bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pyrimidine-Dependent UV-Mediated Cross-Linking Magnifies Minor Genetic or Epigenetic Changes in Clinical Samples
Authors: Yu Fangyan , Ahmed Farzana , Smilkou Stavroula , Yasmin-Karim Sayeda , Darbeheshti Farzaneh , Markou Athina , Bullock Martyn , Boukovinas Ioannis , Adalsteinsson Viktor A , Lianidou Evi , Makrigiorgos G Mike 
Published: July 2024

Abstract

Background
Detection of minor DNA allele alterations is becoming increasingly important for early detection and monitoring of cancer. We describe a new method that uses ultraviolet light to eliminate wild-type DNA alleles and enables improved detection of minor genetic or epigenetic changes.

Methods
Pyrimidine-dependent UV-based minor-allele enrichment (PD-UVME) employed oligonucleotide probes that incorporated a UVA-sensitive 3-cyanovinylcarbazole (CNVK), placed directly opposite interrogated pyrimidines, such as thymine (T) or cytosine (C) in wild-type (WT) DNA. Upon UVA-illumination, CNVK cross-linked with T/C, preventing subsequent amplification. Mutations that removed the T/C escaped cross-linking and were amplified and detected. Similarly, CNVK discriminated between methylated and unmethylated cytosine in CpG dinucleotides, enabling direct enrichment of unmethylated DNA targets. PD-UVME was combined with digital droplet PCR (ddPCR) to detect serine/threonine-protein kinase B-Raf (BRAF) V600E mutations in model systems, thyroid patient cancer tissue samples, and circulating DNA of tumor origin (ctDNA) from melanoma patients.

Results
One thyroid cancer sample out of 9, and 6 circulating-DNA samples out of 7 were found to be BRAF V600E-positive via PD-UVME while classified as negative by conventional ddPCR. Positive samples via conventional ddPCR were also found positive via PD-UVME. All 10 circulating cell-free DNA (cfDNA) samples obtained from normal volunteers were negative via both approaches. Furthermore, preferential enrichment of unmethylated alleles in MAGEA1 promoters using PD-UVME was demonstrated.

Conclusions
PD-UVME mutation/methylation enrichment performed prior to ddPCR magnifies low-level mutations or epigenetic changes and increases sensitivity and confidence in the results. It can assist with clinical decisions that hinge on the presence of trace alterations like BRAF V600E.
Cross-species single-cell RNA sequencing reveals divergent phenotypes and activation states of adaptive immunity in human carotid and experimental murine atherosclerosis
Authors: Horstmann Hauke , Michel Nathaly Anto , Sheng Xia , Hansen Sophie , Lindau Alexandra , Pfeil Katharina , Fernández Marbely C , Marchini Timoteo , Winkels Holger , Mitre Lucia Sol , Abogunloko Tijani , Li Xiaowei , Mwinyella Timothy Bon-Nawul , Gissler Mark Colin , Bugger Heiko , Heidt Timo , Buscher Konrad , Hilgendorf Ingo , Stachon Peter , Piepenburg Sven , Verheyen Nicolas , Rathner Thomas , Gerhardt Teresa , Siegel Patrick Malcolm , Oswald Wolfgang Kurt , Cohnert Tina , Zernecke Alma , Madl Josef , Kohl Peter , Foks Amanda C , von zur Muehlen Constantin , Westermann Dirk , Zirlik Andreas , Wolf Dennis 
Published: July 2024

Abstract

Aims
The distinct functions of immune cells in atherosclerosis have been mostly defined by pre-clinical mouse studies. Contrastingly, the immune cell composition of human atherosclerotic plaques and their contribution to disease progression are only poorly understood. It remains uncertain whether genetic animal models allow for valuable translational approaches.

Methods and results
Single-cell RNA-sequencing (scRNA-seq) was performed to define the immune cell landscape in human carotid atherosclerotic plaques. The human immune cell repertoire demonstrated an unexpectedly high heterogeneity and was dominated by cells of the T-cell lineage, a finding confirmed by immunohistochemistry. Bioinformatical integration with 7 mouse scRNA-seq data sets from adventitial and atherosclerotic vascular tissue revealed a total of 51 identities of cell types and differentiation states, of which some were only poorly conserved between species and exclusively found in humans. Locations, frequencies, and transcriptional programmes of immune cells in mouse models did not resemble the immune cell landscape in human carotid atherosclerosis. In contrast to standard mouse models of atherosclerosis, human plaque leucocytes were dominated by several T-cell phenotypes with transcriptional hallmarks of T-cell activation and memory formation, T-cell receptor, and pro-inflammatory signalling. Only mice at the age of 22 months partially resembled the activated T-cell phenotype. In a validation cohort of 43 patients undergoing carotid endarterectomy, the abundance of activated immune cell subsets in the plaque defined by multi-colour flow cytometry associated with the extent of clinical atherosclerosis.

Conclusion
Integrative scRNA-seq reveals a substantial difference in the immune cell composition of murine and human carotid atherosclerosis—a finding that questions the translational value of standard mouse models for adaptive immune cell studies. Clinical associations suggest a specific role for T-cell driven (auto-)immunity in human plaque formation and instability.
Integrating QTL mapping and transcriptomics to decipher the genetic architecture of sterol metabolism in Brassica napus L
Authors: Xiong Yiyi , Lu Guangyuan , Li Huaixin , He Jianjie , Fan Shipeng , Yan Shuxiang , Zhang Liangxiao , Jia Haibo , Li Maoteng 
Published: July 2024

Abstract
Sterols are secondary metabolites commonly found in rapeseed that play crucial physiological roles in plants and also benefit human health. Consequently, unraveling the genetic basis of sterol synthesis in rapeseed is highly important. In this study, 21 individual sterols as well as total sterol (TS) content were detected in a double haploid (DH) population of Brassica napus, and a total of 24 quantitative trait loci (QTL) and 157 mQTL were identified that were associated with TS and different individual sterols. Time-series transcriptomic analysis showed that the differentially expressed genes (DEGs) involved in sterol and lipid biosynthesis pathways were enriched. Additionally, a regulatory network between sterol-related DEGs and transcription factors (TFs) was established using coexpression analysis. Some candidate genes were identified with the integration of transcriptomic analysis and QTL mapping, and the key candidate gene BnSQS1.C03 was selected for further functional analysis. BnSQS1.C03 demonstrated squalene synthase activity in vitro and increased the TS by 3.8% when overexpressed in Arabidopsis. The present results provide new insights into sterol regulatory pathways and a valuable genetic basis for breeding rapeseed varieties with high sterol content in the future.
Chromosome-scale reference genome of an ancient landrace: unveiling the genetic basis of seed weight in the food legume crop pigeonpea (Cajanus cajan)
Authors: Liu Chun , Ding Xipeng , Wu Yuanhang , Zhang Jianyu , Huang Rui , Li Xinyong , Liu Guodao , Liu Pandao 
Published: July 2024

Abstract
Pigeonpea (Cajanus cajan) is a nutrient-rich and versatile food legume crop of tropical and subtropical regions. In this study, we describe the de novo assembly of a high-quality genome for the ancient pigeonpea landrace ‘D30’, achieved through a combination of Pacific Biosciences high-fidelity (PacBio HiFi) and high-throughput chromatin conformation capture (Hi-C) sequencing technologies. The assembled ‘D30’ genome has a size of 813.54 Mb, with a contig N50 of 10.74 Mb, a scaffold N50 of 73.07 Mb, and a GC content of 35.67%. Genomic evaluation revealed that the ‘D30’ genome contains 99.2% of Benchmarking Universal Single-Copy Orthologs (BUSCO) and achieves a 29.06 long terminal repeat (LTR) assembly index (LAI). Genome annotation indicated that ‘D30’ encompasses 431.37 Mb of repeat elements (53.02% of the genome) and 37 977 protein-coding genes. Identification of single-nucleotide polymorphisms (SNPs), insertions/deletions (indels), and structural variations between ‘D30’ and the published genome of pigeonpea cultivar ‘Asha’ suggests that genes affected by these variations may play important roles in biotic and abiotic stress responses. Further investigation of genomic regions under selection highlights genes enriched in starch and sucrose metabolism, with 42.11% of these genes highly expressed in seeds. Finally, we conducted genome-wide association studies (GWAS) to facilitate the identification of 28 marker–trait associations for six agronomic traits of pigeonpea. Notably, we discovered a calmodulin-like protein (CcCML) that harbors a dominant haplotype associated with the 100-seed weight of pigeonpea. Our study provides a foundational resource for developing genomics-assisted breeding programs in pigeonpea.
On the convergence of Fourier spectral methods involving noncompact operators
Authors: Trogdon Thomas 
Published: July 2024

Abstract
Motivated by Fredholm theory, we develop a framework to establish the convergence of spectral methods for operator equations $\mathcal L u = f$. The framework posits the existence of a left-Fredholm regulator for $\mathcal L$ and the existence of a sufficiently good approximation of this regulator. Importantly, the numerical method itself need not make use of this extra approximant. We apply the framework to Fourier finite-section and collocation-based numerical methods for solving differential equations with periodic boundary conditions and to solving Riemann–Hilbert problems on the unit circle. We also obtain improved results concerning the approximation of eigenvalues of differential operators with periodic coefficients.
Intraguild species presence alters Aphidoletes aphidimyza (Diptera: Cecidomyiidae) and Aphidius gifuensis (Hymenoptera: Braconidae) foraging responses
Authors: Yu Xiao-fei , Wang Xiong , Gou Jian-yu , Shen Xiu-xian , Wu Hui-zi , Huang Chun-yang , Yang Mao-fa 
Published: July 2024

Abstract
The predatory gall midge, Aphidoletes aphidimyza (Rondani), and tobacco aphid cocoon wasp, Aphidius gifuensis Ashmead, are important natural enemies of Myzus persicae (Sulzer) (Hemiptera: Aphididae). Predation by A. aphidimyza and A. gifuensis can regulate M. persicae; however, how interspecific interference competition affects their foraging efficiency is unknown. Here, we investigated the consumption and parasitization abilities of A. aphidimyza 3rd instar larva and A. gifuensis adults under various conditions. Consumption of parasitized aphids by A. aphidimyza 3rd instar larvae was significantly lower than that of nonparasitized controls, with a substantial increase in handling time. The presence of A. gifuensis adults did not significantly affect the predation capacity of A. aphidimyza larvae. Relative to controls, A. aphidimyza larvae predation trace (PT) and imago activity significantly decreased A. gifuensis parasitism rates at different aphid densities. Further, A. aphidimyza larvae PT increased the A. gifuensis handling time of M. persicae, whereas the presence of A. aphidimyza adults had the opposite effect. Coexistence with heterospecific natural enemies reduced the parasitic capacity of A. gifuensis, whereas A. aphidimyza larvae predation capability was influenced to a lesser extent. Our results demonstrate that intraguild interactions strongly influence the predatory and parasitic efficacy of A. aphidimyza and A. gifuensis, although the effect on A. gifuensis was more pronounced. For effective biological control of M. persicae using A. aphidimyza and A. gifuensis, we recommend releasing A. aphidimyza first to mitigate intraguild predation and enhance the overall success of the pest control program.
A single CAA interrupt in a DNA three-way junction containing a CAG repeat hairpin results in parity-dependent trapping
Authors: Cadden Gillian M , Wilken Svea J , Magennis Steven W 
Published: July 2024

Abstract
An increasing number of human disorders are attributed to genomic expansions of short tandem repeats (STRs). Secondary DNA structures formed by STRs are believed to play an important role in expansion, while the presence of nucleotide interruptions within the pure repeat sequence is known to delay the onset and progression of disease. We have used two single-molecule fluorescence techniques to analyse the structure and dynamics of DNA three-way junctions (3WJs) containing CAG repeat hairpin slipouts, with and without a single CAA interrupt. For a 3WJ with a (CAG)10 slipout, the CAA interrupt is preferentially located in the hairpin loop, and the branch migration dynamics are 4-fold slower than for the 3WJ with a pure (CAG)10, and 3-fold slower than a 3WJ with a pure (CAG)40 repeat. The (CAG)11 3WJ with CAA interrupt adopts a conformation that places the interrupt in or near the hairpin loop, with similar dynamics to the pure (CAG)10 and (CAG)11 3WJs. We have shown that changing a single nucleotide (G to A) in a pure repeat can have a large impact on 3WJ structure and dynamics, which may be important for the protective role of interrupts in repeat expansion diseases.
GIBBERELLIN PERCEPTION SENSOR 2 reveals genesis and role of cellular GA dynamics in light-regulated hypocotyl growth
Authors: Griffiths Jayne , Rizza Annalisa , Tang Bijun , Frommer Wolf B , Jones Alexander M 
Published: July 2024

Abstract
The phytohormone gibberellic acid (GA) is critical for environmentally sensitive plant development including germination, skotomorphogenesis, and flowering. The Förster resonance energy transfer biosensor GIBBERELLIN PERCEPTION SENSOR1, which permits single-cell GA measurements in vivo, has been used to observe a GA gradient correlated with cell length in dark-grown, but not light-grown, hypocotyls. We sought to understand how light signaling integrates into cellular GA regulation. Here, we show how the E3 ligase CONSTITUTIVE PHOTOMORPHOGENESIS1 (COP1) and transcription factor ELONGATED HYPOCOTYL 5 (HY5) play central roles in directing cellular GA distribution in skoto- and photomorphogenic hypocotyls, respectively. We demonstrate that the expression pattern of the GA biosynthetic enzyme gene GA20ox1 is the key determinant of the GA gradient in dark-grown hypocotyls and is a target of COP1 signaling. We engineered a second generation GPS2 biosensor with improved orthogonality and reversibility. GPS2 revealed a previously undetectable cellular pattern of GA depletion during the transition to growth in the light. This GA depletion partly explains the resetting of hypocotyl growth dynamics during photomorphogenesis. Achieving cell-level resolution has revealed how GA distributions link environmental conditions with morphology and morphological plasticity. The GPS2 biosensor is an ideal tool for GA studies in many conditions, organs, and plant species.
A module involving HIGH LEAF TEMPERATURE1 controls instantaneous water use efficiency
Authors: Xiao Chuanlei , Guo Huimin , Li Ruiying , Wang Yuehua , Yin Kaili , Ye Peipei , Hu Honghong 
Published: July 2024

Abstract
Drought stress inhibits plant growth and agricultural production. Improving plant instantaneous water use efficiency (iWUE), which is strictly regulated by stomata, is an effective way to cope with drought stress. However, the mechanisms of iWUE regulation are poorly understood. Through genetic screening for suppressors of mpk12-4, an Arabidopsis (Arabidopsis thaliana) mutant with a major iWUE quantitative trait locus gene MITOGEN-ACTIVATED PROTEIN KINASE12 deleted, we identified HIGH LEAF TEMPERATURE1 (HT1). Genetic interaction and physiological analyses showed that MPK12 controls iWUE through multiple modules in a high CO2-induced stomatal closing pathway that regulate SLOW ANION CHANNEL-ASSOCIATED1 (SLAC1) activity. HT1 acts downstream of MPK12, whereas OPEN STOMATA1 (OST1) and GUARD CELL HYDROGEN PEROXIDE-RESISTANT1 (GHR1) function downstream of HT1 by activating SLAC1 in iWUE. Photosynthetic-CO2 response curves and biomass analyses under different water-supply conditions showed that HT1 dysfunction improved iWUE and also increased plant growth capacity, and products of HT1 putative orthologs from Brassica (Brassica napus) and rice (Oryza sativa) exhibited functions similar to that of Arabidopsis HT1 in iWUE and the CO2-signaling pathway. Our study revealed the mechanism of MPK12-mediated iWUE regulation in Arabidopsis and provided insight into the internal relationship between iWUE and CO2 signaling in guard cells and a potential target for improving crop iWUE and drought tolerance.
Epigenetic factors direct synergistic and antagonistic regulation of transposable elements in Arabidopsis
Authors: Hsieh Jo-Wei Allison , Yen Ming-Ren , Hung Fu-Yu , Wu Keqiang , Chen Pao-Yang 
Published: July 2024

Abstract
Arabidopsis (Arabidopsis thaliana) HISTONE DEACETYLASE 6 (HDA6) and HISTONE DEMETHYLASES LSD-LIKE 1 (LDL1) and LDL2 synergistically regulate the expression of long non-coding RNAs associated with H3Ac and H3K4me2. The underlying mechanisms of such highly coordinated interactions among genetic and epigenetic factors contributing to this collaborative regulation remain largely unclear. We analyzed all transposable elements (TEs) across the Arabidopsis genome and the individual and combined roles of HDA6 and LDL1/LDL2 by dissecting multilayered epigenomes and their association with transcription. Instead of an individual synergistic effect, we observed dual synergistic and antagonistic effects, which are positively associated with H3Ac and H3K4me2 while maintaining a negative but moderate association with DNA methylation. Specifically, 2 modes of synergistic regulation were discovered in TEs: 74% are primarily regulated by HDA6, with less dependence on LDL1/LDL2, and the remaining 26% are co-regulated by both. Between the 2 modes, we showed that HDA6 has a strong effect on TE silencing, whereas LDL1/LDL2 plays a weaker yet crucial role in co-regulation with HDA6. Our results led to a model of epigenomic regulation—the differential de-repression between the 2 modes of synergistic regulation of TEs was determined by H3Ac and H3K4me2 levels, where TEs are in accessible chromatins free of DNA methylation, and this open chromatin environment precedes transcriptional changes and epigenome patterning. Our results discovered unbalanced effects of genetic factors in synergistic regulation through delicately coordinated multilayered epigenomes and chromatin accessibility.
Sex differences in patient-reported outcome measures and the association with clinical factors in axial spondyloarthritis patients treated with tumour necrosis factor inhibitors
Authors: Hellamand Pasoon , van de Sande Marleen G H , Nurmohamed Michael T , van Vollenhoven Ronald F , Hollick Rosemary J , Rotariu Ovidiu , Rotar Ziga , Pirkmajer Katja P , Nordström Dan , Hokkanen Anna-Mari , Michelsen Brigitte , Kvien Tore K , Glintborg Bente , Hetland Merete L , Østergaard Mikkel , Loft Anne G , Pavelka Karel , Zavada Jakub , Castrejon Isabel , Otero-Varela Lucia , Gudbjornsson Bjorn , Palsson Olafur , Olofsson Tor , Wallman Johan K , Ciurea Adrian , Nissen Michael J , Yildirim Tuba D , Onen Fatos , Codreanu Catalin , Mogosan Corina , Santos Maria J , Vieira-Sousa Elsa , Iannone Florenzo , Frediani Bruno , Ørnbjerg Lykke M , Twisk Jos W R , van der Horst-Bruinsma Irene E 
Published: July 2024

Abstract

Objectives
To investigate sex differences in patient-reported outcome measures (PROMs) among axSpA patients initiating their first TNFi and identify factors contributing to these disparities over the follow-up.

Methods
Data were included from 15 EuroSpA registries and consisted of axSpA patients initiating their first TNFi, with ≥2 measurements for each analysed PROM (BASDAI and BASFI, scale 0–100) taken at any time point. Linear mixed models were employed to analyse sex differences in PROMs over 24 months and to evaluate how baseline characteristics were related to the observed sex differences.

Results
We analysed 13 102 (38% women) in the BASDAI analyses and 10 623 (38% women) in the BASFI analyses. At follow-up, mean sex differences in BASDAI increased from 4.3 units at baseline (95% CI, 3.5–5.1) to 8.0 (7.2–8.8) at 6 months, and in BASFI from 2.2 (1.4–3.1) to 4.6 (3.6–5.5), with consistently worse scores in women. Baseline characteristics could not substantially account for the observed sex differences over time; however, the magnitude of the sex differences was reduced by HLA-B27 positivity, longer disease duration, and increased CRP levels, but increased by TNFi initiation in later years and peripheral arthritis.

Conclusion
In axSpA patients initiating their first TNFi, baseline sex differences in BASDAI and BASFI increased two-fold after 6 months of treatment and persisted thereafter, with worse scores in women. Several baseline characteristics moderated the sex differences, though none could fully account for them. These findings improve our understanding of sex differences and underscore their importance in axSpA.
Mouse developmental defects, but not paraganglioma tumorigenesis, upon conditional Complex II loss in early Sox10+ cells
Authors: Lewis Elizabeth P. , Al Khazal Fatimah , Wilbanks Brandon , Gades Naomi M. , Ortega‐Sáenz Patricia , López‐Barneo José , Adameyko Igor , Maher L. James 
Published: July 2024

AbstractIn humans, loss of heterozygosity for defective alleles of any of the four subunits of mitochondrial tricarboxylic acid cycle enzyme succinate dehydrogenase (SDH, also Complex II of the electron transport chain) can lead to paraganglioma tumors in neuroendocrine cells. With the goal of developing mouse models of this rare disorder, we have developed various SDH conditional loss strategies. Based on recent lineage tracing studies, we hypothesized that conditional SDHC loss in early embryogenesis during migration of primordial neural crest cells that form the susceptible chromaffin cells of the adrenal medulla might induce paraganglioma. We triggered low levels of detectable SDHC loss in Sox10+ cells at E11.5 of mouse development. We report that, rather than developing adrenal medulla paraganglioma (pheochromocytoma), offspring survived with evidence of neural crest cell dysfunction. Phenotypes included mild lower extremity gait anomalies suggestive of neural tube closure defects and patches of unpigmented fur consistent with neural crest‐derived melanocyte dysfunction. These defects were not observed in mice lacking Sdhc knockout. Our results add to existing data suggesting that, unlike humans, even early embryonic (Sox10‐driven) SDHx loss is inadequate to trigger paraganglioma in mice of the genetic backgrounds that have been investigated. Instead, low levels of tricarboxylic acid cycle‐deficient neural crest cells cause mild developmental defects in hind limb and melanocyte function. This new model may be of interest for studies of metabolism during early neural crest cell development.