bluuebunny/crossref_metadata_2025_split huggingface dataset:
Developmental trajectories of EEG aperiodic and periodic components: Implications for understanding thalamocortical development during infancy
Authors: Wilkinson Carol L. , Yankowitz Lisa , Chao Jerry Y. , Gutiérrez Rodrigo , Rhoades Jeff L. , Shinnar Shlomo , Purdon Patrick L. , Nelson Charles A. 
Published: July 2023

AbstractThe development of neural circuits has long-lasting effects on brain function, yet our understanding of early circuit development in humans remains limited. Here, periodic EEG power features and aperiodic components were examined from longitudinal EEGs collected from 592 healthy 2–44 month-old infants, revealing age-dependent nonlinear changes suggestive of distinct milestones in early brain maturation. Consistent with the transient developmental progression of thalamocortical circuitry, we observe the presence and then absence of periodic alpha and high beta peaks across the three-year period, as well as the emergence of a low beta peak (12-20Hz) after six months of age. We present preliminary evidence that the emergence of the low beta peak is associated with higher thalamocortical-dependent, anesthesia-induced alpha coherence. Together, these findings suggest that early age-dependent changes in alpha and beta periodic peaks may reflect the state of thalamocortical network development.
Whole genomes of the amazonianCacajaoreveal complex connectivity and fast differentiation driven by high environmental dynamism
Authors: Hermosilla-Albala Núria , Silva Felipe Ennes , Cuadros-Espinoza Sebastián , Fontsere Claudia , Valenzuela-Seba Alejandro , Pawar Harvinder , Gut Marta , Kelley Joanna L. , Ruibal-Puertas Sandra , Alentorn-Moron Pol , Faella Armida , Lizano Esther , Farias Izeni , Hrbek Tomas , Valsecchi Joao , Gut Ivo G. , Rogers Jeffrey , Farh Kyle Kai-How , Kuderna Lukas F. K. , Marques-Bonet Tomas , Boubli Jean P. 
Published: July 2023

AbstractDespite showing the greatest primate diversity on the planet, genomic studies on Amazonian primates show very little representation in the literature. With 48 geolocalized high coverage whole genomes from wild uakari monkeys, we present the first population-level study on platyrrhines using whole genome data. In a very restricted range of the Amazon rainforest, eight uakari species (Cacajaogenus) have been described and categorized into bald and black uakaris, based on phenotypic and ecological differences. Despite a slight habitat overlap, we show that posterior to their split 0.92 Mya, bald and black uakaris have remained independent, without gene flow. Nowadays, these two groups present distinct genetic diversity and group-specific variation linked to pathogens. We propose differing hydrology patterns and effectiveness of geographic barriers have modulated the intra-group connectivity and structure of uakari populations. Beyond increasing their representation, with this work we explored the effects of the Amazon rainforest’s dynamism on platyrrhine species.
Fine-scale contemporary recombination variation and its fitness consequences in adaptively diverging stickleback fish
Authors: Venu Vrinda , Harjunmaa Enni , Dreau Andreea , Brady Shannon , Absher Devin , Kingsley David , Jones Felicity 
Published: July 2023

AbstractDespite deep evolutionary conservation, recombination varies greatly across the genome, among individuals, sexes, and populations and can be a major evolutionary force in the wild. Yet this variation in recombination and its impact on adaptively diverging populations is not well understood. To elucidate the nature and potential consequences of recombination rate variation, we characterized fine-scale recombination landscapes by combining pedigrees, functional genomics and field fitness measurements in an adaptively divergent pair of marine and freshwater threespine stickleback populations from River Tyne, Scotland. Through whole-genome sequencing of large nuclear families, we identified the genomic location of almost 50,000 crossovers and built recombination maps for 36 marine, freshwater, and hybrid individuals at 3.8 kilobase resolution. Using these maps, we quantified the factors driving variation in recombination rate: we find strong heterochiasmy between sexes (68% of the variation) but also differences among ecotypes (21.8%). Hybrids show evidence of significant recombination suppression, both in overall map length and in individual loci. We further tested and found reduced recombination rates both within single marine–freshwater adaptive loci and between loci on the same chromosome, suggestive of selection on linked ‗cassettes‘. We tested theory supporting the evolution of linked selection using temporal sampling along a natural hybrid zone, and found that recombinants with shuffled alleles across loci show traits associated with reduced fitness. Our results support predictions that divergence in cis-acting recombination modifiers whose mechanisms are disrupted in hybrids, may have an important role to play in the maintenance of differences among adaptively diverging populations.
Biophysical principles predict fitness of SARS-CoV-2 variants
Authors: Wang Dianzhuo , Huot Marian , Mohanty Vaibhav , Shakhnovich Eugene I. 
Published: July 2023

AbstractSARS-CoV-2 employs its spike protein’s receptor binding domain (RBD) to enter host cells. The RBD is constantly subjected to immune responses, while requiring efficient binding to host cell receptors for successful infection. However, our understanding of how RBD’s biophysical properties contribute to SARS-CoV-2’s epidemiological fitness remains largely incomplete. Through a comprehensive approach, comprising large-scale sequence analysis of SARS-CoV-2 variants and the discovery of a fitness function based on binding thermodynamics, we unravel the relationship between the biophysical properties of RBD variants and their contribution to viral fitness. We developed a biophysical model that uses statistical mechanics to map the molecular phenotype space, characterized by binding constants of RBD to ACE2, LY-CoV016, LY-CoV555, REGN10987, and S309, onto a epistatic fitness landscape. We validate our findings through experimentally measured and machine learning (ML) estimated binding affinities, coupled with infectivity data derived from population-level sequencing. Our analysis reveals that this model effectively predicts the fitness of novel RBD variants and can account for the epistatic interactions among mutations, including explaining the later reversal of Q493R. Our study sheds light on the impact of specific mutations on viral fitness and delivers a tool for predicting the future epidemiological trajectory of previously unseen or emerging low frequency variants. These insights offer not only greater understanding of viral evolution but also potentially aid in guiding public health decisions in the battle against COVID-19 and future pandemics.Significance StatementThis research presents a biophysical model that maps the molecular properties of SARS-CoV-2’s receptor binding domain into an epistatic fitness landscape. By linking the binding affinities of the virus to its epidemic fitness, we offer a powerful tool for understanding and predicting the emergence and success of new viral variants. Our model, validated with real-world data and informed by theoretical insights, provides a foundation for interpreting the evolutionary trajectory of past pandemics and predicting those of the future. The adaptability of this biophysical model extends to the key proteins of other viruses as well, signifying its potential in guiding public health interventions, and advancing our understanding of viral evolution.
Activation of the mevalonate pathway in response to anti-cancer treatments drives glioblastoma recurrences through activation of Rac-1
Authors: He Ling , Ioannidis Angeliki , Arambula Evelyn , Hoffman Carter J. , Joshi Purva , Kathiravan Anoushka , Whitelegge Julian , Liau Linda M. , Kornblum Harley I. , Pajonk Frank 
Published: July 2023

AbstractGlioblastoma is the deadliest adult brain cancer. Under the current standard of care almost all patients succumb to the disease and novel treatments are urgently needed. Dopamine receptor antagonists have been shown to target cancer cell plasticity in GBM and repurposing these FDA-approved drugs in combination with radiation improves the efficacy of radiotherapy in glioma models. In cells surviving this combination treatment the mevalonate pathway is upregulated at the transcriptional and functional level.Here we report that glioblastoma treatments that converge in the immediate early response to radiation through activation of the MAPK cascade universally upregulate the mevalonate pathway and increase stemness of GBM cells through activation of the Rho-GTPase Rac-1. Activation of the mevalonate pathway and Rac-1 is inhibited by statins, which leads to improved survival in mouse models of glioblastoma when combined with radiation and drugs that target the glioma stem cell pool and plasticity of glioma cells.
ME3BP-7 is a targeted cytotoxic agent that rapidly kills pancreatic cancer cells expressing high levels of monocarboxylate transporter MCT1
Authors: Rincon-Torroella Jordina , Dal Molin Marco , Mog Brian , Han Gyuri , Watson Evangeline , Wyhs Nicolas , Ishiyama Shun , Ahmedna Taha , Minn Il , Azad Nilofer S. , Bettegowda Chetan , Papadopoulos Nickolas , Kinzler Kenneth W. , Zhou Shibin , Vogelstein Bert , Gabrielson Kathleen , Sur Surojit 
Published: July 2023

AbstractNearly 30% of Pancreatic ductal adenocarcinoma (PDAC)s exhibit a marked overexpression of Monocarboxylate Transporter 1 (MCT1) offering a unique opportunity for therapy. However, biochemical inhibitors of MCT1 have proven unsuccessful in clinical trials. In this study we present an alternative approach using 3-Bromopyruvate (3BP) to target MCT1 overexpressing PDACs. 3BP is a cytotoxic agent that is known to be transported into cells via MCT1, but its clinical usefulness has been hampered by difficulties in delivering the drug systemically. We describe here a novel microencapsulated formulation of 3BP (ME3BP-7), that is effective against a variety of PDAC cells in vitro and remains stable in serum. Furthermore, systemically administered ME3BP-7 significantly reduces pancreatic cancer growth and metastatic spread in multiple orthotopic models of pancreatic cancer with manageable toxicity. ME3BP-7 is, therefore, a prototype of a promising new drug, in which the targeting moiety and the cytotoxic moiety are both contained within the same single small molecule.One Sentence SummaryME3BP-7 is a novel formulation of 3BP that resists serum degradation and rapidly kills pancreatic cancer cells expressing high levels of MCT1 with tolerable toxicity in mice.
Sex-specific actions of estradiol and testosterone on human fibroblast and endothelial cell proliferation, bioenergetics, and vasculogenesis
Authors: Martier Ashley T. , Maurice Yasmin V. , Conrad K. Michael , Mauvais-Jarvis Franck , Mondrinos Mark J. 
Published: July 2023

AbstractProgress toward the development of sex-specific tissue engineered systems has been hampered by the lack of research efforts to define the effects of sex-specific hormone concentrations on relevant human cell types. Here, we investigated the effects of defined concentrations of estradiol (E2) and dihydrotestosterone (DHT) on primary human dermal and lung fibroblasts (HDF and HLF), and human umbilical vein endothelial cells (HUVEC) from female (XX) and male (XY) donors in both 2D expansion cultures and 3D stromal vascular tissues. Sex-matched E2 and DHT stimulation in 2D expansion cultures significantly increased the proliferation index, mitochondrial membrane potential, and the expression of genes associated with bioenergetics (Na+/K+ ATPase, somatic cytochrome C) and beneficial stress responses (chaperonin) in all cell types tested. Notably, cross sex hormone stimulation, i.e., DHT treatment of XX cells in the absence of E2 and E2 stimulation of XY cells in the absence of DHT, decreased bioenergetic capacity and inhibited cell proliferation. We used a microengineered 3D vasculogenesis assay to assess hormone effects on tissue scale morphogenesis. E2 increased metrics of vascular network complexity compared to vehicle in XX tissues. Conversely, and in line with results from 2D expansion cultures, E2 potently inhibited vasculogenesis compared to vehicle in XY tissues. DHT did not significantly alter vasculogenesis in XX or XY tissues but increased the number of non-participating endothelial cells in both sexes. This study establishes a scientific rationale and adaptable methods for using sex hormone stimulation to develop sex-specific culture systems.
Inducible nitric oxide synthase (iNOS) is necessary for GBP-mediatedT. gondiirestriction in murine macrophages via vacuole nitration and intravacuolar network collapse
Authors: Zhao Xiao-Yu , Lempke Samantha L. , Urbán Arroyo Jan C. , Yin Bocheng , Holness Nadia K. , Smiley Jamison , Ewald Sarah E. 
Published: July 2023

AbstractToxoplasma gondiiis an obligate intracellular, protozoan pathogen of rodents and humans.T. gondii’sability to grow within cells and evade cell-autonomous immunity depends on the integrity of the parasitophorous vacuole (PV). Interferon-inducible guanylate binding proteins (GBPs) are central mediators ofT. gondiiclearance, however, the precise mechanism linking GBP recruitment to the PV andT. gondiirestriction is not clear. This knowledge gap is linked to heterogenous GBP-targeting across a population of vacuoles and the lack of tools to selectively purify the intact PV. To identify mediators of parasite clearance associated with GBP2-positive vacuoles, we employed a novel protein discovery tool automated spatially targeted optical micro proteomics (autoSTOMP). This approach identified inducible nitric oxide synthetase (iNOS) enriched at levels similar to the GBPs in infected bone marrow-derived myeloid cells. iNOS expression on myeloid cells was necessary for mice to controlT. gondiigrowth in vivo and survive acute infection.T. gondiiinfection of IFNγ-primed macrophage was sufficient to robustly induce iNOS expression. iNOS restrictedT. gondiiinfection through nitric oxide synthesis rather than arginine depletion, leading to robust and selective nitration of the PV. Optimal parasite restriction by iNOS and vacuole nitration depended on the chromosome 3 GBPs. Notably, GBP2 recruitment and ruffling of the PV membrane occurred in iNOS knockouts, however, these vacuoles contained dividing parasites. iNOS activity was necessary for the collapse of the intravacuolar network of nanotubular membranes which connects parasites to each other and the host cytosol. Based on these data we conclude reactive nitrogen species generated by iNOS cooperate with the chromosome 3 GBPs to target distinct biology of the PV that are necessary for optimal parasite clearance in murine myeloid cells.
Extant interspecific hybridization among trematodes within theSchistosoma haematobiumspecies complex in Nigeria
Authors: Ajakaye OG , Enabulele EE , Balogun JB , Oyeyemi OT , Grigg ME 
Published: July 2023

AbstractBackgroundNatural interspecific hybridization between the human parasite (Schistosoma haematobium[Sh]) and bovine parasites (S. bovis[Sb], S. curassoni[Sc]) is increasingly reported in Africa. We developed a multi-locus PCR DNA-Seq strategy that amplifies two unlinked nuclear (transITS,BF) and two linked organellar genome markers (CO1,NAD5) to genotypeS. haematobiumeggs collected from infected people in Ile Oluji/Oke Igbo, Ondo State (an agrarian community) and Kachi, Jigawa State (a pastoral community) in Southwestern and Northern Nigeria, respectively.Principal FindingsWe applied this methodology against 57 isolates collected from a total of 219 participants. All patients from Jigawa state were infected with just one of two haplotypes of anS. haematobium x S. bovishybrid based on sequences obtained atCO1,NAD5, transITSandBFmarkers. Whereas samples collected from Ondo state were varied. Mitonuclear discordance was observed in all 17 patients, worms possessed anSbmitochondrial genome but one of four different haplotypes at the nuclear markers, either admixed (heterozygous betweenSh x ScorSh x Sb) at both markers (n=10),ShatBFand admixed attransITS(Sh x Sc) (n=5), admixed (Sh x Sc) atBFand homozygousScattransITS(n=1) or homozygousShatBFand homozygousScattransITS(n=1).SignificancePrevious work suggested that zoonotic transmission ofS. bovisin pastoral communities, where humans and animals share a common water source, is a driving factor facilitating interspecific hybridization. However, our data showed that all isolates were hybrids, with greater diversity identified in Southwestern Nigeria, a non-pastoral site. Further, one patient possessed anS. bovismitochondrial genome but was homozygous forS. haematobiumatBFand homozygous forS. curassoniattransITSsupporting at least two separate backcrosses in its origin, suggesting that interspecific hybridization may be an ongoing process.Author SummaryInterspecific hybridization between trematode parasites poses serious health risks to humans. Many systems have shown possible hybridization between different schistosome species. As evidence of natural hybridization between humanS. haematobiumand animalS. bovisorS. curassonihas grown in recent years, epidemiological surveys across potential hybrid zones are required, particularly in endemic African regions. According to several reports, indiscriminate human-animal water contact is a major factor contributing to hybridization of human and animal schistosomes. We collected and genotyped 57 parasite isolates from pastoral and non-pastoral communities in Kachi, Jigawa state, and Ile Oluji/Oke Igbo, Ondo state, Nigeria to screen for hybrids. In both sites, we foundSchistosomahybrids with mitonuclear discordance and repeated backcrossing betweenS. haematobium,S. bovis, andS. curassoni. Contrary to previous reports,Schistosomahybrids appear to be widespread and not solely dependent on human-animal water interactions.
Stochastic model of vesicular stomatitis virus replication reveals mutational effects on virion production
Authors: King Connor R. , Berezin Casey-Tyler , Peccoud Jean 
Published: July 2023

AbstractWe present the first complete stochastic model of vesicular stomatitis virus (VSV) intracellular replication. Previous models developed to capture VSV’s intracellular replication have either been ODE-based or have not represented the complete replicative cycle, limiting our ability to understand the impact of the stochastic nature of early cellular infections on virion production between cells and how these dynamics change in response to mutations. Our model accurately predicts changes in mean virion production in gene-shuffled VSV variants and can capture the distribution of the number of viruses produced. This model has allowed us to enhance our understanding of intercellular variability in virion production, which appears to be influenced by the duration of the early phase of infection, and variation between variants, arising from balancing the time the genome spends in the active state, the speed of incorporating new genomes into virions, and the production of viral components. Being a stochastic model, we can also assess other effects of mutations beyond just the mean number of virions produced, including the probability of aborted infections and the standard deviation of the number of virions produced. Our model provides a biologically interpretable framework for studying the stochastic nature of VSV replication, shedding light on the mechanisms underlying variation in virion production. In the future, this model could enable the design of more complex viral phenotypes when attenuating VSV, moving beyond solely considering the mean number of virions produced.Author SummaryThis study presents the first complete stochastic model of vesicular stomatitis virus (VSV) replication. Our model captures the dynamic process of VSV’s replication within host cells, accounting for the stochastic nature of early cellular infections and how these dynamics change in response to mutations. By accurately predicting changes in mean virion production and the distribution of viruses in gene-shuffled VSV variants, our model enhances our understanding of viral replication and the variation we see in virion production. Importantly, our findings shed light on the mechanisms underlying the production of VSV virions, revealing the influence of factors such as the duration of the early infection phase and the interplay between the genome’s ability to switch into an inactive state and viral protein production. We go beyond assessing the mean number of virions produced and examine other effects of mutations, including the probability of aborted infections and the variability in virion production. This stochastic model provides a valuable framework for studying the complex nature of viral replication, contributing to our understanding of single-cell viral dynamics and variability. Ultimately, this knowledge could pave the way for designing more effective strategies to attenuate VSV.
A humoral stress response protectsDrosophilatissues from antimicrobial peptides
Authors: Rommelaere Samuel , Carboni Alexia , Bada Juarez Juan F. , Boquete Jean-Philippe , Abriata Luciano A. , Meireles Fernando Teixeira Pinto , Rukes Verena , Vincent Crystal , Kondo Shu , Dionne Marc S. , Dal Peraro Matteo , Cao Chan , Lemaitre Bruno 
Published: July 2023

AbstractThe immune response against an invading pathogen is generally associated with collateral tissue damage caused by the immune system itself. Consequently, several resilience mechanisms have evolved to attenuate the negative impacts of immune effectors. Antimicrobial peptides (AMPs) are small, cationic peptides that contribute to innate defenses by targeting negatively charged membranes of microbes1, 2. While being protective against pathogens, AMPs can be cytotoxic to host cells1, 3. Little is known of mechanisms that protect host tissues from AMP-induced immunopathology. Here, we reveal that a family of stress-induced proteins, the Turandots4, 5, protectDrosophilahost tissues from AMPs, increasing resilience to stress. Deletion of severalTurandotgenes increases fly susceptibility to environmental stresses due to trachea apoptosis and poor oxygen supply. Tracheal cell membranes expose high levels of phosphatidylserine, a negatively charged phospholipid, sensitizing them to the action of AMPs. Turandots are secreted from the fat body upon stress and bind to tracheal cells to protect them against AMPs.In vitro, Turandot A binds to phosphatidylserine on membranes and inhibits the pore-forming activity ofDrosophilaand human AMPs on eukaryotic cells without affecting their microbicidal activity. Collectively, these data demonstrate that Turandot stress proteins mitigate AMP cytotoxicity to host tissues and therefore improve their efficacy. This provides a first example of a humoral mechanism used by animals limiting host-encoded AMP collateral damages.