bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efgartigimod efficacy and safety in refractory Myasthenia Gravis - UK’s first real-world experience
Authors: Dionísio J Moniz , Ambrose P , Burke G , Farrugia M , Garcia-Reitboeck P , Hewamadduma C , Hill M , Howard RS , Jacob S , Kullmann DM , Leite MI , Miller J , Pinto A , Pritchard J , Riswick T , Sathasivam S , Thambarigjah N , Viegas S , Norwood F , Spillane J 
Published: February 2024

ABSTRACTBackgroundWe report our experience of patients with generalised MG (gMG) treated with Efgartigimod, an FcN antagonist, under the Early Access to Medicine Scheme (EAMS) in the UK.MethodsData from all UK patients treated with Efgartigimod under the EAMS June 22-July 23 were collected retrospectively. Efgartigimod was administered as per the ADAPT protocol (consisting of a treatment cycle of 4 infusions at weekly intervals with further cycles given according to clinical need).Results48 patients with AChR antibody-positive gMG were treated in 12 centres. Most (75%) were female and most had a disease duration of over 10 years. The average MG-ADL score at baseline was 11.2. Most (72.9%) patients had undergone thymectomy. 77.0% were taking prednisolone at baseline. All patients had utilized non-steroidal immunosuppressant treatments, the average number tried was 2.6 (range 1-6). 51% had received Rituximab. 54.2% of patients required regular IVIg/PLEX.75% of patients had a mean reduction in the MG-ADL of ≥2 points in the first cycle and this remained stable throughout the study. The mean intracycle reduction in the MG-ADL score in the 1st, 2nd, 3rd and 4th cycles were -4.6, -3.9, -3.4 and -4.2 respectively. Side effects were generally mild though one patient stopped treatment due to severe hypokalemia. No rescue treatments were required. At the end of the study, 96% of patients remained on Efgartigimod.ConclusionEfgartigimod is a safe and effective treatment for patients with refractory, treatment-resistant gMG.
Intraocular pressure, primary open-angle glaucoma and the risk of retinal vein occlusion: a Mendelian randomization mediation analysis
Authors: Katsimpris Andreas , Baumeister Sebastian-Edgar , Voulgari Nafsika , Baurecht Hansjörg , Kandarakis Stylianos , Nolde Michael 
Published: February 2024

AbstractBackgroundThe etiological connection between intraocular pressure (IOP) and the risk of retinal vein occlusion (RVO) remains elusive, particularly regarding whether this risk emanates from the direct influence of elevated intraocular pressure (IOP), irrespective of the presence of primary open-angle glaucoma (POAG), or if it arises as a consequence of the sequelae of POAG. Therefore, we conducted a Mendelian Randomization (MR) mediation analysis to elucidate the mediating role of POAG in the association between IOP and RVO.MethodsWe identified 47 single-nucleotide polymorphisms (SNPs) associated with IOP (P-value < 5×10-8) leveraging data from a genome-wide association study (GWAS) (N = 97,653) obtained from the UK Biobank and 50 SNPs associated with POAG (P-value < 5×10-8) from a GWAS meta-analysis (16,677 cases and 199,580 controls). We related these SNPs with RVO using a GWAS of 775 RVO cases and 376,502 controls from FinnGen. By utilizing univariable and multivariable MR analyses we calculated the total effect of IOP on RVO and estimated the degree to which POAG mediates this association.ResultsMR analyses showed that higher IOP is associated with higher RVO risk (odds ratio of RVO per 1 mmHg increase in IOP: 1.53; 95% confidence interval: 1.04 to 2.26; p-value = 0.03). Moreover, our MR mediation analysis suggested that 91.6% of the total effect of IOP on RVO risk was mediated through POAG. The primary results were consistent with estimates of pleiotropy-robust MR methods.ConclusionOur findings suggest that higher IOP increases the risk of RVO and that the majority of this effect is mediated through POAG.
Improved Complexity Stratification in Congenital Heart Disease; the Impact of Including Procedural Data on Accuracy and Reliability
Authors: Chami Jason , Nicholson Calum , Baker David , Cordina Rachael , Strange Geoff , Celermajer David S. 
Published: February 2024

AbstractIntroductionIn order to manage a class of diseases as broad as congenital heart disease (CHD), multiple “manually generated” classification systems defining CHDs as mild, moderate and severe have been developed and used to good effect. As databases have grown, however, such “manual” complexity scoring has become infeasible. Though past attempts have been made to determine CHD complexity algorithmically using a list of diagnoses alone, missing data and lack of procedural information have been significant limitations.MethodsWe built an algorithm that can stratify the complexity of patients with CHD by integrating their diagnoses with a list of their previous procedures. Specific procedures which address a missing diagnosis or imply a certain operative status were used to supplement the diagnosis list. To verify this algorithm, CHD specialists manually checked the classification of 100 children and 100 adults across four hospitals in Australia.ResultsOur algorithm was 99.5% accurate in the manually checked cohort (100% in children and 99% in adults), and was able to automatically classify more than 90% of a cohort of over 24,000 CHD patients, including 92.5% of children (vs 84.4% without procedures, p < 0.0001) and 91.1% of adults (vs 70.4% without procedures; p < 0.0001).ConclusionsCHD complexity scoring is significantly improved by access to procedural history and can be automatically calculated with high accuracy.
The DBD-α4 helix of EWSR1::FLI1 is required for GGAA microsatellite binding that underlies genome regulation in Ewing sarcoma
Authors: Bayanjargal Ariunaa , Taslim Cenny , Showpnil Iftekhar A. , Selich-Anderson Julia , Crow Jesse C. , Lessnick Stephen L. , Theisen Emily R. 
Published: February 2024

AbstractEwing sarcoma is the second most common bone cancer in children and young adults. In 85% of patients, a translocation between chromosomes 11 and 22 results in a potent fusion oncoprotein, EWSR1::FLI1. EWSR1::FLI1 is the only genetic alteration in an otherwise unaltered genome of Ewing sarcoma tumors. The EWSR1 portion of the protein is an intrinsically disordered domain involved in transcriptional regulation by EWSR1::FLI1. The FLI portion of the fusion contains a DNA binding domain shown to bind core GGAA motifs and GGAA repeats. A small alpha-helix in the DNA binding domain of FLI1, DBD-α4 helix, is critical for the transcription function of EWSR1::FLI1. In this study, we aimed to understand the mechanism by which the DBD-α4 helix promotes transcription, and therefore oncogenic transformation. We utilized a multi-omics approach to assess chromatin organization, active chromatin marks, genome binding, and gene expression in cells expressing EWSR1::FLI1 constructs with and without the DBD-α4 helix. Our studies revealed DBD-α4 helix is crucial for cooperative binding of EWSR1::FLI1 at GGAA microsatellites. This binding underlies many aspects of genome regulation by EWSR1::FLI1 such as formation of TADs, chromatin loops, enhancers and productive transcription hubs.
A multi-transcriptomics approach reveals the coordinated action of the endoribonuclease DNE1 and the decapping machinery in orchestrating mRNA decay
Authors: Pouclet Aude , Pflieger David , Merret Rémy , Carpentier Marie-Christine , Schiaffini Marlene , Zuber Hélène , Gagliardi Dominique , Garcia Damien 
Published: February 2024

AbstractDecapping is a crucial step of mRNA degradation in eucaryotes and requires the formation of the holoenzyme complex between the decapping enzyme DCP2 and the decapping enhancer DCP1. In Arabidopsis, we recently identified DNE1, a NYN domain endoribonuclease, as a direct protein partner of DCP1. The function of both DNE1 and decapping are necessary to maintain phyllotaxis, the regularity of organ emergence in the apex. In this study we combinedin vivomRNA editing, RNA degradome, transcriptomics and small RNA-omics to identify targets of DNE1 and study how DNE1 and DCP2 cooperate in controlling mRNA fate. Our data reveal that DNE1 mainly contacts and cleaves mRNAs in the CDS and has sequence cleavage preferences. We found that DNE1 targets are also degraded through decapping, and that both RNA degradation pathways influence the production of mRNA-derived siRNAs. Finally, we detected mRNA features enriched in DNE1 targets including RNA G-quadruplexes and translated upstream-ORFs. Combining these four complementary high-throughput sequencing strategies greatly expands the range of DNE1 targets and allowed us to build a conceptual framework describing the influence of DNE1 and decapping on mRNA fate. These data will be crucial to unveil the specificity of DNE1 action and understand its importance for developmental patterning.
Variation of carbon, nitrogen and phosphorus content in fungi reflects their ecology and phylogeny
Authors: Pánek Matěj , Vlková Tereza , Michalová Tereza , Borovička Jan , Tedersoo Leho , Adamczyk Bartosz , Baldrian Petr , Lopéz-Mondéjar Rubén 
Published: February 2024

AbstractFungi are an integral part of the nitrogen and phosphorus cycling in trophic networks, as they participate in biomass decomposition and facilitate plant nutrition through root symbioses. Nutrient content varies considerably between the main fungal habitats, such as soil, plant litter or decomposing dead wood, but there are also large differences within habitats. While some soils are heavily loaded with N, others are limited by N or P. One way in which nutrient availability can be reflected in fungi is their content in biomass. In this study, we determined the C, N, and P content (in dry mass) of sporocarps of 214 fungal species to inspect how phylogeny and membership in ecological guilds (soil saprotrophs, wood saprotrophs, and ectomycorrhizal fungi) affect the nutrient content of fungal biomass. The C content of sporocarps (415 ± 25 mg g-1) showed little variation (324-494 mg g-1), while the range of N (46 ± 20 mg g-1) and P (5.5 ± 3.0 mg g-1) contents was within one order of magnitude (8-103 mg g-1and 1.0-18.9 mg g-1, respectively). Importantly, the N and P contents were significantly higher in the biomass of soil saprotrophic fungi compared to wood saprotrophic and ectomycorrhizal fungi. While the average C/N ratio in fungal biomass was 11.2, values exceeding 40 were recorded for some fungi living on dead wood, typically characterized by low N content. The N and P content of fungal mycelium also showed a significant phylogenetic signal, with differences in nutrient content being relatively low within species and genera of fungi. A strong correlation was found between N and P content in fungal biomass, while the correlation of N content and the N-containing fungal cell wall biopolymer – chitin showed only weak significance. The content of macronutrients in fungal biomass is influenced by the fungal life style and nutrient availability and is also limited by phylogeny.
Host lipids regulate multicellular behavior of a predator of a human pathogen
Authors: Kidner Ria Q. , Goldstone Eleanor B. , Laidemitt Martina R. , Sanchez Melissa C. , Gerdt Catherine , Brokaw Lorin P. , Ros-Rocher Núria , Morris Jamie , Davidson W. Sean , Gerdt Joseph P. 
Published: February 2024

ABSTRACTAs symbionts of animals, microbial eukaryotes benefit and harm their hosts in myriad ways. A model microeukaryote (Capsaspora owczarzaki) is a symbiont ofBiomphalaria glabratasnails and may prevent transmission of parasitic schistosomes from snails to humans. However, it is unclear which host factors determineCapsaspora’s ability to colonize snails. Here, we discovered thatCapsasporaforms multicellular aggregates when exposed to snail hemolymph. We identified a molecular cue for aggregation: a hemolymph-derived phosphatidylcholine, which becomes elevated in schistosome-infected snails. Therefore,Capsasporaaggregation may be a response to the physiological state of its host, and it may determine its ability to colonize snails and exclude parasitic schistosomes. Furthermore,Capsasporais an evolutionary model organism whose aggregation may be ancestral to animals. This discovery, that a prevalent lipid inducesCapsasporamulticellularity, suggests that this aggregation phenotype may be ancient. Additionally, the specific lipid will be a useful tool for further aggregation studies.
Bacterium secretes chemical inhibitor that sensitizes competitor to bacteriophage infection
Authors: Zang Zhiyu , Zhang Chengqian , Park Kyoung Jin , Schwartz Daniel A. , Podicheti Ram , Lennon Jay T. , Gerdt Joseph P. 
Published: February 2024

AbstractTo overtake competitors, microbes produce and secrete secondary metabolites that kill neighboring cells and sequester nutrients. This natural product-mediated competition likely evolved in complex microbial communities that included viral pathogens. From this ecological context, we hypothesized that microbes secrete metabolites that “weaponize” natural pathogens (i.e., bacteriophages) to lyse their competitors. Indeed, we discovered a bacterial secondary metabolite that sensitizes other bacteria to phage infection. We found that this metabolite provides the producer (aStreptomycessp.) with a fitness advantage over its competitor (Bacillus subtilis) by promoting phage infection. The phage-promoting metabolite, coelichelin, sensitizedB. subtilisto a wide panel of lytic phages, and it did so by preventing the early stages of sporulation through iron sequestration. Beyond coelichelin, other natural products may provide phage-mediated competitive advantages to their producers—either by inhibiting sporulation or through yet-unknown mechanisms.
High density linkage to physical mapping in a unique Tall x Dwarf Coconut (Cocos nuciferaL.) outbred F2uncovers a major QTL for flowering time colocalized with theFLOWERING LOCUS T (FT)
Authors: Grattapaglia Dario , Alves Wellington Bruno dos Santos , Pacheco Cleso Antônio Patto 
Published: February 2024

AbstractIntroductionThe coconut tree crop (Cocos nuciferaL.) provides vital resources for millions of people worldwide. Coconut germplasm is largely classified into ‘Tall’ (Typica) and ‘Dwarf’ (Nana) types. While Tall coconuts are outcrossing, more productive, stress tolerant and late flowering, Dwarf coconut are inbred, flower early with a high rate of bunch emission. Precocity determines earlier production of a plantation and facilitates management and harvest.MethodsWe used a unique outbred F2population generated by intercrossing F1hybrids between Brazilian Green Dwarf from Jiqui (BGDJ) and West African Tall (WAT) cultivars. SNP markers fixed for alternative alleles in the two varieties, segregating in an F2configuration were used to build a high-density linkage map with ∼3,000 SNPs, anchored to the existing chromosome-level genome assemblies, and a QTL mapping analysis was carried out.ResultsThe linkage map established the chromosomes numbering correspondence between the two reference genome versions and the relationship between recombination rate, physical distance and gene density in the coconut genomes. Leveraging the strong segregation for precocity inherited from the Dwarf cultivar in the F2, a major effect QTL with incomplete dominance was mapped for flowering time.FLOWERING LOCUS T(FT) gene homologs of coconut previously described as putatively involved in flowering time by alternative splice variant analysis, were colocalized within a ∼200kb window of the major effect QTL (LOD=11.86).DiscussionOur work provides strong phenotype-based evidence for the role of the FT locus as the putative underlying functional variant for the flowering time difference between Dwarf and Tall coconuts. Major effect QTLs were also detected for developmental traits of the palm, plausibly suggesting pleiotropism of theFTlocus for other precocity traits. Haplotypes of the two SNPs flanking the flowering time QTL inherited from the Dwarf parent BGDJ caused a reduction in the time to flower of around 400 days. These SNPs could be used for high throughput marker assisted selection of early flowering and higher productivity recombinant lines, providing innovative genetic material to the coconut industry.
Modular mechanisms of immune priming and growth inhibition mediated by plant effector-triggered immunity
Authors: Chhillar Himanshu , Yeh Pei-Min , Nguyen Hoang Hung , Jones Jonathan DG , Ding Pingtao 
Published: February 2024

SummaryExcessive activation of effector-triggered immunity (ETI) in plants inhibits plant growth and activates cell death. ETI mediated by intracellular Toll/Interleukin-1 receptor/Resistance protein (TIR) nucleotide-binding leucine-rich-repeat receptors (NLRs) involves two partially redundant signalling nodes in Arabidopsis, EDS1-PAD4-ADR1 and EDS1-SAG101-NRG1. Genetic and transcriptomic analyses show that EDS1-PAD4-ADR1 primarily enhances the immune component abundance and is critical for limiting pathogen growth, whereas EDS1-SAG101-NRG1 mainly activates the hypersensitive cell death response (HR) but is dispensable for immune priming. This study enhances our understanding of the distinct contributions of these two signalling modules to ETI and suggests potential strategies for improving disease resistance in crops without compromising yield.
Leveraging genomics and temporal high-throughput phenotyping to enhance association mapping and yield prediction in sesame
Authors: Sabag Idan , Bi Ye , Sahoo Maitreya Mohan , Herrmann Ittai , Morota Gota , Peleg Zvi 
Published: February 2024

AbstractSesame (Sesamum indicum) is an important oilseed crop with rising demand due to its high oil quality. To meet these future demands, there is an urgent need to develop and integrate new breeding strategies. While genomic resources have advanced genetic research in sesame, implementation of high-throughput phenotyping and genetic analysis of longitudinal traits remains limited. Here, we combined high-throughput phenotyping and random regression models to investigate the dynamics of plant height, leaf area index, and five spectral vegetation indices throughout the sesame growing seasons in a diversity panel. Modeling the temporal phenotypic and additive genetic trajectories revealed distinct patterns corresponding to the sesame growth cycle. We also conducted longitudinal genomic prediction and association mapping of plant height using various models and cross-validation schemes. Moderate prediction accuracy was obtained when predicting new genotypes at each time point, and moderate to high values were obtained when forecasting future phenotypes. Association mapping revealed three genomic regions in linkage groups 6, 8, and 11 conferring trait variation over time and growth rate. Furthermore, we leveraged correlations between the temporal trait and seed-yield and applied multi-trait genomic prediction. We obtained an improvement over single-trait analysis, especially when phenotypes from earlier time points were used, highlighting the potential of using a high-throughput phenotyping platform as a selection tool. Our results shed light on the genetic control of longitudinal traits in sesame and underscore the potential of high-throughput phenotyping to detect a wide range of traits and genotypes that can inform sesame breeding efforts to enhance yield.
A shade-responsive microProtein in the ArabidopsisATHB2gene regulates elongation growth and root development
Authors: Edwards Ashleigh , Chiurazzi Maurizio Junior , Blaakmeer Anko , Vittozzi Ylenia , Sharma Ashish , Matton Sanne , Kruusvee Valdeko , Straub Daniel , Sessa Giovanna , Carabelli Monica , Morelli Giorgio , Wenkel Stephan 
Published: February 2024

AbstractThe ability of plants to thrive under suboptimal light conditions, such as shade, is crucial for their overall survival and reproductive success. Here, we show that Arabidopsis seedlings produce a large number of alternative transcripts when exposed to shade. Notably, one of the identified transcript candidates, which was upregulated in shade conditions, was found to be an alternative transcript of theATHB2gene. ATHB2 belongs to the HD-ZIPII class of transcription factors and is a well-established regulator of the shade avoidance response. The function of the alternative transcript and the small leucine zipper protein encoded by it, ATHB2miP, was investigated. We found that ATHB2miP is primarily expressed in the shoot meristem and interacts with full-length ATHB2 protein to inhibit its activity through a negative feedback mechanism. Deletion of the genomic region encoding the leucine zipper domain of theATHB2gene using CRISPR, resulted in plants exhibiting altered shade avoidance responses and root development. We show that the leucine zipper domain is required for dimerising and localising to nuclear photobodies. There is a significant overlap in deregulated genes between plants ectopically expressing ATHB2miP andathb2mutant plants. The analysis of gene ontology and clustering revealed that the most affected processes are auxin synthesis and signaling, root development, and iron homeostasis. Shade growth experiments at different iron concentrations revealed a role forATHB2in regulating iron uptake and showed that iron availability affects shade growth in anATHB2-dependent manner. This study identifies ATHB2miP as a novel regulator of shade avoidance responses in Arabidopsis, highlighting the intricate transcriptional regulation underlying these processes.
Incompatibility of gravity theories with auxiliary fields with the standard model
Authors: Ventagli Giulia , Pani Paolo , Sotiriou Thomas P. 
Published: February 2024

Theories of gravity with auxiliary fields are of particular interest since they are able to circumvent Lovelock’s theorem while avoiding the introduction of new degrees of freedom. This type of theories introduces derivatives of the stress-energy tensor in the modified Einstein equation. This peculiar structure of the field equations was shown to lead to spacetime singularities on the surface of stars. Here we focus on yet another problem afflicting gravity theories with auxiliary fields. We show that such theories can generically introduce parametrically large deviations to the Standard Model unless one severely constrains the parameters of the theory, preventing them to produce significant phenomenology at large scales. We first consider the specific case of Palatini f(R) gravity, to clarify the results previously obtained in Ref. [1]. We show that the matter fields satisfy the Standard Model field equations which reduce to those predicted by general relativity in the local frame only at tree level, whereas at higher orders in perturbation theory they are affected by corrections that percolate from the gravity sector regardless of the specific f(R) model considered. Finally, we show that this is a more general issue affecting theories with auxiliary fields connected to the same terms responsible for the appearance of surface singularities.

Published by the American Physical Society
2024
Gamma-ray lines in 15 years of Fermi-LAT data: New constraints on Higgs portal dark matter
Authors: De La Torre Luque Pedro , Smirnov Juri , Linden Tim 
Published: February 2024

Monoenergetic γ-ray spectral lines are among the cleanest signatures of dark matter annihilation. We analyze 15 years of Fermi-LAT data, find no spectral lines, and place strong constraints on dark matter annihilation to monoenergetic γ-rays. Additionally, we produce the first double-line analysis of the coupled signals from γγ and Zγ lines, which proves particularly powerful for dark matter masses above ∼150  GeV. From our constraints on a double-line feature, we investigate and constrain some minimal models where the Galactic Center Excess can be fit by dark matter annihilation through the Higgs boson into Standard Model particles.

Published by the American Physical Society
2024