bluuebunny/crossref_metadata_2025_split huggingface dataset:
Not your private tête-à-tête: leveraging the power of higher-order networks to study animal communication
Authors: Iacopini Iacopo , Foote Jennifer R. , Fefferman Nina H. , Derryberry Elizabeth P. , Silk Matthew J. 
Published: May 2024

Animal communication is frequently studied with conventional network representations that link pairs of individuals who interact, for example, through vocalization. However, acoustic signals often have multiple simultaneous receivers, or receivers integrate information from multiple signallers, meaning these interactions are not dyadic. Additionally, non-dyadic social structures often shape an individual’s behavioural response to vocal communication. Recently, major advances have been made in the study of these non-dyadic, higher-order networks (e.g. hypergraphs and simplicial complexes). Here, we show how these approaches can provide new insights into vocal communication through three case studies that illustrate how higher-order network models can: (i) alter predictions made about the outcome of vocally coordinated group departures; (ii) generate different patterns of song synchronization from models that only include dyadic interactions; and (iii) inform models of cultural evolution of vocal communication. Together, our examples highlight the potential power of higher-order networks to study animal vocal communication. We then build on our case studies to identify key challenges in applying higher-order network approaches in this context and outline important research questions that these techniques could help answer.
This article is part of the theme issue ‘The power of sound: unravelling how acoustic communication shapes group dynamics’.
Adaptation of redox metabolism in drug-tolerant persister cells is a vulnerability to prevent relapse in pancreatic cancer
Authors: Hadi Nadine Abdel , Reyes-Castellanos Gabriela , Gicquel Tristan , Gallardo-Arriaga Scarlett , Boet Emeline , Sarry Jean-Emmanuel , Masoud Rawand , Iovanna Juan , Carrier Alice 
Published: May 2024

ABSTRACTPancreatic Ductal Adenocarcinoma (PDAC) remains a major unresolved disease because of its remarkable therapeutic resistance. Even patients who respond to initial therapy experience relapse in most cases. The mechanisms underlying therapy-acquired resistance supporting relapse are poorly understood. In this study, we aimed to determine the metabolic features of PDAC during relapse, specifically adaptations of mitochondrial and redox metabolism. We used preclinical PDAC mouse models (patient-derived xenografts and murine syngeneic allografts) that present complete regression under initial chemotherapeutic treatment but relapse after a certain time. Relapsed tumors were analyzedex vivoby flow cytometry to measure mitochondrial and redox characteristics. Molecular mechanisms were investigated by quantification of ATP and antioxidants levels, RT-qPCR and bulk RNA-sequencing. Our findings show that mitochondrial metabolism is reprogrammed during relapse, with increased mitochondrial mass, ATP levels, mitochondrial superoxide anions, and total ROS levels, in relapsed compared to control tumors in both models; mitochondrial membrane potential is increased in the xenografts model only. This mitochondrial metabolic reprogramming occurs during treatment-induced regression and at relapse onset. At the molecular level, antioxidant defenses are increased in relapsed tumors and during treatment. These data suggest that treatment-induced oxidative stress may cause the appearance of treatment-adapted cells, known as drug-tolerant persister (DTP) cells. Finally, the combined treatment of arsenic trioxide (ROS inducer) and buthionine sulfoximine (glutathione synthesis inhibitor) is able to completely prevent relapse in PDAC xenografts. In conclusion, targeting redox metabolism via ROS production and antioxidant inhibition is a very promising approach to prevent relapse in PDAC patients.SignificanceMitochondrial and redox metabolisms are reprogrammed during treatment-acquired resistance in pancreatic cancer promoting the survival of drug-tolerant persister cancer cells, opening up new avenues for better therapeutic management of patients.
Theautophagy-related genes AtATG5andAtATG7influence reserve mobilisation and responses to ABA during seed germination inArabidopsis thaliana
Authors: Contreras Estefanía , Pastor-Mora Elena , Aylón-Rodríguez Mar , González-Ceballos Mar , Delgado-Gutiérrez Miguel Ángel , Sánchez-Vicente Inmaculada , Lorenzo Óscar , Vicente-Carbajosa Jesús , Iglesias-Fernández Raquel 
Published: May 2024

ABSTRACTAutophagy is a cell recycling mechanism that degrades cytoplasmic components. Although classically considered a non-selective bulk degradation mechanism, autophagy also functions selectively. Here, we investigate the impact of autophagy on seed development by studying the autophagy-related (ATG) genesAtATG5andAtATG7in Arabidopsis, focusing on their role in ABA responses. Seeds ofatg5andatg7mutants germinate significantly slower than Col-0, especially in the presence of ABA. Transcriptomic analyses comparing imbibedatg7and Col-0 seeds reveal differences in gene expression associated with lipid storage and seed maturation ontology categories. Germinating seeds ofatgmutants show histochemical alterations in the organisation of lipid droplets and protein storage vacuoles (PSV) in the emerging radicle. Notably, immunolocalization of ATG8 is observed in PSV in Col-0, but not inatgmutants. In the presence of ABA, approximately 10% of the transcriptome induced inatg7and repressed in Col-0 has been reported to be under control of the transcription factors ABI3 and ABI5, master regulators of ABA signaling in the seed. Yeast-two hybrid assays confirmed their direct interaction with the autophagy machinery through ATG8. Interestingly, the decrease in ABI5 observed in Col-0 seeds after imbibition is delayed inatgmutants, which also show altered accumulation in developing seeds of the ABI5 homolog bZIP67 that regulates reserve biosynthesis. Taken together, our data highlight the relevance of autophagy in controlling seed reserve mobilisation, its impact on seed germination, and the perception of environmental signals through ABA responses that include a transcription factor decay mechanism.
Reduced glucose supply during neonatal infection attenuates neurological and renal pathology via modulation of innate and Th1 immunity
Authors: Zhong Jingren , Bæk Ole , Doughty Richard , Jørgensen Benjamin Meyer , Jensen Henrik Elvang , Thymann Thomas , Sangild Per Torp , Brunse Anders , Nguyen Duc Ninh 
Published: May 2024

AbstractBackgroundPremature infants are highly susceptible to infections that can lead to sepsis with life-threatening organ dysfunctions. The clinical practice of high parenteral glucose supply in preterm infants can exacerbate infection outcomes through excessive glycolysis-induced inflammatory response. This in turn can affect the health of vital preterm organs, including the brain and kidneys. We hypothesized that reducing glucose supply in infected preterm newborns may help protect against pathology in these two key organs.MethodsCaesarean-delivered preterm pigs were nourished with high or low parenteral glucose levels, infected withStaphylococcus epidermidisor saline, and cared for until 22h. Blood, brain, and kidney samples were collected at the end of the study for analyses.ResultsInfection led to multiple pathological changes, increased inflammation and tissue injury and dysfunction in both brain and kidneys of preterm piglets. Reduced glucose supply in infected animals alleviated neurological degradation, hyperemia and enhanced M2 microglial phenotype in the brain. This intervention also reduced plasma creatinine, renal edema, tubular vacuolization and dilatation. Multiple genes related to innate and Th1 immunity in both organs were highly correlated and dampened by reduced glucose supply, but there were clear signs that renal inflammation was closely connected to systemic inflammation while neuroinflammation was likely driven by immune response to the bacteria translocated into the brain.ConclusionReduced glucose supply can protect brain and kidney health in infected preterm neonates.
Extracellular Matrix-Induced Genes May Reduce Response to Rapamycin in LAM
Authors: Clements D , Babaei-Jadidi R , Johnson J , Miller S , Shah N , Sand JMB , Leeming DJ , Borthwick LA , Fisher AJ , Dufour A , Johnson SR 
Published: May 2024

AbstractRationaleLymphangioleiomyomatosis (LAM) is a rare cystic lung disease driven by nodules containing TSC2-/-‘LAM cells’ and recruited LAM associated fibroblasts (LAFs). Although rapamycin reduces lung function loss, some patients continue to decline meaning additional therapies are needed.ObjectivesTo investigate how the LAM nodule environment affects LAM cell proliferation and the response to rapamycin.MethodsChanges in advanced LAM were identified using shotgun proteomics and immunohistochemistry in tissue from carefully phenotyped patients. Genes potentially associated with rapamycin insensitivity of cells grown on LAF-derived extracellular matrix were identified by RNA sequencing and validated using repurposed pharmacologic inhibitors.Main ResultsMore advanced disease was associated with increasing nodules adjacent to lung cysts and greater decline in forced expiratory volume in 1 sec (FEV1) when treated with rapamycin (p=0.005). In late-stage LAM, proteomics identified upregulation of pathways associated with accumulation of activated fibroblasts, including extracellular matrix deposition, glucose metabolism and the actin cytoskeleton. Picrosirius red staining and immunohistochemistry confirmed deposition of extracellular matrix within LAM nodules. The growth of TSC2-/-model LAM cells was increased on LAF-derived extracellular matrix (LAF ECM), and incompletely supressed by rapamycin (p<0.0001). RNA sequencing of cells grown on LAF ECM identified upregulation of pathways driving cell cycle control, transcription and metabolism in cells. Tractable, pro-proliferative, rapamycin insensitive genes includedCDK7,GAS6andPLAU.Repurposed inhibitors of these pathways inhibited LAM cell proliferation and enhanced the anti-proliferative effect of rapamycin.ConclusionsExtracellular matrix deposited by LAM associated fibroblasts upregulates expression of genes which potentially blunt the response to rapamycin, but offer additional therapeutic opportunities for patients with established LAM.
High-throughput phenotyping of soybean transpiration response curves to rising atmospheric drying in a mapping population
Authors: Monnens Daniel , McCoy Erik , Tamang Bishal G. , Lorenz Aaron J. , Sadok Walid 
Published: May 2024

AbstractIn soybean, limiting whole-plant transpiration rate (TR) response to increasing vapor pressure deficit (VPD) has been associated with the ‘slow-wilting’ phenotype and with water- conservation enabling higher yields under terminal drought. Despite the promise of this trait, it is still unknown whether it has a genetic basis in soybean, a challenge limiting the prospects of breeding climate-resilient varieties. Here we present the results of a first attempt at a high- throughput phenotyping of TR and stomatal conductance response curves to increasing VPD conducted on a soybean mapping population consisting of 140 recombinant inbred lines (RIL). This effort was conducted over two consecutive years, using a controlled-environment, gravimetric phenotyping platform which enabled characterizing 900 plants for these responses, yielding regression parameters (R2from 0.92 to 0.99) that were used for genetic mapping. Several quantitative trait loci (QTL) were identified for these parameters on chromosomes (Ch) 4, 6 and 10, including a VPD-conditional QTL on Ch 4 and a ‘constitutive’ QTL controlling all parameters on Ch 6. This study demonstrated for the first time that canopy water use in response to rising VPD has a genetic basis in soybean, opening novel avenues for identifying alleles enabling water conservation under current and future climate scenarios.
Microglial depletion decreases Müller cell maturation and inner retinal vascular density
Authors: Rowthorn-Apel Nathaniel , Vridhachalam Naveen , Connor Kip M. , Bonilla Gracia M. , Sadreyev Ruslan , Singh Charandeep , Gnanaguru Gopalan 
Published: May 2024

AbstractThe neuroretinal vascular system is comprised of three interconnected layers. The initial superficial vascular plexus formation is guided by astrocytes around birth in mice. The formation of the deep and intermediate vascular plexuses occurs in the second postnatal week and is driven by Müller-cell-derived angiogenic signaling. Previously, we reported that microglia play an important role in regulating astrocyte density during superficial vascular plexus formation. Here, we investigated the role for microglia in regulating Müller-cell-dependent inner retinal vascular development. Results from this study show that microglia closely interact with Müller cells and the growing inner retinal vasculature. Depletion of microglia resulted in reduced inner retinal vascular layers densities and decreased Vegfa isoforms transcript levels. RNA-seq analysis further revealed that microglial depletion significantly reduced specific Müller cell maturation markers including glutamine synthetase, responsible for glutamine biosynthesis, which is needed for angiogenesis. Thus, our study reveals an important role for microglia in Müller cell maturation and inner retinal angiogenesis.
Theoretical Models of Obligate Mutualism to Link Micro- with Macro-Coevolutionary Dynamics
Authors: Eaton Carrie Diaz , Moore Christopher M. 
Published: May 2024

AbstractThere is a need to link micro- and macro-coevolution to bridge mechanistic theory and observations of micro-coevolutionary change with observations of macro-coevolutionary patterns. This need is particularly conspicuous in theoretical models of obligate mutualism, where phylogenetic matching is the predicted outcome. However, these theoretical models of obligate mutualism create a mismatch with empirical studies of obligate mutualism, which experience extensive phylogenetic discordance. Although environmental variation on geographic scales is often invoked, there are other, non-mutually exclusive mechanisms that can possibly explain genetic diversity and co-phylogenetic patterns in mutualistic communities. In this study, we use a genetic-explicit mathematical model of obligate mutualism that explain host-switching outcomes and, consequently, discordance in cophylogenies. We then explore the role of temporal variation in maintenance of genetic variation (i.e., phenology), which can further account for phylogenetic discordance. These insights are possible due to the focus on initial conditions and short-term behavior of model results. This work ultimately supports the continued importance of theoretical work which expands its analysis of outcomes beyond asymptotic behavior.
Reduced ZMPSTE24 expression leads to prelamin accumulation and development of steatosis in MASLD patients
Authors: Schinderle Joseph D. , Wu Anqi , Bochkis Irina M. 
Published: May 2024

AbstractMutations of nuclear lamina-associated proteins LMNA and ZMPSTE24 have been associated with fatty liver. We report that the changes at the nuclear envelope we described in MASLD patients are caused by downregulation of ZMPSTE24, an enzyme that processes prelamin to mature lamin A. In addition,Zmpste24mutant mice develop hepatic steatosis and exhibit upregulation of p53 target genes. p53 activity is also induced in genes differentially expressed in MASLD patients. Furthermore, p53 regulates genes bound by FOXA2 in these individuals, corresponding to observations inZmpste24mutants. In contrast, expression of glucose and insulin regulated genes is reduced in MASLD patients, suggesting altered glucose metabolism and insulin resistance, hallmarks of type 2 diabetes (T2D). Hence, our genomics data show that MASLD patients with severe steatosis but yet without MASH are already suffering from severe metabolic consequences and underscore the need for treatment at this stage of the disease.
fmo-4promotes longevity and stress resistance via ER to mitochondria calcium regulation inC. elegans
Authors: Tuckowski AM , Beydoun S , Kitto ES , Bhat A , Howington MB , Sridhar A , Bhandari M , Chambers K , Leiser SF 
Published: May 2024

AbstractFlavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models. Previous work supports thatC. elegans fmo-2promotes longevity, stress resistance, and healthspan by rewiring endogenous metabolism. However, there are fiveC. elegansFMOs and five mammalian FMOs, and it is not known whether promoting longevity and health benefits is a conserved role of this gene family. Here, we report that expression ofC. elegans fmo-4promotes lifespan extension and paraquat stress resistance downstream of both dietary restriction and inhibition of mTOR. We find that overexpression offmo-4in just the hypodermis is sufficient for these benefits, and that this expression significantly modifies the transcriptome. By analyzing changes in gene expression, we find that genes related to calcium signaling are significantly altered downstream offmo-4expression. Highlighting the importance of calcium homeostasis in this pathway,fmo-4overexpressing animals are sensitive to thapsigargin, an ER stressor that inhibits calcium flux from the cytosol to the ER lumen. This calcium/fmo-4interaction is solidified by data showing that modulating intracellular calcium with either small molecules or genetics can change expression offmo-4and/or interact withfmo-4to affect lifespan and stress resistance. Further analysis supports a pathway wherefmo-4modulates calcium homeostasis downstream of activating transcription factor-6 (atf-6), whose knockdown induces and requiresfmo-4expression. Together, our data identifyfmo-4as a longevity-promoting gene whose actions interact with known longevity pathways and calcium homeostasis.
Morphological single-cell analysis of peripheral blood mononuclear cells from 390 healthy blood donors with Blood Cell Painting
Authors: Högel-Starck Caroline , Timonen Veera A. , Atarsaikhan Gantugs , Mogollon Isabel , Polso Minttu , Hassinen Antti , Honkanen Jarno , Soini Julius , Ruokoranta Tanja , Ahlnäs Toveann , Juvila Julianna , Miettinen Juho J. , Rodosthenous Rodosthenis S. , Arvas Mikko ,   FinnGen, Heckman Caroline A. , Partanen Jukka , Daly Mark , Palotie Aarno , Paavolainen Lassi , Pietiäinen Vilja , Pitkänen Esa 
Published: May 2024

AbstractRecent molecular profiling and phenotyping methods combined with machine learning based analyses enable genotype-phenotype discovery at an unprecedented scale. The challenge now lies in unraveling the biological mechanisms underpinning these associations. High content imaging is a cost-effective approach for morphological and functional profiling of single cells that has provided insight into mechanisms of disease phenotypes, and consequences of genetic and drug perturbations. However, the morphological variability of healthy immune cells − instrumental to understanding disease-specific deviations from the healthy state − is still relatively uncharacterized. To elucidate this variability at scale, we generated high-resolution fluorescent confocal imaging data of peripheral blood mononuclear cell (PBMC) samples from 390 healthy blood donors with the Blood Cell Painting protocol. The protocol, developed here from the popular Cell Painting morphological profiling assay, optimizes for efficiency and throughput, and includes PBMC thawing, plating and fluorescence marker staining of non-adherent blood cells, followed by confocal and widefield imaging with a high content microscope. We assigned cell types based on cellular features with a classifier trained expert annotations, and observed monocytes to be five-fold more frequent in imaging data compared to flow cytometry baseline, with B and T cells being two-fold less frequent. We hypothesize this discrepancy is due to differential adherence between the cell types. We also evaluated three computational methods for correcting batch effects in imaging data, and found Harmony to perform the best, compatible with previous reports. Finally, we performed the Blood Cell Painting protocol on PBMCs in acute myeloid leukemia, and showed the protocol to be able to distinguish between AML FAB subtypes. Our study highlights the utility of high-content imaging with Cell Painting in characterizing and understanding health and disease phenotypes, opening avenues to further studies with integrated imaging and molecular profiling data.This manuscript is a work in progress, and we anticipate incorporating additional results into subsequent versions.
Previously unmeasured genetic diversity explains part of Lewontin’s paradox in ak-mer-based meta-analysis of 112 plant species
Authors: Roberts Miles , Josephs Emily B. 
Published: May 2024

AbstractAt the molecular level, most evolution is expected to be neutral. A key prediction of this expectation is that the level of genetic diversity in a population should scale with population size. However, as was noted by Richard Lewontin in 1974 and reaffirmed by later studies, the slope of the population size-diversity relationship in nature is much weaker than expected under neutral theory. We hypothesize that one contributor to this paradox is that current methods relying on single nucleotide polymorphisms (SNPs) called from aligning short reads to a reference genome underestimate levels of genetic diversity in many species. To test this idea, we calculated nucleotide diversity (π) andk-mer-based metrics of genetic diversity across 112 plant species, amounting to over 205 terabases of DNA sequencing data from 27,488 individual plants. We then compared how these different metrics correlated with proxies of population size that account for both range size and population density variation across species. We found that our population size proxies scaled anywhere from about 3 to over 20 times faster withk-mer diversity than nucleotide diversity after adjusting for evolutionary history, mating system, life cycle habit, cultivation status, and invasiveness. The relationship betweenk-mer diversity and population size proxies also remains significant after correcting for genome size, whereas the analogous relationship for nucleotide diversity does not. These results suggest that variation not captured by common SNP-based analyses explains part of Lewontin’s paradox in plants.Lay SummaryEven after many revolutions in our ability to sequence and understand DNA, many important biological questions remain unsolved. One such problem is Lewontin’s paradox, named after Richard Lewontin who first described it in 1974. The core of the paradox is a simple idea: species with more individuals should be more genetically diverse. The reasoning is that more individuals means more replication of DNA, and thus more opportunities for mutation to create new variation. However, species that differ massively in population size often have similar diversity levels. Lewontin’s paradox has several potential, previously investigated mechanisms but what if one contributor is simply that our measurements of genetic diversity are off? Most studies estimate diversity by comparing sample genomes to a standard reference genome. While this approach is useful, it is impossible to measure variation in DNA that is not represented in the reference - a phenomenon known as reference bias. We estimate metrics of diversity that are free of reference-bias and re-investigate Lewontin’s paradox in plants. Overall, we find that reference-free diversity metrics scale more with population size, compared to the reference-biased approach. While it is unlikely that reference-bias fully explains Lewontin’s paradox, our analyses suggest that reference-bias plays an important role.