bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Product neutrality function defining genetic interactions emerges from mechanistic models of cell growth
Authors: Fuentes Valenzuela Lucas , Francois Paul , Skotheim Jan 
Published: December 2024

AbstractGenetic analyses, which examine the phenotypic effects of mutations both individually and in combination, have been fundamental to our understanding of cellular functions. Such analyses rely on a neutrality function that predicts the expected phenotype for double mutants based on the phenotypes of the two individual non-interacting mutations. In this study, we examine fitness, the most fundamental cellular phenotype, through an analysis of the extensive colony growth rate data for budding yeast. Our results confirm that the Product neutrality function describes the colony growth rate, or fitness, of a double mutant as the product of the fitnesses of the individual single mutants. This Product neutrality function performs better than additive or minimum neutrality functions, supporting its continued use in genetic interaction studies. Furthermore, we explore the mechanistic origins of this neutrality function by analyzing two theoretical models of cell growth. We perform a computational genetic analysis to show that in both models the product neutrality function naturally emerges due to the interdependence of cellular processes that maximize growth rates. Thus, our findings provide mechanistic insight into how the Product neutrality function arises and affirm its utility in predicting genetic interactions affecting cell growth and proliferation.
An integrative approach for profiling antibody responses in bats to human pathogens
Authors: Toshkova Nia , Zhelyzkova Violeta , Koseva Kaloyana , Dimitrova Katrin , Elshaer Farida , Lacombe Robin V. , Lecerf Maxime , Pashov Anastas , Dimitrov Jordan D. 
Published: December 2024

AbstractSerological analyses are a fundamental tool for identifying infections by a wide range of pathogens. They offer a current overview of pathogen prevalence and insight into past infections. This is particularly relevant for bats, given their high capacity to tolerate pathogens and their role as reservoirs of zoonotic diseases. At present, serological studies in bats have predominantly employed traditional techniques such as enzyme-linked immunosorbent assay (ELISA). However, these techniques have several limitations, including low throughput and the lack of bat-specific detection antibodies. To address these limitations, we developed an integrative approach for systemic serological analyses based on microarray technology, which enables the simultaneous detection of bat IgG antibodies against >190 human pathogens (viruses, bacteria, protists). The results of our analyses demonstrated an antibody response in bats targeting multiple epitopes from different pathogens, thereby proving the method’s high-throughput capability. Furthermore, this approach does not rely on the use of IgG detection reagents, thereby allowing for its application to a diverse range of bat species. This assay offers insights into the infections of bats with pathogens, thereby enhancing our comprehension of zoonotic disease dynamics and facilitating targeted pathogen surveillance.
From Micro to Macro: Avian Chromosome Evolution is Dominated by Natural Selection
Authors: Alfieri James M. , Bolwerk Kevin , Hu Zhaobo , Blackmon Heath 
Published: December 2024

AbstractBirds display striking variation in chromosome number, defying the traditional view of highly conserved avian karyotypes. However, the evolutionary drivers of this variability remain unclear. To address this, we fit probabilistic models of chromosome number evolution across birds, enabling us to estimate rates of evolution for total chromosome number and the number of microchromosomes and macrochromosomes while simultaneously accounting for the impact of other evolving traits. Our analyses revealed higher rates of chromosome fusion than fission across all bird lineages. Notably, much of this signal was driven by Passeriformes, where migratory species showed a particularly strong bias towards fusions compared to sedentary counterparts. Furthermore, a robust correlation between the rearrangement rates of microchromosomes and macrochromosomes suggests that genome-wide processes drive rates of structural evolution. Additionally, we found that lineages with larger population sizes exhibited higher rates of both fusion and fission, indicating that positive selection plays a dominant role in driving divergence in chromosome number. Our findings illuminate the evolutionary dynamics of avian karyotypes and highlight that, while the fitness effects of random structural mutations are often deleterious, beneficial mutations may dominate karyotype divergence in some clades.
AtSDR4L and paralog promote seed-to-seedling transition in multiple seed compartments
Authors: Lu Bailan , Go Dongeun , Shan Jiayi , Song Liang 
Published: December 2024

AbstractArabidopsis thalianaSEED DORMANCY 4-LIKE (AtSDR4L) and its paralog Dynamic Influencer of Gene Expression 2 (DIG2) act as transcriptional co-repressors to promote seed-to-seedling phase transition. Their regulatory roles at the temporal and tissue-specific scales remain elusive. Here, we show thatAtsdr4l dig2seeds over-accumulate multiple hormones, and the mutant phenotypes are alleviated by abscisic acid (ABA) antagonists and gibberellin (GA). Dissected mutant embryos exhibit stunted growth due to reduced cell differentiation and expansion. The double mutant results in extensive changes in gene expression in both the seed coat and the embryo, including many transcription factors genes, with a subset of the genes differentially expressed tissue-specifically. Transcriptomes ofAtsdr4l-5 dig2seed compartments form a distinct cluster from those of the mutant seedlings ofAtsdr4land Polycomb Repressive Complex (PRC)-related genes, suggesting developmental stage-specific role of these regulators. Together, these results demonstrated that AtSDR4L and DIG2 work in concert to launch the growth potential in the embryo and alleviate the constraints in the seed coat to prepare seeds for germination.
Hypoxia inducible factors drive miRNA-mediated downregulation ofL2HGDHandHIF1Ain clear cell renal cancer independent of 14q deletion
Authors: Seal Soma , Luchtel Rebecca A. , Akram Talia , Isaila Bogdan , Perry Kent T. , Procissi Daniele , Hafizi Sassan , Shenoy Niraj K. 
Published: December 2024

AbstractClear cell renal cell carcinoma (ccRCC) is characterized by pseudohypoxic signaling as well as metabolic and epigenetic aberrations of increasing severity during its pathogenesis and progression. Upon identifying that the markedly lower expression ofL2HGDHandHIF1Ain ccRCC tumors is not explained only by 14q deletion (⁓40% of ccRCC), we sought to elucidate the mechanisms underscoring their down-regulation independent of 14q deletion, given the marked translational and scientific importance. While lowerL2HGDHexpression was found to portend a strikingly worse prognosis in a multivariate survival analysis of ccRCC patients (n=509; TCGA) highlighting its translational importance, the paradoxical downregulation ofHIF1AmRNA in ccRCC despite the upregulation of HIF1α protein (secondary to VHL loss) is of significant scientific interest. Using a comprehensive array of in vitro assays, clinicogenomic bioinformatic analyses of large ccRCC datasets, and theCdh16-CreVhl-fl mouse model with kidney specificVhl-loss, we show that the hypoxia-inducible factors upregulate miR21-3p and miR155-5p, which subsequently targetL2HGDHandHIF1Arespectively, during ccRCC pathogenesis and progression. In doing so, we unveil a conserved inhibitory feedback loop forHIF1Ain ccRCC (HIFs→miR155→HIF1A), providing a mechanistic explanation forHIF1Adownregulation despite elevated HIF1α protein. Furthermore- and most importantly-we show that inhibition of hypoxia-inducible factors reverses the adverse loss ofL2HGDHand hydroxymethylcytosine in ccRCC, implicating both HIF2α (primarily) and HIF1α in these metabolic-epigenetic aberrations.Graphical Abstract
Beyond Stimulus Onset: Ongoing Fixations Within an Object Do Not Re-evoke Category Representations During Free-Viewing
Authors: Auerbach-Asch Carmel Ruth , Deouell Leon Y 
Published: December 2024

AbstractHuman visual perception in natural conditions involves multiple fixations within single objects. While traditional studies focus on transient neural responses to initial stimuli, this study investigates how object-category representations evolve across sequential fixations on an object. Using electroencephalography (EEG) and eye-tracking, we analyzed fixation-related potentials (FRPs) and applied multivariate pattern analysis (MVPA) to decode neural representations of faces and watches during prolonged viewing. Results revealed robust category-selective responses, including the N170 component, at stimulus onset, with sustained representations persisting throughout object presentation. Temporal signal deconvolution showed that subsequent fixations did not re-evoke the N170 but elicited transient occipital responses, likely reflecting low-level differences. These findings underscore the dynamic interplay between transient and sustained neural processes during naturalistic vision and highlight the importance of disentangling overlapping neural signals during free viewing.
Cortical dynamics in hand/forelimb S1 and M1 evoked by brief photostimulation of the mouse’s hand
Authors: Novo Daniela Piña , Gao Mang , Yu Jianing , Barrett John M. , Shepherd Gordon M. G. 
Published: December 2024

ABSTRACTSpiking activity along synaptic circuits linking primary somatosensory (S1) and motor (M1) areas is fundamental for sensorimotor integration in cortex. Circuits along the ascending somatosensory pathway through mouse hand/forelimb S1 and M1 were recently described in detail (Yamawaki et al., 2021). Here, we characterize the peripherally evoked spiking dynamics in these two cortical areas in the same system. Brief (5 ms) optogenetic photostimulation of the hand generated short (∼25 ms) barrages of activity first in S1 (onset latency 15 ms) then M1 (10 ms later). The estimated propagation speed was 20-fold faster from hand to S1 than from S1 to M1. Response amplitudes in M1 were strongly attenuated to approximately a third of those in S1. Responses were typically triphasic, with suppression and rebound following the initial peak. Parvalbumin (PV) inhibitory interneurons were involved in each phase, accounting for three-quarters of the initial spikes generated in S1, and their selective photostimulation sufficed to evoke suppression and rebound in both S1 and M1. Partial silencing of S1 by PV activation during hand stimulation reduced the M1 sensory responses. These results provide quantitative measures of spiking dynamics of cortical activity along the hand/forelimb-related transcortical loop; demonstrate a prominent and mechanistic role for PV neurons in each phase of the response; and, support a conceptual model in which somatosensory signals reach S1 via high-speed subcortical circuits to generate characteristic barrages of cortical activity, then reach M1 via densely polysynaptic corticocortical circuits to generate a similar but delayed and attenuated profile of activity.
Detection and characterization of Langya virus inCrocidura lasiura, Republic of Korea
Authors: Natasha Augustine , Pye Sarah E. , Park Kyungmin , Rajoriya Shivani , Yang Intae , Park Jieun , Pangestu Haryo Seno , Kim Jongwoo , Oh Yeonsu , López Carolina B. , Song Jin-Won , Kim Won-Keun 
Published: December 2024

AbstractThis study reports the identification of Langya virus Korea (LayV KOR) during the surveillance of shrews in the Republic of Korea. LayV KOR represents the first identification of LayV outside of China, exhibiting approximately 80% and 95.5% homologies at nucleotide and amino acid levels.
Best practice mass photometry: A guide to optimal single molecule mass measurement
Authors: Kratochvíl Jiří , van Wee Raman , Loewenthal Dan , Thiele Jan Christoph , Bardzil Jack , Iqbal Kishwar , Thorpe Stephen , Kukura Philipp 
Published: December 2024

AbstractMass photometry (MP) has emerged as a powerful approach to study biomolecular structure, dynamics and interactions. The capabilities of the method ultimately hinge on the ability to accurately measure the tiny optical contrast generated by individual molecules landing at a glass-water interface, which enables mass-resolved quantification of biomolecular mixtures. Ideally, this capability is only limited by shot noise inherent to photon detection, but in practice depends on additional parameters and details of the assay. Here, we focus on the key parameters affecting MP performance, and present simple steps that can be taken to achieve optimal MP performance in terms of mass resolution, quantitative detection limit and analyte concentration range without compromising the ease and simplicity of the technique.
The respiratory phase modulates task-related neural representations of visual stimuli
Authors: Stetza Lisa , Hehemann Lena , Kayser Christoph 
Published: December 2024

AbstractWe investigate how respiration influences cognition by examining the interaction between respiratory phase and task-related brain activity during two visual categorization tasks. While prior research shows that cognitive performance varies along the respiratory cycle, the underlying neurophysiological mechanisms remain poorly understood. Though some studies have shown that large-scale neural activity reflecting changes in the excitation-inhibition balance is co-modulated with the respiratory cycle, it remains unclear whether respiration directly shapes the quality by which task-relevant sensory information is encoded. We address this gap by applying single-trial multivariate analyses to EEG data obtained in humans, allowing us to track how respiration modulates the sensory evidence in this neurophysiological signal. Confirming previous studies, our data show that participant’s performance varies with the respiratory phase prior and during a trial. Importantly, they also suggest that respiration directly influences the sensory evidence carried by parieto-occipital processes emerging around 300 to 200 ms prior to participant’s responses. Hence, respiration and sensory-cognitive processes are not only highly intertwined but respiration directly facilitates the representation of behaviourally-relevant signals in the brain.
Exploring mitonuclear interactions in the regulation of cell physiology: insights from interspecies cybrids
Authors: Gaertner Kateryna , Tapanainen Riikka , Saari Sina , Fekete Zsófia , Goffart Steffi , Pohjoismäki Jaakko L. O. , Dufour Eric 
Published: December 2024

AbstractBrown hares (Lepus europaeus) and mountain hares (Lepus timidus) frequently hybridize in regions where their range overlaps, producing fertile offspring and enabling gene flow between the species. Despite this, no hybrid species has emerged, suggesting that hybrid backcrosses may incur fitness costs. One potential mechanism for such costs involves the interactions between mitochondrial and nuclear gene products, where incompatibilities between species-specific alleles may reinforce species barriers and lead to hybrid breakdown. However, direct experimental evidence for this hypothesis remains limited.In this study, we used fibroblasts derived from skin biopsies of wild-caught hares to generate cytoplasmic hybrid (cybrid) cell lines, wherein mitochondria and mtDNA from one species were transferred to mitochondria-depleted cells of the other species, creating novel mitonuclear gene combinations while preserving the original diploid nuclear background. Employing a range of techniques – including transcriptomics, metabolomics, microscopy, and respirometry – we explored the consequences of mitochondrial transfer between these hare species. Our results reveal that in the studied species mitonuclear incompatibilities exhibit strong effects on cellular fitness but are limited to specific genotypes. We propose mechanisms of cellular-level incompatibility and their potential consequences for interspecific hybrids, offering new insights into the complexity of mitonuclear interactions.
The mammalian SKI complex is a broad-spectrum antiviral drug target that upregulates cellular cholesterol to inhibit viral replication
Authors: Weston Stuart , Baracco Lauren , Taylor Louis , Scott Alison , Kumar Gaurav , Shapiro Paul , MacKerell Alexander D. , Frieman Matthew B. 
Published: December 2024

AbstractThere is a need for the development of broad-spectrum antiviral compounds that can act as first line therapeutic countermeasures to emerging viral infections. Host-directed approaches present a promising avenue of development and carry the benefit of mitigating risks of viral escape mutants. We have previously found the SKI (super killer) complex to be a broad-spectrum, host-target with our lead compound ("UMB18") showing activity against influenza, coronaviruses, and filoviruses. The SKI complex is a cytosolic RNA helicase and we previously found that targeting it with UMB18 inhibited viral RNA production but did not further define the mechanism. Here, transcriptomic analysis of UMB18 treated A549 cells revealed an upregulation of genes in the mevalonate pathway which drives cholesterol synthesis. Further investigation validated the genetic upregulation and confirmed an increase in total cellular cholesterol. This upregulation was dependent on the SKI complex, the sterol regulatory element binding proteins (SREBPs) and their regulator SCAP, the major regulators for cholesterol and fatty acid synthesis. Depletion of the SREBPs or SCAP with siRNA, or extraction of cholesterol with methyl β-cyclodextrin attenuated UMB18 antiviral activity, emphasizing the role of increased cholesterol synthesis in this mechanism of action. Our findings further define the antiviral mechanism of a developmental host-directed therapeutic approach with broad applicability against emerging viral pathogens.Author SummaryThe COVID-19 pandemic has underscored the urgent need for effective countermeasures to novel and emerging viral pathogens. Our research presented here builds upon our previously published data on an experimental novel antiviral compound termed UMB18. We have found this compound capable of inhibiting replication of influenza A virus, coronaviruses and the filoviruses Marburg and Ebola virus, but did not fully define a mechanism of action. In this work, we demonstrate that UMB18 exerts antiviral activity by modulating cellular cholesterol levels. By targeting the SKI complex, UMB18 triggers an increase in endogenous cellular cholesterol which disrupts the fine balance viruses rely on for efficient infection. We demonstrate that this mechanism inhibits replication of SARS-CoV-2, revealing a previously undescribed host-directed strategy for antiviral intervention. These findings highlight UMB18’s potential as a broad-spectrum antiviral agent and pave the way for further research into its mechanism and therapeutic applications, offering a promising avenue for development of antiviral countermeasures to current, novel and emerging pathogens.
Identification of anti-resorptive GPCRs by high-content imaging in human osteoclasts
Authors: Price Maria L. , Wyatt Rachael A. , Correia Joao , Areej Zakia , Hinds Maisie , Crastin Ana , Hardy Rowan S. , Frost Morten , Gorvin Caroline M. 
Published: December 2024

AbstractOsteoporosis diagnoses are increasing in the ageing population and although several treatments exist, these have several disadvantages, highlighting the need to identify new drug targets. G protein-coupled receptors (GPCRs) are transmembrane proteins whose surface expression and extracellular activation make them desirable drug targets. Our previous studies have identified 144 GPCR genes to be expressed in primary human osteoclasts, which could provide novel drug targets. The development of high-throughput assays to assess osteoclast activity would improve the efficiency at which we could assess the effect of GPCR activation on human bone cells and could be utilised for future compound screening. Here we assessed the utility of a high-content imaging (HCI) assay that measured cytoplasmic-to-nuclear translocation of the nuclear factor of activated T cells-1 (NFATc1), a transcription factor that is essential for osteoclast differentiation and resorptive activity. We first demonstrated that the HCI assay detected changes in NFATc1 nuclear translocation in human primary osteoclasts using GIPR as a positive control, then developed an automated analysis platform to assess NFATc1 in nuclei in an efficient and unbiased manner. We assessed six GPCRs simultaneously and identified four receptors (FFAR2, FFAR4, FPR1, GPR35) that reduced osteoclast activity. Bone resorption assays and measurements of TRAP activity verified that activation of these GPCRs reduced osteoclast activity, and that receptor-specific antagonists prevented these effects. These studies demonstrate that HCI of NFATc1 can accurately assess osteoclast activity in human cells, reducing observer bias and increasing efficiency of target detection for future osteoclast-targeted osteoporosis therapies.
TheDictyostelium discoideum – Mycobacterium marinuminfection model, a powerful high throughput screening platform for anti-infective compounds
Authors: Nitschke Jahn , Hanna Nabil , Soldati Thierry 
Published: December 2024

SummaryTuberculosis is among the world’s deadliest diseases, causing approximately 2 million deaths annually. The urgent need for new antitubercular drugs has been intensified by the rise of drug-resistant strains. Despite recent advancements, most hits identified through traditional target-based screening exhibit limited efficacyin vivo. Consequently, there is a growing demand for whole-cell-based approaches that directly utilize host-pathogen systems. TheDictyostelium discoideum–Mycobacterium marinumhost–pathogen system is a well-established and powerful alternative model system to study mycobacterial infections. In this article, the phenotypic host-pathogen protocol assay is presented here which relies on monitoringM. marinumduring its infection of the amoebaD. discoideum. This assay is characterized by its scalability for high-throughput screening, robustness, and ease of manipulation, making it an effective system for compound screening. This system provides not only bacterial load readout via a bioluminescentM. marinumstrain, but now also host survival and growth via a fluorescentD. discoideumstrain enabling further host characterization by quantifying growth inhibition and potential cytotoxicity. Finally, the system was benchmarked with selected antibiotics and anti-infectives and calculated IC50s and MICs where applicable, demonstrating its capability to differentiate between antibiotics and anti-infective compounds.ImportanceThis methods paper introduces a robust, scalable, and high-throughput phenotypic host-pathogen assay based on the well-establishedDictyostelium discoideum–Mycobacterium marinumsystem. In contrast to conventional target-based drug screening approaches, which often struggle to translate effectivelyin vivo, this platform directly monitors pathogen-host interactions, providing comprehensive insights into bacterial load, host survival, and potential cytotoxicity. By employing bioluminescentM. marinumand fluorescentD. discoideumstrains, we validated the system using established antibiotics and anti-infective compounds, effectively distinguishing their effects through IC50 and MIC calculations.