretches; 2-on ssDNA, gene conversion (GC) versus nonconservative single-strand annealing (SSA) or alternative end-joining (A-EJ). Here, we addressed the mechanisms by which RAD51 regulates this second step, preventing nonconservative repair in human cells. Silencing RAD51 or BRCA2 stimulated both SSA and A-EJ, but not C-NHEJ, validating the two-step model. Three different RAD51 dominant-negative forms (DN-RAD51s) repressed GC and stimulated SSA/A-EJ. However, a fourth DN-RAD51 repressed SSA/A-EJ, although it efficiently represses GC. In living cells, the three DN-RAD51s that stimulate SSA/A-EJ failed to load efficiently onto damaged chromatin and inhibited the binding of endogenous RAD51, while the fourth DN-RAD51, which inhibits SSA/A-EJ, efficiently loads on damaged chromatin. Therefore, the binding of RAD51 to DNA, rather than its ability to promote GC, is required for SSA/A-EJ inhibition by RAD51. We showed that RAD51 did not limit resection of endonuclease-induced DSBs, but prevented spontaneous and RAD52-induced annealing of complementary ssDNA in vitro. Therefore, RAD51 controls the selection of the DSB repair pathway, protecting genome integrity from nonconservative DSB repair through ssDNA occupancy, independently of the promotion of CG.
Transcriptomic and genomic studies classify NKL54 as a histone deacetylase inhibitor with indirect influence on MEF2-dependent transcription
Authors: Minisini Martina , Di Giorgio Eros , Kerschbamer Emanuela , Dalla Emiliano , Faggiani Massimo , Franforte Elisa , Meyer-Almes Franz-Josef , Ragno Rino , Antonini Lorenzo , Mai Antonello , Fiorentino Francesco , Rotili Dante , Chinellato Monica , Perin Stefano , Cendron Laura , Weichenberger Christian X , Angelini Alessandro , Brancolini Claudio 
Published: January 2022

Abstract
In leiomyosarcoma class IIa HDACs (histone deacetylases) bind MEF2 and convert these transcription factors into repressors to sustain proliferation. Disruption of this complex with small molecules should antagonize cancer growth. NKL54, a PAOA (pimeloylanilide o-aminoanilide) derivative, binds a hydrophobic groove of MEF2, which is used as a docking site by class IIa HDACs. However, NKL54 could also act as HDAC inhibitor (HDACI). Therefore, it is unclear which activity is predominant. Here, we show that NKL54 and similar derivatives are unable to release MEF2 from binding to class IIa HDACs. Comparative transcriptomic analysis classifies these molecules as HDACIs strongly related to SAHA/vorinostat. Low expressed genes are upregulated by HDACIs, while abundant genes are repressed. This transcriptional resetting correlates with a reorganization of H3K27 acetylation around the transcription start site (TSS). Among the upregulated genes there are several BH3-only family members, thus explaining the induction of apoptosis. Moreover, NKL54 triggers the upregulation of MEF2 and the downregulation of class IIa HDACs. NKL54 also increases the binding of MEF2D to promoters of genes that are upregulated after treatment. In summary, although NKL54 cannot outcompete MEF2 from binding to class IIa HDACs, it supports MEF2-dependent transcription through several actions, including potentiation of chromatin binding.
Deuterium magnetic resonance spectroscopy enables noninvasive metabolic imaging of tumor burden and response to therapy in low-grade gliomas
Authors: Taglang Céline , Batsios Georgios , Mukherjee Joydeep , Tran Meryssa , Gillespie Anne Marie , Hong Donghyun , Ronen Sabrina M , Artee Luchman Hema , Pieper Russell O , Viswanath Pavithra 
Published: January 2022

Abstract

Background
The alternative lengthening of telomeres (ALT) pathway is essential for tumor proliferation in astrocytomas. The goal of this study was to identify metabolic alterations linked to the ALT pathway that can be exploited for noninvasive magnetic resonance spectroscopy (MRS)-based imaging of astrocytomas in vivo.

Methods
Genetic and pharmacological methods were used to dissect the association between the ALT pathway and glucose metabolism in genetically engineered and patient-derived astrocytoma models. 2H-MRS was used for noninvasive imaging of ALT-linked modulation of glycolytic flux in mice bearing orthotopic astrocytomas in vivo.

Results
The ALT pathway was associated with higher activity of the rate-limiting glycolytic enzyme phosphofructokinase-1 and concomitantly elevated flux of glucose to lactate in astrocytoma cells. Silencing the ALT pathway or treating with the poly(ADP-ribose) polymerase inhibitor niraparib that induces telomeric fusion in ALT-dependent astrocytoma cells abrogated glycolytic flux. Importantly, this metabolic reprogramming could be non-invasively visualized by 2H-MRS. Lactate production from [6,6′-2H]-glucose was higher in ALT-dependent astrocytoma tumors relative to the normal brain in vivo. Furthermore, treatment of orthotopic astrocytoma-bearing mice with niraparib reduced lactate production from [6,6′-2H]-glucose at early timepoints when alterations in tumor volume could not be detected by anatomical imaging, pointing to the ability of [6,6′-2H]-glucose to report on pseudoprogression in vivo.

Conclusions
We have mechanistically linked the ALT pathway to elevated glycolytic flux and demonstrated the ability of [6,6′-2H]-glucose to non-invasively assess tumor burden and response to therapy in astrocytomas. Our findings point to a novel, clinically translatable method for metabolic imaging of astrocytoma patients.
Predictors of Secondhand Smoke Exposure During Pregnancy in Costa Rica, the Dominican Republic, and Honduras
Authors: Quiñones Zahira , Li Dongmei , McIntosh Scott , Avendaño Esteban , Sánchez José Javier , DiMare-Hering Carmen , Flores-Golfin Daniel , Wang Sijiu , Pérez-Ramos José G , Dye Timothy D V , Ossip Deborah J 
Published: January 2022

Abstract

Introduction
Secondhand smoke (SHS) exposure poses risks to pregnant women and children. Though smoking among pregnant women in many low- and middle-income countries is low, exposure to SHS might be higher. We examined the prevalence and predictors of SHS among pregnant women from Costa Rica, the Dominican Republic, and Honduras.

Methods
Postpartum women 18+ years old who completed pregnancy in past 5 years were surveyed in health care and community settings.

Results
Data for 1,081 women indicated low tobacco use (1.0%–3.7%), frequent exposure to active smokers (29.0%–34.0%), often being close enough to breathe others’ smoke (49.4%–66.5%), and most having smoke-free home policies (70.8%–76.2%). Women reporting unintended pregnancy (adjusted odds ratio [aOR]: 1.44, 95% confidence interval [CI] 1.03, 2.00) and alcohol consumption (aOR: 1.92, 95% CI 1.34, 2.77) were more likely to be close enough to breathe others’ smoke. Women with health problems during pregnancy (aOR: 1.48 95% CI 1.07, 2.06) were more likely to have home smoking policies. Tobacco use was associated with all SHS exposure outcomes.

Conclusions
SHS exposure was high during pregnancy; women with higher risk variables, that is, tobacco use, alcohol consumption, and unintended pregnancy were more likely to be exposed. Addressing SHS exposure in pregnancy in low- and middle-income countries can improve maternal health outcomes in vulnerable populations.

Implications
The study results suggest a cluster of multiple risk factors associated with a high prevalence of exposure to SHS among pregnant women in LIMCs from Latin America and Caribbean Region. Interventions, regulations, and policies need to address specific high-risk factors to change behaviors and improve maternal and child health outcomes especially in vulnerable populations.
Gender, Tobacco Control Policies, and Persistent Smoking Among Older Adults: A Longitudinal Analysis of 11 European Countries
Authors: Gao Manjing , Lee Chioun , Park Soojin 
Published: January 2022

Abstract

Introduction
Little is known about sociodemographic and macro-level predictors of persistent smoking when one has developed a health condition that is likely caused by smoking.

Aims and Methods
We investigate the impact of gender, education, and tobacco control policies (TCPs) on persistent smoking among older Europeans. Respondents (aged 50 +) with a smoking history and at least one smoking-related health condition were pooled from the Survey of Health, Aging and Retirement in Europe (SHARE) and the English Longitudinal Study of Ageing (ELSA) from four waves from 2004 to 2013. We fitted gender-specific logistic regression models with two-way fixed effects (country and year) and tested interaction terms between gender, education, and TCPs.

Results
Although women are less likely to smoke than men, they were more likely to smoke persistently. The effects of education and general TCPs on persistent smoking were significant for women only. Compared to women with low levels of education, those with moderate education (odds ratio [OR] = .63; .49–.82) and high education (OR = .57; .34–.98) are less likely to be persistent smokers. TCPs are associated with a reduced risk of women’s persistent smoking (OR = .70; .51–.95) and the association is stronger for those having less education.

Conclusions
Older women, particularly those with low levels of education, are vulnerable to persistent smoking. TCPs might be effective in reducing persistent smoking for older women, with greater effects for less-educated women. Future studies are needed to understand mechanisms that explain gender differences in responsiveness to TCPs.

Implications
Persistent smoking is a particularly harmful smoking behavior as it is associated with greater risks of comorbidity and mortality. By employing the framework of the multilevel social determinants of health, this study examined the behavior of persistent smoking among older adults in European countries. Women, especially women with low levels of education are vulnerable to persistent smoking. Moreover, TCPs, in general, are significantly related to a reduction in persistent smoking among older women only and the negative association is stronger for those having less education, indicating gender and socioeconomic differences in responsiveness to TCPs.
Can States Continue to Set the Agenda for Tobacco 21? Insights From US News Coverage Between 2012 and 2020
Authors: Hrywna Mary , Singh Binu , Wackowski Olivia A , Hudson Shawna V , Delnevo Cristine D 
Published: January 2022

Abstract

Introduction
Existing research on media examining the news content related to Tobacco 21 (T21) predate the adoption of most T21 laws. This study examined the discussion of T21 laws in top-circulating print media sources in the United States between 2012 and 2020.

Aims and Methods
Systematic database searches using Access World News and Factiva identified T21-related news articles appearing in the top daily circulating newspapers in each state between January 2012 and December 2020 (n = 586 articles). Content analyses documented prevalence, types of articles and context related to framing of arguments for or against T21 laws.

Results
Newspaper coverage of T21 was highest in 2019 (42.8% of articles). The majority were news or features (75.4%) followed by editorials or opinions (24.6%) which largely supported T21. Most articles focused on state or local T21 action. Coverage of federal T21 increased in 2019. The most common argument supporting T21 included reducing youth tobacco prevalence (64.8%) while the most frequent objection was freedom infringement (25.1%). Tobacco and vape industries began voicing support for T21 in 2019.

Conclusions
News coverage of state-level T21 in the United States began to increase in 2015 and peaked in 2019 with enactment of federal T21, a newsworthy event. As states adopt and amend T21 laws to align with federal law, advocates can use media to help shape the narrative and encourage strong T21 policies.

Implications
This study described the volume and content of T21 print media coverage from 2012 to 2020, including common arguments used to support and oppose T21. Arguments in support of T21 included reducing youth tobacco use, particularly use of e-cigarettes, and related health effects while arguments against T21 focused on individual rights. Support for T21 reached a tipping point in 2019, including the tobacco industry’s reversal in opposing such laws. States can and should continue to improve existing T21 laws and policies and increase public awareness about critical policy components such as inspection procedures and penalties.