bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interacting galaxies in the IllustrisTNG simulations – VI: Reconstructed orbits, close encounters, and mergers
Authors: Patton David R , Faria Lawrence , Hani Maan H , Torrey Paul , Ellison Sara L , Thakur Shivani D , Westlake Raven I 
Published: February 2024

ABSTRACT
Cosmological simulations have been used to study interacting galaxies as a function of galaxy pair separation, enabling comparisons with observational studies of galaxy pairs. The study of interacting galaxies as a function of time (i.e. merger stage) has mostly been limited to high-resolution merger simulations, due to the poor time sampling available in cosmological simulations. Building on an earlier study of galaxy pairs in the IllustrisTNG cosmological simulations, we reconstruct the orbits of galaxy pairs involving massive galaxies (M* &gt; 1010 M⊙) at redshifts of 0 ≤ z &lt; 1, using a novel kinematic interpolation scheme to model the orbits in between the IllustrisTNG snapshots (which are separated by 162 Myr, on average). We assess the accuracy of these interpolations using a pre-existing suite of merger simulations, and find that kinematic interpolations provide a remarkable improvement in accuracy compared with interpolations that use only radial separations or 3D positions. We find that nearly 90 per cent of the closest pairs (r &lt; 25 kpc) have had a pericentre encounter within the past Gyr. Many of these close pairs are found on rapidly shrinking orbits, and roughly 85 per cent of these pairs will merge within 1 Gyr. However, approximately 3 per cent of these close pairs appear to be flyby systems that will never merge. These reconstructed orbits will be used in future studies to investigate how and when galaxy properties change during close encounters and mergers between galaxies in IllustrisTNG.
Influence of maternal folate depletion on Art3 DNA methylation in the murine adult brain; potential consequences for brain and neurocognitive health
Authors: Kok Dieuwertje E , Saunders Rachael , Nelson Andrew , Smith Darren , Ford Dianne , Mathers John C , McKay Jill A 
Published: February 2024

Abstract
The developmental origins of health and disease hypothesis suggest early-life environment impacts health outcomes throughout the life course. In particular, epigenetic marks, including DNA methylation, are thought to be key mechanisms through which environmental exposures programme later-life health. Adequate maternal folate status before and during pregnancy is essential in the protection against neural tube defects, but data are emerging that suggest early-life folate exposures may also influence neurocognitive outcomes in childhood and, potentially, thereafter. Since folate is key to the supply of methyl donors for DNA methylation, we hypothesize that DNA methylation may be a mediating mechanism through which maternal folate influences neurocognitive outcomes. Using bisulphite sequencing, we measured DNA methylation of five genes (Art3, Rsp16, Tspo, Wnt16, and Pcdhb6) in the brain tissue of adult offspring of dams who were depleted of folate (n = 5, 0.4 mg folic acid/kg diet) during pregnancy (~19–21 days) and lactation (mean 22 days) compared with controls (n = 6, 2 mg folic acid/kg diet). Genes were selected as methylation of their promoters had previously been found to be altered by maternal folate intake in mice and humans across the life course, and because they have potential associations with neurocognitive outcomes. Maternal folate depletion was significantly associated with Art3 gene hypomethylation in subcortical brain tissue of adult mice at 28 weeks of age (mean decrease 6.2%, P = .03). For the other genes, no statistically significant differences were found between folate depleted and control groups. Given its association with neurocognitive outcomes, we suggest Art3 warrants further study in the context of lifecourse brain health. We have uncovered a potential biomarker that, once validated in accessible biospecimens and human context, may be useful to track the impact of early-life folate exposure on later-life neurocognitive health, and potentially be used to develop and monitor the effects of interventions.
BISCUIT: an efficient, standards-compliant tool suite for simultaneous genetic and epigenetic inference in bulk and single-cell studies
Authors: Zhou Wanding , Johnson Benjamin K , Morrison Jacob , Beddows Ian , Eapen James , Katsman Efrat , Semwal Ayush , Habib Walid Abi , Heo Lyong , Laird Peter W , Berman Benjamin P , Triche Timothy J , Shen Hui 
Published: February 2024

Abstract
Data from both bulk and single-cell whole-genome DNA methylation experiments are under-utilized in many ways. This is attributable to inefficient mapping of methylation sequencing reads, routinely discarded genetic information, and neglected read-level epigenetic and genetic linkage information. We introduce the BISulfite-seq Command line User Interface Toolkit (BISCUIT) and its companion R/Bioconductor package, biscuiteer, for simultaneous extraction of genetic and epigenetic information from bulk and single-cell DNA methylation sequencing. BISCUIT’s performance, flexibility and standards-compliant output allow large, complex experimental designs to be characterized on clinical timescales. BISCUIT is particularly suited for processing data from single-cell DNA methylation assays, with its excellent scalability, efficiency, and ability to greatly enhance mappability, a key challenge for single-cell studies. We also introduce the epiBED format for single-molecule analysis of coupled epigenetic and genetic information, facilitating the study of cellular and tissue heterogeneity from DNA methylation sequencing.
COSA-1 mediated pro-crossover complex formation promotes meiotic crossing over in C. elegans
Authors: Yang Yuejun , Wang Nan , Liu Guoteng , Nan Wencong , Wang Bin , Gartner Anton , Zhang Hongtao , Hong Ye 
Published: February 2024

Abstract
Accurate chromosome segregation during meiosis requires the establishment of at least one crossover (CO) between each pair of homologous chromosomes. CO formation depends on a group of conserved pro-CO proteins, which colocalize at CO-designated sites during late meiotic prophase I. However, it remains unclear whether these pro-CO proteins form a functional complex and how they promote meiotic CO formation in vivo. Here, we show that COSA-1, a key component required for CO formation, interacts with other pro-CO factors, MSH-5 and ZHP-3, via its N-terminal disordered region. Point mutations that impair these interactions do not affect CO designation, but they strongly hinder the accumulation of COSA-1 at CO-designated sites and result in defective CO formation. These defects can be partially bypassed by artificially tethering an interaction-compromised COSA-1 derivate to ZHP-3. Furthermore, we revealed that the accumulation of COSA-1 into distinct foci is required to assemble functional ‘recombination nodules’. These prevent early CO-designated recombination intermediates from being dismantled by the RTEL-1 helicase and protect late recombination intermediates, such as Holliday junctions, until they are resolved by CO-specific resolvases. Altogether, our findings provide insight into COSA-1 mediated pro-CO complex assembly and its contribution to CO formation.
Tracking pairwise genomic loci by the ParB–ParS and Noc-NBS systems in living cells
Authors: He Xiaohui , Tan Yuxi , Feng Ying , Sun Yadong , Ma Hanhui 
Published: February 2024

Abstract
The dynamics of genomic loci pairs and their interactions are essential for transcriptional regulation and genome organization. However, a robust method for tracking pairwise genomic loci in living cells is lacking. Here we developed a multicolor DNA labeling system, mParSpot (multicolor ParSpot), to track pairs of genomic loci and their interactions in living cells. The mParSpot system is derived from the ParB/ParS in the parABS system and Noc/NBS in its paralogous nucleoid occlusion system. The insertion of 16 base-pair palindromic ParSs or NBSs into the genomic locus allows the cognate binding protein ParB or Noc to spread kilobases of DNA around ParSs or NBSs for loci-specific visualization. We tracked two loci with a genomic distance of 53 kilobases and measured their spatial distance over time. Using the mParSpot system, we labeled the promoter and terminator of the MSI2 gene span 423 kb and measured their spatial distance. We also tracked the promoter and terminator dynamics of the MUC4 gene in living cells. In sum, the mParSpot is a robust and sensitive DNA labeling system for tracking genomic interactions in space and time under physiological or pathological contexts.
Structural insights into the morpholino nucleic acid/RNA duplex using the new XNA builder Ducque in a molecular modeling pipeline
Authors: Rihon Jérôme , Mattelaer Charles-Alexandre , Montalvão Rinaldo Wander , Froeyen Mathy , Pinheiro Vitor Bernardes , Lescrinier Eveline 
Published: February 2024

Abstract
The field of synthetic nucleic acids with novel backbone structures [xenobiotic nucleic acids (XNAs)] has flourished due to the increased importance of XNA antisense oligonucleotides and aptamers in medicine, as well as the development of XNA processing enzymes and new XNA genetic materials. Molecular modeling on XNA structures can accelerate rational design in the field of XNAs as it contributes in understanding and predicting how changes in the sugar–phosphate backbone impact on the complementation properties of the nucleic acids. To support the development of novel XNA polymers, we present a first-in-class open-source program (Ducque) to build duplexes of nucleic acid analogs with customizable chemistry. A detailed procedure is described to extend the Ducque library with new user-defined XNA fragments using quantum mechanics (QM) and to generate QM-based force field parameters for molecular dynamics simulations within standard packages such as AMBER. The tool was used within a molecular modeling workflow to accurately reproduce a selection of experimental structures for nucleic acid duplexes with ribose-based as well as non-ribose-based nucleosides. Additionally, it was challenged to build duplexes of morpholino nucleic acids bound to complementary RNA sequences.
UPF1 ATPase autoinhibition and activation modulate RNA binding kinetics and NMD efficiency
Authors: Chapman Joseph H , Youle Alice M , Grimme Acadia L , Neuman Keir C , Hogg J Robert 
Published: February 2024

Abstract
The RNA helicase UPF1 interacts with mRNAs, mRNA decay machinery, and the terminating ribosome to promote nonsense-mediated mRNA decay (NMD). Structural and biochemical data have revealed that UPF1 exists in an enzymatically autoinhibited ‘closed’ state. Upon binding the NMD protein UPF2, UPF1 undergoes an extensive conformational change into a more enzymatically active ‘open’ state, which exhibits enhanced ATPase and helicase activity. However, mechanically deficient UPF1 mutants (i.e. poorly processive, slow, and mechanochemically uncoupled) can support efficient NMD, bringing into question the roles of UPF1 enzymatic autoinhibition and activation in NMD. Here, we identify two additional important features of the activated open state: slower RNA binding kinetics and enhanced ATP-stimulated RNA dissociation kinetics. Computational modeling based on empirical measurements of UPF1, UPF2 and RNA interaction kinetics predicts that the majority of UPF1–RNA binding and dissociation events in cells occur independently of UPF2 binding. We find that UPF1 mutants with either reduced or accelerated dissociation from RNA have NMD defects, whereas UPF1 mutants that are more dependent on UPF2 for catalytic activity remain active on well-established NMD targets. These findings support a model in which the kinetics of UPF1-mRNA interactions are important determinants of cellular NMD efficiency.
Ribosomal quality control factors inhibit repeat-associated non-AUG translation from GC-rich repeats
Authors: Tseng Yi-Ju , Krans Amy , Malik Indranil , Deng Xiexiong , Yildirim Evrim , Ovunc Sinem , Tank Elizabeth M H , Jansen-West Karen , Kaufhold Ross , Gomez Nicolas B , Sher Roger , Petrucelli Leonard , Barmada Sami J , Todd Peter K 
Published: February 2024

Abstract
A GGGGCC (G4C2) hexanucleotide repeat expansion in C9ORF72 causes amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), while a CGG trinucleotide repeat expansion in FMR1 leads to the neurodegenerative disorder Fragile X-associated tremor/ataxia syndrome (FXTAS). These GC-rich repeats form RNA secondary structures that support repeat-associated non-AUG (RAN) translation of toxic proteins that contribute to disease pathogenesis. Here we assessed whether these same repeats might trigger stalling and interfere with translational elongation. We find that depletion of ribosome-associated quality control (RQC) factors NEMF, LTN1 and ANKZF1 markedly boost RAN translation product accumulation from both G4C2 and CGG repeats while overexpression of these factors reduces RAN production in both reporter assays and C9ALS/FTD patient iPSC-derived neurons. We also detected partially made products from both G4C2 and CGG repeats whose abundance increased with RQC factor depletion. Repeat RNA sequence, rather than amino acid content, is central to the impact of RQC factor depletion on RAN translation—suggesting a role for RNA secondary structure in these processes. Together, these findings suggest that ribosomal stalling and RQC pathway activation during RAN translation inhibits the generation of toxic RAN products. We propose augmenting RQC activity as a therapeutic strategy in GC-rich repeat expansion disorders.
Structural insights into the N-terminal APHB domain of HrpA: mediating canonical and i-motif recognition
Authors: Xin Ben-Ge , Huang Ling-Yun , Yuan Ling-Gang , Liu Na-Nv , Li Hai-Hong , Ai Xia , Lei Dong-Sheng , Hou Xi-Miao , Rety Stephane , Xi Xu-Guang 
Published: February 2024

Abstract
RNA helicases function as versatile enzymes primarily responsible for remodeling RNA secondary structures and organizing ribonucleoprotein complexes. In our study, we conducted a systematic analysis of the helicase-related activities of Escherichia coli HrpA and presented the structures of both its apo form and its complex bound with both conventional and non-canonical DNAs. Our findings reveal that HrpA exhibits NTP hydrolysis activity and binds to ssDNA and ssRNA in distinct sequence-dependent manners. While the helicase core plays an essential role in unwinding RNA/RNA and RNA/DNA duplexes, the N-terminal extension in HrpA, consisting of three helices referred to as the APHB domain, is crucial for ssDNA binding and RNA/DNA duplex unwinding. Importantly, the APHB domain is implicated in binding to non-canonical DNA structures such as G-quadruplex and i-motif, and this report presents the first solved i-motif-helicase complex. This research not only provides comprehensive insights into the multifaceted roles of HrpA as an RNA helicase but also establishes a foundation for further investigations into the recognition and functional implications of i-motif DNA structures in various biological processes.
DNA-PKcs suppresses illegitimate chromosome rearrangements
Authors: Wang Jinglong , Sadeghi Cheyenne A , Frock Richard L 
Published: February 2024

Abstract
Two DNA repair pathways, non-homologous end joining (NHEJ) and alternative end joining (A-EJ), are involved in V(D)J recombination and chromosome translocation. Previous studies reported distinct repair mechanisms for chromosome translocation, with NHEJ involved in humans and A-EJ in mice predominantly. NHEJ depends on DNA-PKcs, a critical partner in synapsis formation and downstream component activation. While DNA-PKcs inhibition promotes chromosome translocations harboring microhomologies in mice, its synonymous effect in humans is not known. We find partial DNA-PKcs inhibition in human cells leads to increased translocations and the continued involvement of a dampened NHEJ. In contrast, complete DNA-PKcs inhibition substantially increased microhomology-mediated end joining (MMEJ), thus bridging the two different translocation mechanisms between human and mice. Similar to a previous study on Ku70 deletion, DNA-PKcs deletion in G1/G0-phase mouse progenitor B cell lines, significantly impairs V(D)J recombination and generated higher rates of translocations as a consequence of dysregulated coding and signal end joining. Genetic DNA-PKcs inhibition suppresses NHEJ entirely, with repair phenotypically resembling Ku70-deficient A-EJ. In contrast, we find DNA-PKcs necessary in generating the near-exclusive MMEJ associated with Lig4 deficiency. Our study underscores DNA-PKcs in suppressing illegitimate chromosome rearrangement while also contributing to MMEJ in both species.
An engineered baculoviral protein and DNA co-delivery system for CRISPR-based mammalian genome editing
Authors: Capin Julien , Harrison Alexandra , Raele Renata A , Yadav Sathish K N , Baiwir Dominique , Mazzucchelli Gabriel , Quinton Loic , Satchwell Timothy J , Toye Ashley M , Schaffitzel Christiane , Berger Imre , Aulicino Francesco 
Published: February 2024

Abstract
CRISPR-based DNA editing technologies enable rapid and accessible genome engineering of eukaryotic cells. However, the delivery of genetically encoded CRISPR components remains challenging and sustained Cas9 expression correlates with higher off-target activities, which can be reduced via Cas9-protein delivery. Here we demonstrate that baculovirus, alongside its DNA cargo, can be used to package and deliver proteins to human cells. Using protein-loaded baculovirus (pBV), we demonstrate delivery of Cas9 or base editors proteins, leading to efficient genome and base editing in human cells. By implementing a reversible, chemically inducible heterodimerization system, we show that protein cargoes can selectively and more efficiently be loaded into pBVs (spBVs). Using spBVs we achieved high levels of multiplexed genome editing in a panel of human cell lines. Importantly, spBVs maintain high editing efficiencies in absence of detectable off-targets events. Finally, by exploiting Cas9 protein and template DNA co-delivery, we demonstrate up to 5% site-specific targeted integration of a 1.8 kb heterologous DNA payload using a single spBV in a panel of human cell lines. In summary, we demonstrate that spBVs represent a versatile, efficient and potentially safer alternative for CRISPR applications requiring co-delivery of DNA and protein cargoes.
LC3B drives transcription-associated homologous recombination via direct interaction with R-loops
Authors: Yoon Junghyun , Hwang Yiseul , Yun Hansol , Chung Jee Min , Kim Soyeon , Kim Gyeongmin , Lee Yeji , Lee Byoung Dae , Kang Ho Chul 
Published: February 2024

Abstract
Exploring the connection between ubiquitin-like modifiers (ULMs) and the DNA damage response (DDR), we employed several advanced DNA damage and repair assay techniques and identified a crucial role for LC3B. Notably, its RNA recognition motif (RRM) plays a pivotal role in the context of transcription-associated homologous recombination (HR) repair (TA-HRR), a particular subset of HRR pathways. Surprisingly, independent of autophagy flux, LC3B interacts directly with R-loops at DNA lesions within transcriptionally active sites via its RRM, promoting TA-HRR. Using native RNA immunoprecipitation (nRIP) coupled with high-throughput sequencing (nRIP-seq), we discovered that LC3B also directly interacts with the 3′UTR AU-rich elements (AREs) of BRCA1 via its RRM, influencing its stability. This suggests that LC3B regulates TA-HRR both proximal to and distal from DNA lesions. Data from our LC3B depletion experiments showed that LC3B knockdown disrupts end-resection for TA-HRR, redirecting it towards the non-homologous end joining (NHEJ) pathway and leading to chromosomal instability, as evidenced by alterations in sister chromatid exchange (SCE) and interchromosomal fusion (ICF). Thus, our findings unveil autophagy-independent functions of LC3B in DNA damage and repair pathways, highlighting its importance. This could reshape our understanding of TA-HRR and the interaction between autophagy and DDR.
A tool to predict the risk of lower extremity amputation in patients starting dialysis
Authors: Akerboom Bram , Janse Roemer J , Caldinelli Aurora , Lindholm Bengt , Rotmans Joris I , Evans Marie , van Diepen Merel 
Published: February 2024

ABSTRACT

Background
Non-traumatic lower extremity amputation (LEA) is a severe complication during dialysis. To inform decision-making for physicians, we developed a multivariable prediction model for LEA after starting dialysis.

Methods
Data from the Swedish Renal Registry (SNR) between 2010 and 2020 were geographically split into a development and validation cohort. Data from Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD) between 1997 and 2009 were used for validation targeted at Dutch patients. Inclusion criteria were no previous LEA and kidney transplant and age ≥40 years at baseline. A Fine–Gray model was developed with LEA within 3 years after starting dialysis as the outcome of interest. Death and kidney transplant were treated as competing events. One coefficient, ordered by expected relevance, per 20 events was estimated. Performance was assessed with calibration and discrimination.

Results
SNR was split into an urban development cohort with 4771 individuals experiencing 201 (4.8%) events and a rural validation cohort with 4.876 individuals experiencing 155 (3.2%) events. NECOSAD contained 1658 individuals experiencing 61 (3.7%) events. Ten predictors were included: female sex, age, diabetes mellitus, peripheral artery disease, cardiovascular disease, congestive heart failure, obesity, albumin, haemoglobin and diabetic retinopathy. In SNR, calibration intercept and slope were –0.003 and 0.912, respectively. The C-index was estimated as 0.813 (0.783–0.843). In NECOSAD, calibration intercept and slope were 0.001 and 1.142 respectively. The C-index was estimated as 0.760 (0.697–0.824). Calibration plots showed good calibration.

Conclusion
A newly developed model to predict LEA after starting dialysis showed good discriminatory performance and calibration. By identifying high-risk individuals this model could help select patients for preventive measures.