bluuebunny/crossref_metadata_2025_split huggingface dataset:
FLASH Bragg-peak irradiation with a therapeutic carbon ion beam: first in vivo results
Authors: Tinganelli Walter , Sokol Olga , Puspitasari Anggraeini , Helm Alexander , Simoniello Palma , Schuy Christoph , Lerchl Sylvie , Eckert Denise , Oppermann Julius , Rehm Anna , Janssen Stefan , Engel Denise , Moeller Ralf , Romano Rossana , Fournier Claudia , Durante Marco , Weber Uli 
Published: July 2024

AbstractBackground and purposeIn recent years, ultra-high dose rate (UHDR) irradiation has emerged as a promising innovative approach to cancer treatment. Characteristic feature of this regimen, commonly referred to as FLASH effect, demonstrated primarily for electrons, photons or protons, is the improved normal tissue sparing, while the tumor control is similar to the one of the conventional dose-rate (CDR) treatments. The FLASH mechanism is, however, unknown. One major question is whether this effect is maintained when using densely ionizing (high-LET) heavy nuclei.Materials and MethodsHere we report the effects of 20 Gy UHDR heavy ion irradiation in clinically relevant conditions, i.e., at high-LET in the spread-out Bragg peak (SOBP) of a12C beam using an osteosarcoma mouse model.ResultsWe show that UHDR irradiation was less toxic in the normal tissue compared to CDR while maintaining tumor control. The immune activation was also comparable in UHDR and CDR groups. We observed that the gut microbiome was altered in mice injected with the tumor compared to healthy animals, but both UHDR and CDR exposures steered the metagenome toward a balanced state.ConclusionsThe results show that the FLASH effect is safe and effective in heavy ion therapy and provide an important benchmark for the current mechanistic FLASH models.Highlights- FLASH irradiation with SOBP carbon ions spares normal tissue in mouse- Tumor control, immune response, and gut microbioma changes are induced at the same extent both at conventional and ultra-high dose rate- FLASH carbon ion irradiation is a safe and effective alternative to conventional radiotherapy.
Card9 and MyD88 differentially regulate Th17 immunity to the commensal yeastMalasseziain the murine skin
Authors: Tuor Meret , Stappers Mark H.T. , Ruchti Fiorella , Desgardin Alice , Sparber Florian , Orr Selinda J. , Gow Neil A.R. , LeibundGut-Landmann Salomé 
Published: July 2024

ABSTRACTThe fungal community of the skin microbiome is dominated by a single genus,Malassezia. Besides its symbiotic lifestyle at the host interface, this commensal yeast has also been associated with diverse inflammatory skin diseases in humans and pet animals. Stable colonization is maintained by antifungal type 17 immunity. The mechanisms driving Th17 responses toMalasseziaremain, however, unclear. Here, we show that the C-type lectin receptors Mincle, Dectin-1, and Dectin-2 recognize conserved patterns in the cell wall ofMalasseziaand induce dendritic cell activationin vitro, while only Dectin-2 is required for Th17 activation during experimental skin colonizationin vivo.In contrast, Toll-like receptor recognition was redundant in this context. Instead, inflammatory IL-1 family cytokines signaling via MyD88 were also implicated in Th17 activation in a T cell-intrinsic manner. Taken together, we characterized the pathways contributing to protective immunity against the most abundant member of the skin mycobiome. This knowledge contributes to the understanding of barrier immunity and its regulation by commensals and is relevant considering how aberrant immune responses are associated with severe skin pathologies.
Species wide inventory ofArabidopsis thalianaorganellar variation reveals ample phenotypic variation for photosynthetic performance
Authors: Theeuwen Tom P.J.M. , Wijfjes Raúl Y. , Dorussen Delfi , Lawson Aaron W. , Lind Jorrit , Jin Kaining , Boekeloo Janhenk , Tijink Dillian , Hall David , Hanhart Corrie , Becker Frank F.M. , van Eeuwijk Fred A. , Kramer David M. , Wijnker Erik , Harbinson Jeremy , Koornneef Maarten , Aarts Mark G.M. 
Published: July 2024

AbstractEfforts to improve photosynthetic performance are increasingly employing natural genetic variation. However, genetic variation in the organellar genomes (plasmotypes) is often disregarded due to the difficulty of studying the plasmotypes and the lack of evidence that this is a worthwhile investment. Here, we systematically phenotyped plasmotype diversity usingArabidopsis thalianaas a model species. A reanalysis of whole genome resequencing data of 1,531 representative accessions shows that the genetic diversity amongst the mitochondrial genomes is eight times lower than amongst the chloroplast genomes. Plasmotype diversity of the accessions divides the species into two major phylogenetic clusters, within which highly divergent subclusters are distinguished. We combined plasmotypes from 60A. thalianaaccessions with the nuclear genomes (nucleotypes) of fourA. thalianaaccessions to create a panel of 232 novel cytonuclear genotypes (cybrids). The cybrid plants were grown in a range of different light and temperature conditions and phenotyped using high-throughput phenotyping platforms. Analysis of the phenotypes showed that several plasmotypes alone or in interaction with the nucleotypes have significant effects on photosynthesis, and that the effects are highly dependent on the environment. Moreover, we introduce Plasmotype Association Studies (PAS) as a novel method to reveal plasmotypic effects. WithinA. thaliana,several organellar variants can influence photosynthetic phenotypes, which emphasizes the valuable role this variation has on improving photosynthetic performance. The increasing feasibility of producing cybrids in various species calls for further research into how these phenotypes may support breeding goals in crop species.Significance statementPhotosynthesis is one of the few crop traits that has been largely unaddressed which can contribute to increasing crop yield potential. Exploiting genetic variation within organellar genomes presents a promising, yet untapped resource to improve photosynthesis. However, the extent of organellar variation and its impact on photosynthesis within a species remains largely unknown. UsingArabidopsis thalianaas a model species, we revealed highly divergent clusters of organellar variation. We constructed 232 novel combinations of species representative organellar and nuclear genomes, referred to as cybrids. High-throughput phenotyping of these cybrids revealed that organellar variants can substantially impact photosynthesis in different environments. These findings indicate that organellar genomes may be a valuable resource for improving photosynthesis in crops.
CompareM2 is a genomes-to-report pipeline for comparing microbial genomes
Authors: Kobel Carl M. , Aho Velma T. E. , Øyås Ove , Nørskov-Lauritsen Niels , Woodcroft Ben J. , Pope Phillip B. 
Published: July 2024

AbstractHere, we present CompareM2, a genomes-to-report pipeline for comparative analysis of bacterial and archaeal genomes derived from isolates and metagenomic assemblies. CompareM2 is easy to install and operate, and integrates community-adopted tools to perform genome quality control and annotation, taxonomic and functional predictions, as well as comparative analyses of core- and pan-genome partitions and phylogenetic relations. The central results generated via the CompareM2 workflow are emphasized in a portable dynamic report document. CompareM2 is free software and welcomes modifications and pull requests from the community on its Git repository athttps://github.com/cmkobel/comparem2.
Rhabdomyosarcoma fusion oncoprotein initially pioneers a neural signature in vivo
Authors: Kucinski Jack , Tallan Alexi , Taslim Cenny , Wang Meng , Cannon Matthew V. , Silvius Katherine M. , Stanton Benjamin Z. , Kendall Genevieve C. 
Published: July 2024

AbstractFusion-positive rhabdomyosarcoma is an aggressive pediatric cancer molecularly characterized by arrested myogenesis. The defining genetic driver, PAX3::FOXO1, functions as a chimeric gain-of-function transcription factor. An incomplete understanding of PAX3::FOXO1’s in vivo epigenetic mechanisms has hindered therapeutic development. Here, we establish a PAX3::FOXO1 zebrafish injection model and semi-automated ChIP-seq normalization strategy to evaluate how PAX3::FOXO1 initially interfaces with chromatin in a developmental context. We investigated PAX3::FOXO1’s recognition of chromatin and subsequent transcriptional consequences. We find that PAX3::FOXO1 interacts with inaccessible chromatin through partial/homeobox motif recognition consistent with pioneering activity. However, PAX3::FOXO1-genome binding through a composite paired-box/homeobox motif alters chromatin accessibility and redistributes H3K27ac to activate neural transcriptional programs. We uncover neural signatures that are highly representative of clinical rhabdomyosarcoma gene expression programs that are enriched following chemotherapy. Overall, we identify partial/homeobox motif recognition as a new mode for PAX3::FOXO1 pioneer function and identify neural signatures as a potentially critical PAX3::FOXO1 tumor initiation event.
Consistent and scalable monitoring of birds and habitats along a coffee production intensity gradient
Authors: Somveille Marius , Grainger-Hull Joe , Ferguson Nicole , Sethi Sarab S. , González-García Fernando , Chassagnon Valentine , Oktem Cansu , Disney Mathias , Bautista Gustavo López , Vandermeer John , Perfecto Ivette 
Published: July 2024

AbstractLand use change associated with agricultural intensification is a leading driver of biodiversity loss in the tropics. To evaluate the habitat-biodiversity relationship in production systems of tropical agricultural commodities, which is critical for certifying and examining the success of biodiversity-friendly agricultural practices, birds are commonly used as indicators. However, consistently and reliably monitoring how bird communities are affected by land use change throughout the annual cycle in a way that can be scalable is challenging using traditional survey methods. In this study, we examined whether the automated analysis of audio data collected by passive acoustic monitoring, together with the analysis of remote sensing data, can be used to efficiently monitor avian biodiversity along the gradient of habitat degradation associated with the intensification of coffee production. Coffee is an important crop produced in tropical forested regions, whose production is expanding and intensifying, and coffee production systems form a gradient of ecological complexity ranging from forest-like shaded polyculture to dense sun-exposed monoculture. We used LiDAR technology to survey the habitat, in combination with autonomous recording units and a vocalisation classification algorithm to assess bird community composition in a coffee landscape comprising a shade-grown coffee farm, a sun coffee farm, and a forest remnant, located in southern Mexico. We found that combining LiDAR with the automated analysis of continuously collected bioacoustics data can capture the expected functional signatures of avian communities as a function of habitat quality in the coffee landscape. Thus, we show that this approach can be a robust way to monitor how biodiversity responds to land use intensification in the tropics. A major advantage of this approach is that it has the potential to be deployed cost-effectively at large scales to help design and certify biodiversity-friendly productive landscapes.
Waves of transcription drive erythroid differentiation and launch the NRF2-activated antioxidant program
Authors: Karppi Ingrid , Pessa Jenny C. , Rabenius Adelina , Himanen Samu V. , Prajapati Bina , Jonsson Emilia Barkman , Vartiainen Maria K. , Sistonen Lea , Vihervaara Anniina 
Published: July 2024

AbstractTranscriptional reprogramming drives differentiation and coordinates cellular responses. While mRNA expression in distinct cell types has been extensively analyzed, the mechanisms that control RNA synthesis upon lineage specifications remain unclear. Here, we induce erythroid differentiation in human cells, track transcription and its regulation at nucleotide-resolution, and identify molecular mechanisms that orchestrate gene and enhancer activity during erythroid specification. We uncover waves of transcription and reveal that a brief differentiation signal launches sustained and propagating changes in RNA synthesis and mRNA expression over cell divisions. NRF2, a strongtrans-activator upon oxidative stress, drives erythroid differentiation without a detectable increase in reactive oxygen species. In erythroid precursors, NRF2 induces architecturally primed, differentiation-linked enhancers, and genes encoding globin and antioxidant proteins. Projecting signal-induced transcription to DNA accessibility and mRNA expression in single human bone marrow cells, reveals ordered activation of myeloid (GABPA) and erythroid (GATA1, TAL1 and HEMGN) factors in lineage-specification, followed by NRF2-triggered antioxidant response in the late erythroid cells. This study establishes molecular mechanisms that prime, execute, and temporally coordinate RNA synthesis during erythroid differentiation. Furthermore, we show that master regulators of differentiation and stress co-orchestrate erythropoiesis and produce the antioxidant machinery before erythroid cells mature to oxygen transporting enucleated erythrocytes.
Upregulation of TNFR2 Precedes TOX Expression by Exhausted T cells and Restricts Antitumor and Antiviral Immunity
Authors: Hoyt-Miggelbrink Alexandra , Waibl Polania Jessica , Wachsmuth Luke , Lorrey Selena , Mohan Aditya , Hardigan Andrew , Blandford Emily , Lerner Emily , Wilkinson Daniel , Hotchkiss Kelly M. , Cook Sarah , Hemmers Saskia , Patel Anoop , Ayasoufi Katayoun , Fecci Peter 
Published: July 2024

AbstractExhaustion represents a collection of programmed T cell differentiation states and an important mode of T cell dysfunction. T cell progression from progenitor to terminal exhaustion is associated with upregulation of the transcription factor TOX and expression of TIM3. Our understanding of factors regulating TOX expression and the transition from progenitor to terminal exhaustion, however, remains incomplete. We reveal here that T cell upregulation of tumor necrosis factor receptor type II (TNFR2) coincides with the gain of phenotypic markers and functions reflective of terminal exhaustion. Meanwhile, knocking out TNFR2 affords a novel population of T cells that express TIM3 but possess diminished TOX levels and functional characteristics of both progenitor and terminally exhausted cells. TIM3+TNFR2 KO T cells exhibit reduced exhaustion transcriptional programs and enhanced AP1 pathway signatures. Finally, TNFR2 KO mice demonstrate improved T cell-dependent control of tumor and chronic lymphocytic choriomeningitis (cLCMV) infection, while pharmacologic antagonism of TNFR2 licenses responses to checkpoint blockade in multiple subcutaneous and intracranial tumor models.
Complex Reticulation in Backbone Subfamily Relationships in Leguminosae
Authors: Stai Jacob , Cardinal-McTeague Warren , Bruneau Anne , Cannon Steven 
Published: July 2024

Contradictory lines of evidence have made it difficult to resolve the phylogenetic history of the legume diversification era; this is true for the backbone topology, and for the number and timing of whole genome duplications (WGDs). By analyzing the transcriptomic data for 473 gene families in 76 species covering all six accepted legume subfamilies, we assessed the phylogenetic relationships of the legume backbone and uncovered evidence of independent whole genome duplications in each of the six legume subfamilies. Three subfamilies — Cercidoideae, Dialioideae, and Caesalpinioideae — bear evidence of an allopolyploid duplication pattern suggestive of ancient hybridization. In Cercidoideae and Dialioideae, the hybridization appears to be within-subfamily, with the generaCercisandPoeppigiaapparently unduplicated descendants of one of the parental lineages; in Caesalpinioideae, the hybridization appears to involve a member of the Papilionoideae lineage, and some other lineage, potentially extinct. Three independent lines of evidence, consisting of a concatenated superalignment, concordance factor analysis of the set of gene family alignments and topologies, and direct inference of reticulation events via maximum pseudo-likelihood implemented by PhyloNet, converged on a single backbone hypothesis and the above hypotheses of reticulate evolution.Significance StatementIn a hybridization event, genes that have already been evolving separately for potentially millions of years become sister chromosomes, yet remain related to one another not at the moment of hybridization, but at the speciation node of the hybrid’s parents. Methodologies based on counts of bursts of duplicated genes, can therefore be fundamentally vulnerable to incorrect and contradictory conclusions about the number and timing of WGD events, unless interpreted carefully and in combination with data from gene trees discordant with the consensus backbone. Our assessment of the legume backbone in that light, resolves previous contradictory findings by concluding that three legume subfamilies are allopolyploid relative to the ur-legume.
Somy evolution in the honey bee infecting trypanosomatid parasite,Lotmaria passim
Authors: Markowitz Lindsey M. , Nearman Anthony , Zhao Zexuan , Boncristiani Dawn , Butenko Anzhelika , de Pablos Luis Miguel , Marin Arturo , Xu Guang , Machado Carlos A. , Schwarz Ryan S. , Palmer-Young Evan C. , Evans Jay D. 
Published: July 2024

ABSTRACTLotmaria passimis a ubiquitous trypanosomatid parasite of honey bees nestled within the medically important subfamily Leishmaniinae. Although this parasite is associated with honey bee colony losses, the original draft genome—which was completed before its differentiation from the closely relatedCrithidia mellificae—has remained the reference for this species despite lacking improvements from newer methodologies. Here we report the updated sequencing, assembly, and annotation of the BRL type strain (ATCC PRA-422) ofLotmaria passim. The nuclear genome assembly has been resolved into 31 complete chromosomes and is paired with an assembled kinetoplast genome consisting of a maxicircle and 30 minicircle sequences. The assembly spans 33.7 Mb and contains very little repetitive content, from which our annotation of both the nuclear assembly and kinetoplast predicted 10,288 protein-coding genes. Analyses of the assembly revealed evidence of a recent chromosomal duplication event within chromosomes 5 and 6 and provides evidence for a high level of aneuploidy in this species, mirroring the genomic flexibility employed by other trypanosomatids as a means of adaptation to different environments. This high-quality reference can therefore provide insights into adaptations of trypanosomatids to the thermally regulated, acidic, and phytochemically rich honey bee hindgut niche, which offers parallels to the challenges faced by other Leishmaniinae during the challenges they undergo within insect vectors, during infection of mammals, and exposure to antiparasitic drugs throughout their multi-host life cycles. This reference will also facilitate investigations of strain-specific genomic polymorphisms, their role in pathogenicity, and the development of treatments for pollinator infection.
The Rbfox1/LASR complex controls alternative pre-mRNA splicing by recognition of multi-part RNA regulatory modules
Authors: Peyda Parham , Lin Chia-Ho , Onwuzurike Kelechi , Black Douglas L. 
Published: July 2024

AbstractThe Rbfox proteins regulate alternative pre-mRNA splicing by binding to the RNA element GCAUG. In the nucleus, most of Rbfox is bound to LASR, a complex of RNA-binding proteins that recognize additional RNA motifs. However, it remains unclear how the different subunits of the Rbfox/LASR complex act together to bind RNA and regulate splicing. We used a nuclease-protection assay to map the transcriptome-wide footprints of Rbfox1/LASR on nascent cellular RNA. In addition to GCAUG, Rbfox1/LASR binds RNA containing motifs for LASR subunits hnRNPs M, H/F, C, and Matrin3. These elements are often arranged in tandem, forming multi-part modules of RNA motifs. To distinguish contact sites of Rbfox1 from the LASR subunits, we analyzed a mutant Rbfox1(F125A) that has lost RNA binding but remains associated with LASR. Rbfox1(F125A)/LASR complexes no longer interact with GCAUG but retain binding to RNA elements for LASR. Splicing analyses reveal that in addition to activating exons through adjacent GCAUG elements, Rbfox can also stimulate exons near binding sites for LASR subunits. Mini-gene experiments demonstrate that these diverse elements produce a combined regulatory effect on a target exon. These findings illuminate how a complex of RNA-binding proteins can decode combinatorial splicing regulatory signals by recognizing groups of tandem RNA elements.
Dietary Branched Chain Amino Acids Modify Post-Infarct Cardiac Remodeling and Function in the Murine Heart
Authors: Nguyen Daniel C. , Wells Collin K. , Taylor Madison S. , Martinez-Ondaro Yania , Brittian Kenneth R. , Brainard Robert E. , Moore Joseph B. , Hill Bradford G. 
Published: July 2024

ABSTRACTIntroductionBranch-chain amino acids (BCAA) are markedly elevated in the heart following myocardial infarction (MI) in both humans and animal models. Nevertheless, it remains unclear whether dietary BCAA levels influence post-MI remodeling. We hypothesize that lowering dietary BCAA levels prevents adverse cardiac remodeling after MI.Methods and ResultsTo assess whether altering dietary BCAA levels would impact circulating BCAA concentrations, mice were fed a low (1/3×), normal (1×), or high (2×) BCAA diet over a 7-day period. We found that mice fed the low BCAA diet had >2-fold lower circulating BCAA concentrations when compared with normal and high BCAA diet feeding strategies; notably, the high BCAA diet did not further increase BCAA levels over the normal chow diet. To investigate the impact of dietary BCAAs on cardiac remodeling and function after MI, male and female mice were fed either the low or high BCAA diet for 2 wk prior to MI and for 4 wk after MI. Although body weights or heart masses were not different in female mice fed the custom diets, male mice fed the high BCAA diet had significantly higher body and heart masses than those on the low BCAA diet. Echocardiographic assessments revealed that the low BCAA diet preserved stroke volume and cardiac output for the duration of the study, while the high BCAA diet led to progressive decreases in cardiac function. Although no discernible differences in cardiac fibrosis, scar collagen topography, or cardiomyocyte cross-sectional area were found between the dietary groups, male mice fed the high BCAA diet showed longer cardiomyocytes and higher capillary density compared with the low BCAA group.ConclusionsProvision of a diet low in BCAAs to mice mitigates eccentric cardiomyocyte remodeling and loss of cardiac function after MI, with dietary effects more prominent in males.