bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genealogies under purifying selection
Authors: Khudiakova Ksenia A. , Boenkost Florin , Tourniaire Julie 
Published: October 2024

AbstractSelection against deleterious mutations, called purifying selection, plays a central role in evolution and acts in all populations. It is known that the genetic patterns observed in genomic regions undergoing purifying selection differ from those resulting from neutral evolution. However, a comprehensive understanding of the underlying mechanisms shaping those patterns is still lacking.In the present work, we use simulations combined with a genealogical approach to identify the effect of purifying selection on the ancestry and thus on the genetic diversity. Our analysis relies on the postulate that the genealogy belongs to the universality class of Beta-coalescents. Under this assumption, we derive statistics measuring the distortion of the genealogy. This approach allows us to consider a wide range of regimes (i.e. arbitrary selection and mutation strengths) and uncover a rich phase diagram. We find that, for strong selection, the limiting genealogy is given by Kingman’s coalescent on a polynomial timescale. As selection gets weaker, Muller’s ratchet starts operating, setting off the emergence of multiple mergers in the genealogical structures. Our results show that while multiple-merger coalescents are often interpreted as the signature of selective sweeps in rapidly adapting populations, these structures can also appear in the context of Muller’s ratchet.
Temporary cerebral ischaemia impairs thromboxane A2 constriction and induces hypertrophic remodelling in peripheral mesenteric arteries of hypertensive rats: limited reversal despite long-term suberoylanilide hydroxamic acid cerebroprotection
Authors: Díaz-Pérez Andrea , Lope-Piedrafita Silvia , Pérez Belén , Vázquez-Sufuentes Paula , Rodriguez-Garcia Maria , Briones Ana M , Navarro Xavier , Penas Clara , Jiménez-Altayó Francesc 
Published: October 2024

AbstractStroke induces brain injury, especially severe in hypertensive patients, and elevates mortality rates through non-neurological complications. However, the potential effects of a transient ischaemic episode on the peripheral vasculature of hypertensive individuals remain unclear. Here, we investigated whether transient cerebral ischaemia (90 min)/reperfusion (1 or 8 days) induces alterations in mesenteric resistance artery (MRA) properties in adult male spontaneously hypertensive rats (SHR). In addition, we assessed whether the reported cerebroprotective effects of suberoylanilide hydroxamic acid (SAHA; 50 mg/kg; administered intraperitoneally at 1, 4, or 6 h after reperfusion onset) extend long-term and include beneficial effects on MRAs. Functional and structural properties of MRAs were examined at 1- and 8-days post-stroke. Nuclei distribution, collagen content, and oxidative stress were assessed. Ischaemic brain damage was evaluated longitudinally using magnetic resonance imaging. Following stroke, MRAs from SHR exhibited non-reversible impaired contractile responses to the thromboxane A2 receptor agonist U46619. Stroke increased the MRA cross-sectional area, wall thickness, and wall/lumen ratio due to augmented collagen deposition. These changes were partially sustained 8 days later. SAHA did not improve U46619-induced contractions but mitigated stroke-induced oxidative stress and collagen deposition, preventing MRA remodelling at 24 h of reperfusion. Furthermore, SAHA induced sustained cerebroprotective effects over 8 days, including reduced brain infarct and oedema, and improved neurological scores. However, SAHA had minimal impact on chronic MRA contractile impairments and remodelling. These findings suggest that stroke causes MRA changes in hypertensive subjects. While SAHA treatment offers long-term protection against brain damage, it cannot fully restore MRA alterations.
RAS/PI3K pathway mutations sensitise epithelial ovarian cancer cells to a PARP/NAMPT inhibitor combination
Authors: Gruet Michael , Xu Yitao , An Lyutong , Ma Yurui , Balcells Cristina , Tyson Katie , Spear Sarah , Xu Yuewei , McKinney Flora , Babuta Julia , Bray Chandler , Wickremesinghe Chiharu , Siskos Alexandros P. , Nijhuis Anke M. , Tate Edward W. , McNeish Iain A. , Benito Adrian , Keun Hector C. 
Published: October 2024

ABSTRACTThe combination of PARP and NAMPT inhibitors (PARPi/NAMPTi) has been explored for the treatment of TNBC, Ewing Sarcoma and high grade serous carcinoma (HGSC). However, dose limiting toxicity has hampered NAMPTi in clinical trials. To maximise the therapeutic window, we set out to identify predictive genomic biomarkers. Bioinformatic analysis and screening of a panel of epithelial ovarian cancer (EOC) cell lines revealed that cells with RAS/PI3K pathway mutations were sensitive to the NAMPTi FK866. Activity of olaparib and FK866 was associated with a reduction in nicotinamide mononucleotide (NMN) and the PARP substrate nicotinamide adenine dinucleotide (NAD+), with coincident increases in ROS production, DNA damage and apoptosis induction. Caspase 3/7 activity was upregulated to a greater extent in RAS/PI3K mutant cell lines. Finally, the combination significantly reduced omental tumour weight and increased overall survival in mice injected with ID8Trp53-/-;Pten-/-cells. This study highlights the potential of the PARPi/NAMPTi combination in RAS/PI3K pathway mutant EOC.
Sensorimotor integration enhances temperature stimulus processing
Authors: Anderson Lindsay S , Costabile Jamie D , Schwinn Sina , Calderon Delia , Haesemeyer Martin 
Published: October 2024

SummaryAnimals optimize behavior by integrating sensory input with motor actions. We hypothe-sized that coupling thermosensory information with motor output enhances the brain’s capacity to process temperature changes, leading to more precise and adaptive behaviors. To test this, we developed a virtual “thermal plaid” environment where zebrafish either actively controlled temperature changes (sensorimotor feedback) or passively experienced the same thermal fluctuations. Our findings demonstrate that sensorimotor feedback amplifies the influence of thermal stimuli on swim initiation, resulting in more structured and organized motor output. We show that previously identified mixed-selectivity neurons that simultaneously encode thermal cues and motor activity enable the integration of sensory and motor feedback to optimize behavior. These results highlight the role of sensorimotor integration in refining thermosensory processing, revealing critical neural mechanisms underlying flexible thermoregulatory behavior. Our study offers new insights into how animals adaptively process environmental stimuli and adjust their actions, contributing to a deeper understanding of the neural circuits driving goal-directed behavior in dynamic environments.
Defense mechanisms inLupinus luteusagainstColletotrichum lupini, involving TIR-NBS-LRR protein, hypersensitive response and phenylpropanoid pathways
Authors: Armijo-Godoy Grace , Levicoy Daniela , Martínez-Hernández J. Eduardo , Rupayan Annally , Hernández Sebastián , Carrasco Makarena , Caligari Peter DS , Baroncelli Riccardo , Salvo-Garrido Haroldo 
Published: October 2024

SUMMARYLupins are key grain legumes for future crop production, providing highly sustainable protein, essential in the face of global warming, food security challenges, and the need for sustainable agriculture. Despite their potential, lupin crops are frequently devastated byColletotrichum lupini, a member of the world’s top ten fungal pathogenic genera. In our previous study, we identifiedLluR1, the firstC. lupiniresistance gene, in a wildLupinus luteusaccession. Further research was necessary to unravel the defense mechanisms involved. Histological analysis revealed a hypersensitive response againstC. lupini, while transcriptome analysis highlighted a complex network of differentially expressed genes, including TIR-NBS-LRR proteins, hypersensitive response, and phenylpropanoid pathways. SNPs were identified that distinguish the protein sequences underlying immunity. These findings, along with orthology in other lupin species, offer valuable insights for developing breeding strategies to enhanceC. lupiniresistance in lupins, with significant potential impacts on food, feed, and human nutrition.
A percolation-type criticality threshold controls immune protein coating of surfaces
Authors: Wang Zhicheng , Kulkarni Sahil , Nong Jia , Zamora Marco , Ebrahimimojarad Alireza , Hood Elizabeth , Shuvaeva Tea , Zaleski Michael , Gullipalli Damodar , Wolfe Emily , Espy Carolann , Arguiri Evguenia , Wang Yufei , Marcos-Contreras Oscar A , Song Wenchao , Muzykantov Vladimir R , Fu Jinglin , Radhakrishnan Ravi , Myerson Jacob W , Brenner Jacob S 
Published: October 2024

AbstractWhen a material enters the body, it is immediately attacked by hundreds of proteins, organized into complex networks of binding interactions and reactions. How do such complex systems interact with a material, “deciding” whether to attack? We focus on the “complement” system of ∼40 blood proteins that bind microbes, nanoparticles, and medical devices, initiating inflammation. We show a sharp threshold for complement activation upon varying a fundamental material parameter, the surface density of potential complement attachment points. This sharp threshold manifests at scales spanning single nanoparticles to macroscale pathologies, shown here for diverse engineered and living materials. Computational models show these behaviors arise from a minimal subnetwork of complement, manifesting percolation-type critical transitions in the complement response. This criticality switch explains the “decision” of a complex signaling network to interact with a material, and elucidates the evolution and engineering of materials interacting with the body.
IOP-induced blood-retinal barrier compromise contributes to RGC death in glaucoma
Authors: Zhang Chi , Simón Marina , Lim Haeyn , Tolman Nicholas G. , Horbal Logan , Juarez Felicia A. , Bhandari Aakriti , Montgomery Christa , John Simon W.M. 
Published: October 2024

AbstractThe integrity of the blood-retinal barrier (BRB) has been largely unexplored in glaucoma. We reveal that elevated intraocular pressure (IOP) partially compromises the BRB in two human-relevant inherited mouse models of glaucoma (DBA/2J andLmx1bV265D). Experimentally increasing IOP in mouse eyes further confirms this. Notably, the compromise induces subtle leakage, happening without bleeding or detected endothelial cell junction disruption, and it precedes neurodegeneration. Leakage occurs from peripheral veins in the retinal ganglion cell layer with a concomitant loss of the transcytosis inhibitor MFSD2A. Importantly, stabilizing β-catenin in retinal endothelial cells prevents both vascular leakage and neurodegeneration in the DBA/2J model. The occurrence of leakage in all 3 high IOP models indicates that BRB compromise may be a common, yet overlooked, mechanism in glaucoma. These findings suggest that IOP-induced BRB compromise plays a critical role in glaucoma, offering a new therapeutic target.
Engineering mtDNA Deletions by Reconstituting End-Joining in Human Mitochondria
Authors: Fu Yi , Land Max , Cui Ruobing , Kavlashvili Tamar , Kim Minsoo , Lieber Toby , Ryu Keun Woo , DeBitetto Emily , Masilionis Ignas , Saha Rahul , Takizawa Meril , Baker Daphne , Tigano Marco , Reznik Ed , Sharma Roshan , Chaligne Ronan , Thompson Craig B. , Pe’er Dana , Sfeir Agnel 
Published: October 2024

SUMMARYRecent breakthroughs in the genetic manipulation of mitochondrial DNA (mtDNA) have enabled the precise introduction of base substitutions and the effective removal of genomes carrying harmful mutations. However, the reconstitution of mtDNA deletions responsible for severe mitochondrial myopathies and age-related diseases has not yet been achieved in human cells. Here, we developed a method to engineer specific mtDNA deletions in human cells by co-expressing end-joining (EJ) machinery and targeted endonucleases. As a proof-of-concept, we used mito-EJ and mito-ScaI to generate a panel of clonal cell lines harboring a ∼3.5 kb mtDNA deletion with the full spectrum of heteroplasmy. Investigating these isogenic cells revealed a critical threshold of ∼75% deleted genomes, beyond which cells exhibited depletion of OXPHOS proteins, severe metabolic disruption, and impaired growth in galactose-containing media. Single-cell multiomic analysis revealed two distinct patterns of nuclear gene deregulation in response to mtDNA deletion accumulation; one triggered at the deletion threshold and another progressively responding to increasing heteroplasmy. In summary, the co-expression of mito-EJ and programable nucleases provides a powerful tool to model disease-associated mtDNA deletions in different cell types. Establishing a panel of cell lines with a large-scale deletion at varying levels of heteroplasmy is a valuable resource for understanding the impact of mtDNA deletions on diseases and guiding the development of potential therapeutic strategies.Graphical AbstractHighlightsCombining prokaryotic end-joining with targeted endonucleases generates specific mtDNA deletions in human cellsEngineering a panel of cell lines with a large-scale deletion that spans the full spectrum of heteroplasmy75% heteroplasmy is the threshold that triggers mitochondrial and cellular dysfunctionTwo distinct nuclear transcriptional programs in response to mtDNA deletions: threshold-triggered and heteroplasmy-sensing
Genes Underlying Adaptive Physiological Shifts Among Hibernating Mammals
Authors: Drabeck Danielle H. , Anderson Myana , Roback Emma Y. , Lusczek Elizabeth R. , Tri Andrew N. , Lassen Jens Flensted , Kowalczyk Amanda E , McGaugh Suzanne , Iles Tinen L 
Published: October 2024

AbstractHibernation has evolved several times in mammals to overcome harsh winter climates and food scarcity. During hibernation, animals undergo extreme shifts in metabolic rate, heart rate, respiration, and body temperature. These changes reduce energy consumption and allow animals to survive solely on their fat reserves. Understanding the mechanisms for these extreme shifts has long been recognized as a model for translational medicine as hibernators do not exhibit the same adverse effects of extended immobility that non-hibernating mammals suffer. Though work on individual species has illuminated important mechanisms of these functional changes, the genomic basis of this phenotype remains largely unknown, and few studies have drawn on comparative work to elucidate commonalities across diverse hibernating mammals. Synthesizing both single species and comparative approaches, we use metabolomic data from active and denning black bears (Ursus americanus) to guide bioinformatic analyses of genes using tests of selection and evolutionary rate convergence across independent lineages of hibernating mammals. We identify several genes with significant signatures of selection and evolutionary rate convergence in hibernators that represent both previously known and novel genetic mechanisms of the hibernation phenotype. These data provide novel insights into the genetic basis of this adaptation and serve to direct clinical research in hibernation-based therapies.
Exploring voltage-gated sodium channel conformations and protein-protein interactions using AlphaFold2
Authors: Lopez-Mateos Diego , Narang Kush , Yarov-Yarovoy Vladimir 
Published: October 2024

AbstractVoltage-gated sodium (NaV) channels are vital regulators of electrical activity in excitable cells, playing critical roles in generating and propagating action potentials. Given their importance in physiology, NaVchannels are key therapeutic targets for treating numerous conditions, yet developing subtype-selective drugs remains challenging due to the high sequence and structural conservation among NaVfamily members. Recent advances in cryo-electron microscopy have resolved nearly all human NaVchannels, providing valuable insights into their structure and function. However, limitations persist in fully capturing the complex conformational states that underlie NaVchannel gating and modulation. This study explores the capability of AlphaFold2 to sample multiple NaVchannel conformations and assess AlphaFold Multimer’s accuracy in modeling interactions between the NaVα-subunit and its protein partners, including auxiliary β-subunits and calmodulin. We enhance conformational sampling to explore NaVchannel conformations using a subsampled multiple sequence alignment approach and varying the number of recycles. Our results demonstrate that AlphaFold2 models multiple NaVchannel conformations, including those from experimental structures, new states not yet experimentally identified, and potential intermediate states. Furthermore, AlphaFold Multimer models NaVcomplexes with auxiliary β-subunits and calmodulin with high accuracy, and the presence of protein partners significantly alters the conformational landscape of the NaVα-subunit. These findings highlight the potential of deep learning-based methods to expand our understanding of NaVchannel structure, gating, and modulation, with significant implications for future drug discovery efforts.
Transfer to different host grapevines causes rapid and widespread transcriptional plasticity in the specialist insectDaktulosphaira vitifoliae
Authors: Collison W. Nate , Zafar Syed Adeel , Groen Simon C. , Nabity Paul D. 
Published: October 2024

AbstractInsect herbivores employ many adaptive mechanisms to successfully colonize host plants. Transcriptional plasticity is one important mechanism that enables host use in polyphagous insects that maintain a broad host range. However, whether specialist herbivores also rely on transcriptional plasticity to feed successfully on different hosts remains largely unexplored. Here, we measure genome-wide transcriptional plasticity of grape phylloxera,Daktulosphaira vitifoliae, a grapevine (Vitisspp.) specialist, after transfer onto different host grapevines for a single generation using RNA-seq. We show that the transcriptome ofD. vitifoliaeis highly plastic and responsive to host genotype – 4,820 genes (37% of the 12,876 expressed genes) are significantly differentially expressed in at least one contrast comparing host genotypes. Genes with functions related to host manipulation (predicted secretory effectors), cuticle and chitin, detoxification of xenobiotics, and development were enriched among host-responsive genes, with predicted secretory effectors being most strongly enriched (Fisher’s exact test odds ratio = 8.3, BH-adjusted p-value = 0). We further linked gene co-expression modules toD. vitifoliaefitness using weighted gene co-expression network analysis. The co-expression module most strongly correlated with fitness was enriched for predicted secretory effectors, including a novel group of proline-rich genes that exist as a tandem gene cluster. The only module negatively correlated with fitness was enriched for genes encoding glycoside hydrolase enzymes that function in carbohydrate metabolism. Overall, our results show that the phylloxerid transcriptome is highly plastic and rapidly reprogrammed when transferred onto distinct hosts, which may be an adaptive mechanism underlying host use in this clonally reproducing herbivore.
Weekly inhaled salmeterol xinafoate, a selective β2 adrenergic receptor agonist drug, therapeutically inhibits cancer growth and prolongs survivalin vivo
Authors: She Xiaofei , Ma Junxian , Gao Hua 
Published: October 2024

AbstractHumans have spent approximately 99.5% of the 2.5 million years of evolutionary history as hunter-gatherers, which helped to evolutionarily mold our minds and bodies to the hunting and gathering lifestyle. Physical activity associated with hunting animals, gathering plants, and evading predators is essential for human survival, evolution, and prosperity. Thus, physical activity (acute stress) is mostly beneficial to the body, whereas psycho-emotional stress (chronic stress) is usually detrimental at the psychological, physiological, and pathological levels. Although physical activity exerts anticancer effects and psycho-emotional stress exhibits cancer-promoting effects, both function through the same pathway involving activation of the sympathetic nervous system, release of catecholamines, and stimulation of β2 adrenergic receptor (β2AR) expressed on cancer cells. Here, salmeterol xinafoate was chosen to mimic physical activity. A once-weekly administration of salmeterol xinafoate by the intraperitoneal, inhalation, or transdermal route, dose-dependently extended latency, reduced cancer incidence and growth, and prolonged survivalin vivo. Remarkably, the best complete response rates were 75%, 30%, and 71.43% for the therapeutic treatment of lung cancer, breast cancer, and melanoma, respectively. Notably, the salmeterol xinafoate doses used in our experiments are comparable to those used in patients. Moreover, in endogenous β2AR knockout cancer cells, the exogenous β2AR mutant with impaired salmeterol xinafoate binding or downstream signaling prevented the anticancer effects of salmeterol xinafoatein vivo, demonstrating the on-target action of salmeterol xinafoate on cancer cells and the requirement of the downstream signaling pathway. Finally, we showed that treatment with salmeterol xinafoate dose-dependently decreased the self-renewal capacity of lung cancer stem cells, breast cancer stem cells, and melanoma stem cells. From the perspective of human evolution into cancer biology, our study reveals that β2AR represents an ideal anticancer drug target and that salmeterol xinafoate monotherapy has strong anticancer activity.
Survey of Lichen Diversity and Abundance in a Florida Scrub in Relation to Various Temporal Stages of Burn Recovery
Authors: Holst Meghan M. , Brandt Cassidy M. , Wolovich Christy K. 
Published: October 2024

AbstractWith the increased use of prescribed burns in recent years, it is critical to understand their impacts not only on their primary target species, but also on the entire biological community. Lichen have intricate symbioses with other neighboring organisms and provide important ecosystem services. In prairie and grassland environments, the prescribed burns may result in the extirpation of some ground-dwelling species of lichen. However, the impacts of fire schedules on the lichen recovery in Florida scrublands remains unknown. The dry, sandy scrub ecosystem houses Florida’s only federally endangered lichen, the Florida Perforate Lichen (Cladonia perforata). As scrub communities are adapted to the presence of fire, prescribed burns are now a routine management practice. Lichen has a key role in early plant succession following fire, influencing the health of Florida scrub. We used a modified Feest’s method to survey the effects of fire regime on terrestrial lichen abundance and diversity in the Lakeland Highlands Scrub, an area of scrub habitat in Polk County in Central Florida. The speed and comparable accuracy of Feest’s method render it an accessible means of assessing biodiversity for land management in protected areas. We estimated percent cover of lichen and estimated species diversity using the Lichen Diversity Value (LDV) in four areas of scrub and scrubby flatwoods habitat with different burn histories (unburned; and two years, eight years, and ten years since last burn). According to the LDV calculations, diversity is highest in the most extreme temporal groups, contradicting our initial prediction that lichen diversity and abundance would be greatest in the intermediately disturbed areas (two and eight years post-burn). These preliminary data suggest implementing prescribed burns more frequently in this scrub habitat would allow lichen communities a greater opportunity to recover. Our study yields beneficial information to assist future decisions made regarding the frequency of fire regimes within the Florida scrublands habitat. Methods of protecting lichen may also be recommended, such as collecting and removing lichen prior to a burn, and returning those lichen samples to the area after (e.g. “Remove and Return”).