bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome sequences of the first Autographiviridae phages infecting marine Roseobacter
Authors: Du Sen , Wu Ying , Ying Hanqi , Wu Zuqing , Yang Mingyu , Chen Feng , Shao Jiabing , Liu He , Zhang Zefeng , Zhao Yanlin
Published: April 2024

The ubiquitous and abundant marine phages play critical roles in shaping the composition and function of bacterial communities, impacting biogeochemical cycling in marine ecosystems. Autographiviridae is among the most abundant and ubiquitous phage families in the ocean. However, studies on the diversity and ecology of Autographiviridae phages in marine environments are restricted to isolates that infect SAR11 bacteria and cyanobacteria. In this study, ten new roseophages that infect marine Roseobacter strains were isolated from coastal waters. These new roseophages have a genome size ranging from 38 917 to 42 634 bp and G+C content of 44.6–50 %. Comparative genomics showed that they are similar to known Autographiviridae phages regarding gene content and architecture, thus representing the first Autographiviridae roseophages. Phylogenomic analysis based on concatenated conserved genes showed that the ten roseophages form three distinct subgroups within the Autographiviridae, and sequence analysis revealed that they belong to eight new genera. Finally, viromic read-mapping showed that these new Autographiviridae phages are widely distributed in global oceans, mostly inhabiting polar and estuarine locations. This study has expanded the current understanding of the genomic diversity, evolution and ecology of Autographiviridae phages and roseophages. We suggest that Autographiviridae phages play important roles in the mortality and community structure of roseobacters, and have broad ecological applications.
Contribution of autosomal rare andde novovariants to sex differences in autism
Authors: Koko Mahmoud , Satterstrom F. Kyle ,   Autism Sequencing Consortium,   APEX consortium, Warrier Varun , Martin Hilary
Published: April 2024

Autism is four times more prevalent in males than females. To study whether this reflects a difference in genetic predisposition attributed to autosomal rare variants, we evaluated the sex differences in effect size of damaging protein-truncating and missense variants on autism predisposition in 47,061 autistic individuals, then compared effect sizes between individuals with and without cognitive impairment or motor delay. Although these variants mediated differential likelihood of autism with versus without motor or cognitive impairment, their effect sizes on the liability scale did not differ significantly by sex exome-wide or in genes sex-differentially expressed in the cortex. Although de novo mutations were enriched in genes with male-biased expression in the fetal cortex, the liability they conferred did not differ significantly from other genes with similar loss-of-function intolerance and sex-averaged cortical expression. In summary, autosomal rare coding variants confer similar liability for autism in females and males.
Deep-learning protein structure predictions suggest likely molecular functions for three uncharacterised polytopic membrane proteins from theP. falciparumapicoplast
Authors: Murphy David L. , Mesdaghi Shahram , Rodríguez Filomeno Sánchez , Simpkin Adam J. , Elliott Luc , Rigden Daniel J.
Published: April 2024

Malaria is a burdensome disease to humanity caused chiefly by the still poorly understood parasite genusPlasmodium. Much of the pathogenic success of these and other related parasites is due to the presence of the apicoplast, a comparatively poorly characterised biosynthetic organelle containing many proteins of unknown function. Here we present AlphaFold2 protein structure predictions together with furtherin silicoanalyses to infer molecular functions for the three uncharacterised transmembrane apicoplast proteins PF3D7_0622700, PF3D7_0908100 and PF3D7_1021300. The targets PF3D7_0622700 and PF3D7_0908100 are shown herein to belong to the polytopic Major Facilitator and Cation-Proton Antiporter and Anion Transporter superfamilies respectively, confirming previous suspicions for PF3D7_0908100 of a transporter function. Importantly, our docking screens further suggest pyridoxal-5-phosphate may be transported by PF3D7_0622700, and PF3D7_0908100 likely transports a larger negatively charged metabolite. These findings will help direct experimental assays to confirm what apicoplast metabolites these proteins may transport. PF3D7_1021300 is proposed to possess a six transmembrane alpha-helix domain of a currently unknown fold which may also possess a transporter molecular function. This work highlights the power of high accuracy protein structure predictions to illuminate proteins of unknown structure and function.
The maternal and fetal metabolic and immune landscapes of gestational diabetes mellitus
Authors: Ni Duan , Nanan Ralph
Published: April 2024

Objectives

Gestational diabetes mellitus (GDM) is the most common pregnancy-related medical complication. It is characterized by the development of hyperglycaemia during pregnancy and is known to lead to higher risk of metabolic disorders and other pathologies in both mothers and offsprings. Some studies probed the impacts of GDM, focusing on specific organs like placenta or adipose tissue, but so far, a systematic overview is lacking. Here, we aimed to curate a comprehensive atlas from currently available transcriptomic data for GDM, to comprehensively unravel how GDM influences the metabolic and immune landscapes in affected pregnancy.

Methods

RNA-sequencing (RNA-seq) data for maternal subcutaneous and omental fat, peripheral blood mononuclear cells (PBMCs), and fetal umbilical vein endothelial cells (HUVECs), amniocytes and cord blood mononuclear cells (CBMCs); and single-cell RNA sequencing (scRNA-seq) data for placenta and CBMCs were collated from previous publications. Comparative analyses and gene set enrichment analyses (GSEA) were carried out for the control versus GDM pregnancy.

Results

Maternal metabolic landscapes were consistently shifted by GDM, with reduced oxidative phosphorylation and fatty acid metabolism in maternal adipose tissues and PBMCs. GDM also caused inflammation solely in maternal subcutaneous fat. scRNA-seq analysis of placenta revealed that GDM reduced granulocytes and myelocytes but increased extravillous trophoblast cells. GDM also differentially impacted the metabolic and immune signals in different placental cell subsets. Contrarily, metabolisms in fetal compartments were minimally influenced by GDM. However, they consistently exhibited elevated inflammatory signals.

Conclusion

GDM differentially reprogrammed the maternal and fetal metabolisms and immunity.
Microglial-Mediated Prevention of Axonal Degeneration in the Injured Spinal Cord: Insights from anIn VivoImaging Study
Authors: Wu Wanjie , He Yingzhu , Chen Yujun , Fu Yiming , He Sicong , Liu Kai , Qu Jianan Y.
Published: April 2024

Microglia, the primary immune cells in the central nervous system, play a critical role in regulating neuronal function and fate through their interaction with neurons. Despite extensive research, the specific functions and mechanisms of microglia-neuron interactions remain incompletely understood. In this study, we demonstrate that microglia establish direct contact with myelinated axons at Nodes of Ranvier in the spinal cord of mice. Under normal physiological conditions, microglia-node contact occurs in a random scanning pattern and is associated with neuronal activity. However, in response to axonal injury, microglia rapidly transform their contact into a robust wrapping form, preventing acute axonal degeneration from extending beyond the nodes. This neuroprotective wrapping behavior of microglia is dependent on the function of their P2Y12 receptors, which may be activated by ATP released through axonal volume-activated anion channels at the nodes. Additionally, voltage-gated sodium channels (NaV) contribute to the interaction between nodes and glial cells following injury, and inhibition of NaV delays axonal degeneration. Throughin vivoimaging, our findings reveal a neuroprotective role of microglia during the acute phase of spinal cord injury, achieved through a novel form of neuron-glia interaction.
Markov Field network model of multi-modal data predicts effects of immune system perturbations on intravenous BCG vaccination in macaques
Authors: Wang Shu , Myers Amy J , Irvine Edward B , Wang Chuangqi , Maiello Pauline , Rodgers Mark A , Tomko Jaime , Kracinovsky Kara , Borish H. Jacob , Chao Michael C , Mugahid Douaa , Darrah Patricia A , Seder Robert A , Roederer Mario , Scanga Charles A , Lin Philana Ling , Alter Galit , Fortune Sarah M , Flynn JoAnne L , Lauffenburger Douglas A
Published: April 2024

Analysis of multi-modal datasets can identify multi-scale interactions underlying biological systems, but can be beset by spurious connections due to indirect impacts propagating through an unmapped biological network. For example, studies in macaques have shown that BCG vaccination by an intravenous route protects against tuberculosis, correlating with changes across various immune data modes. To eliminate spurious correlations and identify critical immune interactions in a public multi-modal dataset (systems serology, cytokines, cytometry) of vaccinated macaques, we applied Markov Fields (MF), a data-driven approach that explains vaccine efficacy and immune correlations via multivariate network paths, without requiring large numbers of samples (i.e. macaques) relative to multivariate features. Furthermore, we find that integrating multiple data modes with MFs helps to remove spurious connections. Finally, we used the MF to predict outcomes of perturbations at various immune nodes, including a B-cell depletion that induced network-wide shifts without reducing vaccine protection, which we validated experimentally.
Post-senescence reproductive rebound inDaphniaassociated with reversal of age-related transcriptional changes
Authors: Dua Ishaan , Pearson A. Catherine , Lowman Rachael L. , Peshkin Leonid , Yampolsky Lev Y.
Published: April 2024

A long-lived species of zooplankton microcrustaceans,Daphnia magna,sometimes exhibits late-life rebound of reproduction, briefly reversing reproductive senescence. Such events are often interpreted as terminal investment in anticipation of imminent mortality. We demonstrate that such post-senescence reproductive events (PSREs) neither cause not anticipate increased mortality. We analyze an RNAseq experiment comparing young, old reproductively senescent, and old PSREDaphniafemales. We first show that overall age-related transcriptional changes are dominated by the increase transcription of guanidine monophosphate synthases and guanylate cyclases, as well as two groups of presumed transposon-encoded proteins and by a drop in transcription of protein synthesis-related genes. We then focus on gene families and functional groups in which full or partial reversal of age-related transcriptional changes occur. This analysis reveals reversal, in the PSRE individuals, of age-related up-regulation of apolipoproteins D, lysosomal lipases, and peptidases and of age-related down-regulation of E3 ubiquitin kinases, V-type proton ATPases, and numerous proteins related to mitochondrial and muscle functions. While it is not certain which of these changes enable reproductive rejuvenation, and which are by-products of processes that lead to it, we present some evidence that post-senescence reproductive events are associated with the reversal of age-related protein and lipid aggregates removal, apoptosis, and with restoration of mitochondrial integrity.

Significance statement

Advances in aging studies revealed the need to extend the old-age health and functionality data from theDrosophila-C.elegans-yeast triad of model organisms to include those that combine the advantages of non-vertebrate models with stronger similarities to mammalian aging. This paper presents a previously unreported phenomenon: reproductive “rejuvenation” inDaphnia– a classic and a re-emerging choice model for longevity studies. These postsenescence reproductive episodes result in fecundity similar to that of young individuals and are accompanied by transcriptional shifts, often reverting age-related changes to youthful levels. Transcripts that show such reversal point to restoration of aggregate removal and of mitochondrial function. We believe that this finding opens a novel window of research towards mechanistic understanding of healthy aging.
Order of amino acid recruitment into the genetic code resolved by Last Universal Common Ancestor’s protein domains
Authors: Wehbi Sawsan , Wheeler Andrew , Morel Benoit , Manepalli Nandini , Minh Bui Quang , Lauretta Dante S. , Masel Joanna
Published: April 2024

The current “consensus” order in which amino acids were added to the genetic code is based on potentially biased criteria, such as absence of sulfur-containing amino acids from the Urey-Miller experiment which lacked sulfur. More broadly, abiotic abundance might not reflect biotic abundance in the organisms in which the genetic code evolved. Here, we instead identify which protein domains date to the last universal common ancestor (LUCA), then infer the order of recruitment from deviations of their ancestrally reconstructed amino acid frequencies from the still-ancient post-LUCA controls. We find that smaller amino acids were added to the code earlier, with no additional predictive power in the previous “consensus” order. Metal-binding (cysteine and histidine) and sulfur-containing (cysteine and methionine) amino acids were added to the genetic code much earlier than previously thought. Methionine and histidine were added to the code earlier than expected from their molecular weights, and glutamine later. Early methionine availability is compatible with inferred early use of S-adenosylmethionine, and early histidine with its purine-like structure and the demand for metal-binding. Even more ancient protein sequences — those that had already diversified into multiple distinct copies prior to LUCA — have significantly higher frequencies of aromatic amino acids (tryptophan, tyrosine, phenylalanine and histidine), and lower frequencies of valine and glutamic acid than single copy LUCA sequences. If at least some of these sequences predate the current code, then their distinct enrichment patterns provide hints about earlier, alternative genetic codes.

Significance Statement

The order in which the amino acids were added to the genetic code was previously inferred from consensus among forty metrics. Many of these reflect abiotic abundance on ancient Earth. However, the abundances that matter are those within primitive cells that already had sophisticated RNA and perhaps peptide metabolism. Here, we directly infer the order of recruitment from the relative ancestral amino acid frequencies of ancient protein sequences. Small size predicts ancient amino acid enrichment better than the previous consensus metric does. We place metal-binding and sulfur-containing amino acids earlier than previously thought, highlighting the importance of metal-dependent catalysis and sulfur metabolism to ancient life. Understanding early life has implications for our search for life elsewhere in the universe.
An assessment of the teacher completed ‘Early Years Foundation Stage Profile’ as a routine measure of child developmental health
Authors: Mooney Kate E. , Welch Charlie , Palliser Gareth , Cheung Rachael W. , Nielsen Dea , Eddy Lucy H. , Blower Sarah L
Published: April 2024

The routine measurement of children’s developmental health varies across educational settings and systems. The Early Years Foundation Stage Profile (EYFSP) is a routinely recorded measure of a child’s development completed at the end of their first school year, for all children attending school in England and Wales. Despite widespread use for research and educational purposes, the measurement properties are unknown. This study examined the internal consistency and structural validity of the EYFSP, investigating whether the summed item-level scores, which we refer to as the ‘total score’, can be used as a summary of children’s developmental health. It also examined predictive validity of the total score with respect to later academic attainment and behavioural, social, and emotional difficulties.

The data source was the longitudinal prospective birth cohort, Born in Bradford (BiB), and routine education data were obtained from Local Authorities. The internal consistency and structural validity of the EYFSP total score were investigated using Confirmatory Factor Analysis and a Rasch model. Predictive validity was assessed using linear mixed effects models for Key Stage 2 (Maths, Reading, Grammar/Punctuation/Spelling), and behavioural, social, and emotional difficulties (Strengths and Difficulties Questionnaire).

We found that the EYFSP items demonstrated internal consistency, however, an Item Response model suggested weak structural validity (n=10,589). Mixed effects regression found the EYFSP total score to predict later academic outcomes (n=2711), and behavioural, social, and emotional difficulties (n=984). The EYFSP total score appears to be a reasonable measure of child developmental health, due to having internal consistency and predictive validity. However, caution should be exercised when interpreting scores of children with very close to ‘average’ ability levels.
Induced electric fields inhibit breast cancer growth and metastasis by modulating the immune tumor microenvironment
Authors: Charan Manish , Jones Travis H. , Ahirwar Dinesh K. , Acharya Nandini , Subramaniam Vish V. , Ganju Ramesh K , Song Jonathan W
Published: April 2024

Despite tremendous advances in oncology, metastatic triple-negative breast cancer remains difficult to treat and manage with established therapies. Here, we show in mice with orthotopic triple-negative breast tumors that alternating (100 kHz), and low intensity (<1 mV/cm) induced electric fields (iEFs) significantly reduced primary tumor growth and distant lung metastases. Non-contact iEF treatment can be delivered safely and non-invasivelyin vivovia a hollow, rectangular solenoid coil. We discovered that iEF treatment enhances anti-tumor immune responses at both the primary breast and secondary lung sites. In addition, iEF reduces immunosuppressive TME by reducing effector CD8+ T cell exhaustion and the infiltration of immunosuppressive immune cells. Furthermore, iEF treatment reduced lung metastasis by increasing CD8+ T cells and reducing immunosuppressive Gr1+ neutrophils in the lung microenvironment. We also observed that iEFs reduced the metastatic potential of cancer cells by inhibiting epithelial-to-mesenchymal transition. By introducing a non-invasive and non-toxic electrotherapeutic for inhibiting metastatic outgrowth and enhancing anti-tumor immune responsein vivo,treatment with iEF technology could add to a paradigm-shifting strategy for cancer therapy.
Estimating the selection pressure and evolutionary rate of proteins on the non-neutral hypothesis of synonymous mutations
Authors: Ye Jiachen , Cui Chunmei , Fan Rui , Cui Qinghua
Published: April 2024

The Nonsynonymous/Synonymous substitution rate ratio (Ka/Ks) is a commonly used metric to estimate the selection pressure and evolutionary rate of proteins in comparative genomics, which plays critical roles in molecular evolution in both biology and medicine. A fundamental assumption of Ka/Ks is that synonymous mutations are evolutionarily neutral and not subject to natural selection as they do not alter protein sequences and function. However, a number of studies have demonstrated that synonymous mutations are non-neutral and may lead to diseases through a number of mechanisms, such as altering miRNA regulation. This further implies that synonymous mutations also participate in the process of natural selection and thus Ka/Ks should be redefined as well. For this purpose, here we propose an improved Ka/Ks ratio,iKa/Ks, which re-computed the neutral substitution rate by taking the altered status of miRNA binding into consideration, and thereby incorporate the impact of synonymous mutations on miRNA regulation. As a result,iKa/Ks shows better performance than Ka/Ks when comparing them using their correlation with expression distance. Moreover, case studies showed thatiKa/Ks is able to identify the positive/negative selection genes that are missed by Ka/Ks. For example, TMEM72/Tmem72 is estimated to be positively selected byiKa/Ks (1.13) but negatively selected by the conventional Ka/Ks ratio (0.21). Further evidence showed its rapid evolution, which further support the power of the new algorithm.
Tracking small animals in complex landscapes: a comparison of localisation workflows for automated radio telemetry systems
Authors: Rueda-Uribe Cristina , Sargent Alyssa J. , Echeverry-Galvis María Ángela , Camargo-Martínez Pedro A. , Capellini Isabella , Lancaster Lesley T. , Rico-Guevara Alejandro , Travis Justin M. J.
Published: April 2024

Automated radio telemetry systems (ARTS) have the potential to revolutionise our understanding of animal movement by providing a near-continuous record of individual locations in the wild. However, localisation error in data generated by ARTS can be very high, especially in natural landscapes with complex vegetation structure and topography. This curtails the ecological questions that may be addressed with this technology. Here, we set up an ARTS grid in a valley with heterogeneous vegetation cover in the Colombian high Andes and applied an analytical pipeline to test the effectiveness of localisation methods. We performed calibration trials to simulate animal movement in high-or low-flight, or walking on the ground, and compared workflows with varying decisions related to signal cleaning, selection, smoothing, and interpretation, along with four multilateration approaches. We also quantified the influence of spatial features on the system’s accuracy. We tested the grid by deploying tags on two high-altitude hummingbirds, the Great Sapphirewing (Pterophanes cyanopterus) and Bronze-tailed Thornbill (Chalcostigma heteropogon). Results showed large variation in localisation error, ranging from only 0.4–43.4 m from known locations up to 474–1929 m, depending on the localisation method used. The lowest average median error across calibration tracks was 105 m. In particular, we found that the selection of higher radio signal strengths and data smoothing based on the temporal autocorrelation in movement data are useful tools to improve accuracy. Moreover, the variables that significantly influence localisation error include terrain ruggedness, height of movement, vegetation type, and the location of animals inside or outside the grid area. In the case of our study system, thousands of location points were successfully estimated for two hummingbird species that previously lacked movement ecology data. Our case study on hummingbirds suggests ARTS grids can be used to estimate small animals’ home ranges, associations with vegetation types, and seasonality in occurrence. We present a comparative localisation pipeline, highlighting the variety of possible decisions while processing radio signal data. Overall, this study provides guidance to improve the resolution of location estimates, broadening the application of this tracking technology in the study of the spatial ecology of wild populations.
An experimental approach to study multi-species interactions implicated in Fusarium-Head Blight complex assembly in wheat
Authors: Corrales Gutiérrez Miguel Ángel , Kaur Harleen , Desiderio Francesca , Douchkov Dimitar Kostadinov , Zhan Jiasui , Vélëz Heriberto , Bourras Salim
Published: April 2024

Fusarium Head Blight (FHB) is a major disease of cereal crops present everywhere where wheat is produced. A complex of several, distinctly different, species from the genusFusariumare responsible for causing the disease, with important taxa beingF. graminearum,F. culmorum, andF. avenaceum. FHB is an adult stage, late season disease affecting wheat at anthesis. However, recent discoveries are now challenging the basic assumption that anthers and spikes are the only ecological niches relevant for resistance to FHB. Most prominently, it has been established that pathogens typically occurring earlier in the season, such asZymoseptoria tritici, induce strong systemic changes in the plant immune system, that expand way beyond their primary ecological niche. Furthermore, taxa implicated in FHB can be isolated from virtually all wheat tissues, including typical blotch symptoms on wheat leaves. Strikingly, such important biological observations about the complex lifestyle of FHB causing taxa are overlooked as potential targets in resistance breeding. In this work we present a simplified approach allowing the dissection of the intricate lifestyles of the FHB causingFusariumtaxa. In doing so, we provide an experimental proof-of-concept that systemic signals fromZ. triticican affect the basic response of wheat toF. graminearum. We further demonstrate that differences inFusariumspecies composition affect the outcome of the interaction in a genotype-specific manner. We argue that efforts to study hidden layers of the biology of FHB associated taxa are crucial to developing new resistance breeding strategies, based on a better understanding of the genetic drivers of the disease.
Vestibular-derived internal models in active self-motion estimation
Authors: van Helvert Milou J.L. , Selen Luc P.J. , van Beers Robert J. , Medendorp W. Pieter
Published: April 2024

Self-motion estimation is thought to depend on sensory information as well as on sensory predictions derived from motor feedback. In driving, the vestibular afference can in principle be predicted based on the steering motor commands if an accurate internal model of the steering dynamics is available. Here, we used a closed-loop steering experiment to examine whether participants can build such an internal model of the steering dynamics. Participants steered a motion platform on which they were seated to align their body with a memorized visual target. We varied the gain between the steering wheel angle and the velocity of the motion platform across trials in three different ways: unpredictable (white noise), moderately predictable (random walk), or highly predictable (constant gain). We examined whether participants took the across-trial predictability of the gain into account to control their steering (internal model hypothesis), or whether they simply integrated the vestibular feedback over time to estimate their travelled distance (path integration hypothesis). Results from a trial series regression analysis show that participants took the gain of the previous trial into account more when it followed a random walk across trials than when it varied unpredictably across trials. Furthermore, on interleaved trials with a large jump in the gain, participants made fast corrective responses, irrespective of gain predictability, suggesting they also rely on vestibular feedback. These findings suggest that the brain can construct an internal model of the steering dynamics to predict the vestibular reafference in driving and self-motion estimation.
The Puerto Rican Infant Metagenomic and Epidemiologic Study of Respiratory Outcomes (PRIMERO): Design and Baseline Characteristics for a Birth Cohort Study of Early-life Viral Respiratory Illnesses and Airway Dysfunction in Puerto Rican Children
Authors: Witonsky Jonathan I. , Elhawary Jennifer R. , Eng Celeste , Oh Sam S. , Salazar Sandra , Contreras Maria G. , Medina Vivian , Secor Elizabeth A. , Zhang Priscilla , Everman Jamie L. , Fairbanks-Mahnke Ana , Pruesse Elmar , Sajuthi Satria P. , Chang Chih-Hao , Guerrero Tsunami Rosado , Fuentes Keyshla Canales , Lopez Natalie , Montanez-Lopez Chris Angely , Otero Richeliz Alfonso , Rivera Raymarie Colon , Rodriguez Leysha , Vazquez Gabriela , Hu Donglei , Huntsman Scott , Jackson Nathan D. , Li Yingchun , Morin Andrew , Nieves Natalie A. , Rios Cydney , Serrano Gonzalo , Williams Blake J. M. , Ziv Elad , Moore Camille M. , Sheppard Dean , Burchard Esteban Gonzalez , Seibold Max A. , Rodriguez Santana Jose R.
Published: April 2024

Epidemiologic studies demonstrate an association between early-life respiratory illnesses (RIs) and the development of childhood asthma. However, it remains uncertain whether these children are predisposed to both conditions or if early-life RIs induce alterations in airway function, immune responses, or other human biology that contribute to the development of asthma. Puerto Rican children experience a disproportionate burden of early-life RIs and asthma, making them an important population for investigating this complex interplay. PRIMERO, thePuerto Rican Infant Metagenomics and Epidemiologic Study of Respiratory Outcomes, recruited pregnant women and their newborns to investigate how the airways develop in early life among infants exposed to different viral RIs, and will thus provide a critical understanding of childhood asthma development. As the first asthma birth cohort in Puerto Rico, PRIMERO will prospectively follow 2,100 term healthy infants. Collected samples include post-term maternal peripheral blood, infant cord blood, the child’s peripheral blood at the year two visit, and the child’s nasal airway epithelium, collected using minimally invasive nasal swabs, at birth, during RIs over the first two years of life, and at annual healthy visits until age five. Herein, we describe the study’s design, population, recruitment strategy, study visits and procedures, and primary outcomes.
Intergenerational transmission of complex traits and the offspring methylome
Authors: Hagenbeek Fiona A. , Pool René , Van Asselt Austin J. , Ehli Erik A. , Smit August B. , Bartels Meike , Hottenga Jouke Jan , Dolan Conor V. , van Dongen Jenny , Boomsma Dorret I.
Published: April 2024

The genetic makeup of parents can directly or indirectly affect their offspring phenome through genetic transmission or via the environment that is influenced by parental heritable traits. Our understanding of the mechanisms by which indirect genetic effects operate is limited. Here, we hypothesize that one mechanism is via the offspring methylome. To test this hypothesis, polygenic scores (PGSs) for schizophrenia, smoking initiation, educational attainment (EA), social deprivation, body mass index (BMI), and height were analyzed in a cohort of 1,528 offspring and their parents (51.5% boys, mean [SD] age = 10 [2.8] years). We modelled parent and offspring PGSs on offspring buccal-DNA methylation, accounting for the own PGS of offspring, and found significant associations between parental PGSs for schizophrenia, EA, BMI, and height, and offspring buccal methylation sites, comprising 16, 2, 1, and 6 sites, respectively (alpha = 2.7 × 10−5). More DNA methylation sites were associated with maternal than paternal PGSs, possibly reflecting the maternal pre- and periconceptional environment or stronger maternal involvement in shaping the offspring’s environment during early childhood.
Sensitivity of unconstrained quantitative magnetization transfer MRI to Amyloid burden in preclinical Alzheimer's disease
Authors: Mao Andrew , Flassbeck Sebastian , Marchetto Elisa , Masurkar Arjun , Rusinek Henry , Assländer Jakob
Published: April 2024

Magnetization transfer MRI is sensitive to semi-solid macromolecules, including amyloid beta, and has previously been used to discriminate Alzheimer's disease (AD) patients from controls. Here, we fit an unconstrained 2-pool quantitative MT (qMT) model, i.e., without constraints on the longitudinal relaxation rate R1s of semi-solids, and investigate the sensitivity of the estimated parameters to amyloid accumulation in preclinical subjects. We scanned 15 cognitively normal volunteers, of which 9 were amyloid positive by [18F]Florbetaben PET. A 12 min hybrid-state qMT scan with an effective resolution of 1.24 mm isotropic and whole-brain coverage was acquired to estimate the unconstrained 2-pool qMT parameters. Group comparisons and correlations with Florbetaben PET standardized uptake value ratios were analyzed at the lobar level. We find that the exchange rate and semi-solid pool's R1s were sensitive to the amyloid concentration, while morphometric measures of cortical thickness derived from structural MRI were not. Changes in the exchange rate are consistent with previous reports in clinical AD, while changes in R1s have not been reported previously as its value is typically constrained in the literature. Our results demonstrate that qMT MRI may be a promising surrogate marker of amyloid beta without the need for contrast agents or radiotracers.
Validation of plasmonic-based biosensors for rapid and sensitive detection of rabbit hemorrhagic and foot-and-mouth disease viruses in biological samples
Authors: Urbinati Chiara , Di Giovanni Vittoria , Pezzoni Giulia , Capucci Lorenzo , Rusnati Marco
Published: April 2024

Biosensing technologies and monoclonal antibodies (MAbs) are gaining increasing importance as powerful tools in the field of virology. Surface plasmon resonance (SPR) is an optical biosensing technology already used in virus detection and in the screening of MAbs of diagnostic and therapeutic value. Rabbit haemorrhagic disease virus 2 (RHDV) and foot-and-mouth disease virus (FMDV) are top veterinary issues for whom, the development of novel methods for their detection in biological samples represents a priority with important livestock healthcare and economic implications. With these premises, here we prepared a series of SPR biosensors containing RHDV2 or its 6S subunit immobilized to the surface by different strategies. The biosensors were then used to characterize the binding capacity of a panel of anti-RHDV2 MAbs. From the comparison of the results obtained, the biosensor composed of intact RHDV2 captured with catcher-MAb covalently immobilized to the surface showed the best analytical performances, that were retained also when the same strategy was adopted to prepare a biosensor containing a different virus (namely, FMVD). The results obtained are discussed in view of the exploitation of SPR in the rapid, sensitive and resilient detection of viruses in biological materials and in the screening of antiviral MAbs libraries.
Cold induces brain region-selective cell activity-dependent lipid metabolism
Authors: Min Hyeonyoung , Yang Yale Y , Yang Yunlei
Published: April 2024

It has been well documented that cold is an enhancer of lipid metabolism in peripheral tissues, yet its effect on central nervous system lipid dynamics is underexplored. It is well recognized that cold acclimations enhance adipocyte functions, including white adipose tissue (WAT) lipid lipolysis and beiging, and brown adipose tissue (BAT) thermogenesis in mammals. However, it remains unclear whether and how lipid metabolism in the brain is also under the control of cold acclimations. Here, we show that cold exposure predominantly increases the expressions of the lipid lipolysis genes and proteins within the paraventricular nucleus of the hypothalamus (PVH). Mechanistically, we find that cold activates cells within the PVH and pharmacological inactivation of cells blunts cold-induced effects on lipid peroxidation, accumulation of lipid droplets (LDs), and lipolysis in the PVH. Together, these findings suggest that PVH lipid metabolism is cold sensitive and integral to cold-induced broader regulatory responses.
Direct and indirect striatal projecting neurons exert strategy-dependent effects on decision-making
Authors: Chaves Rodriguez Elena , Naudé Jérémie , Rial Daniel , de Kerchove d’Exaerde Alban
Published: April 2024

The striatum plays a key role in decision-making, with its effects varying with anatomical location and direct and indirect pathway striatal projecting neuron (d- and i-SPN) populations. Using a mouse gambling task with a reinforcement-learning model, we described of individual decision-making profiles as a combination of three archetypal strategies: Optimizers, Risk-averse, Explorers. Such strategies reflected stable differences in the parameters generating decisions (sensitivity to the reward magnitude, to risk or to punishment) derived from a reinforcement-learning model of animal choice. Chemogenetic manipulation showed that dorsomedial striatum (DMS) neurons substantially impact decision-making, while the nucleus accumbens (NAc) and dorsolateral striatum neurons (DLS) have lesser or no effects, respectively. Specifically, DMS dSPNs decrease risk aversion by increasing the perceived value of risky choices, while DMS iSPNs emphasize large gains, affecting decisions depending on decision-making profiles. Hence, we propose that striatal populations from different subregions influence distinct decision-making parameters, leading to profile-dependent choices.
Opposing actions of co-released GABA and neurotensin on the activity of preoptic neurons and on body temperature
Authors: Tabarean Iustin V.
Published: April 2024

Neurotensin (Nts) is a neuropeptide acting as a neuromodulator in the brain. Pharmacological studies have identified Nts as a potent hypothermic agent. The medial preoptic area, a region that plays an important role in the control of thermoregulation, contains a high density of neurotensinergic neurons and Nts receptors. The conditions in which neurotensinergic neurons play a role in thermoregulation are not known. In this study optogenetic stimulation of preoptic Nts neurons induced a small hyperthermia.In vitro, optogenetic stimulation of preoptic Nts neurons resulted in synaptic release of GABA and net inhibition of the preoptic pituitary adenylate cyclase-activating polypeptide (PACAP) neurons firing activity. GABA-A receptor antagonist or genetic deletion of VGAT in Nts neurons unmasked also an excitatory effect that was blocked by a Nts receptor 1 antagonist. Stimulation of preoptic Nts neurons lacking VGAT resulted in excitation of PACAP neurons and hypothermia. Mice lacking VGAT expression in Nts neurons presented changes in the fever response and in the responses to heat or cold exposure as well as an altered circadian rhythm of body temperature. Chemogenetic activation of all Nts neurons in the brain induced a 4-5 °C hypothermia, which could be blocked by Nts receptor antagonists in the preoptic area. Chemogenetic activation of preoptic neurotensinergic projections resulted in robust excitation of preoptic PACAP neurons. Taken together our data demonstrate that endogenously released Nts can induce potent hypothermia and that excitation of preoptic PACAP neurons is the cellular mechanism that triggers this response.
Natural variation in circadian period correlates with diverse phenological measures in Boechera stricta
Authors: McMinn Robby , Salmela Matti , Weinig Cynthia
Published: April 2024

The circadian clock is a time-keeping mechanism that enables adaptive responses to temporal environmental changes. Circadian period exhibits significant segregating genetic variation within and among populations along an elevational cline, potentially resulting from variable selection across microsites on outputs of the circadian clock. Reproductive timing is an important clock output and selection may favor delayed phenology. We performed a three-year common garden field study with the short-lived perennial Boechera stricta to quantify life history differences among 20 populations from an elevational gradient and among 20 maternal families within one population. We measured days to bolting and later life history transitions such as days to flowering; in the same genotypes, we measured circadian period. The timing of all life history transitions varied among growing seasons, suggesting adaptive life history evolution to local climate conditions. Life history transitions after bolting were also associated with circadian period, such that lengthened period was associated with delayed life history transitions. Structural equation modeling indicated that indirect selection via days to flowering and fruit production favored lengthened clock period in the low elevation common garden site, suggesting that selection on phenology could explain the evolution of variable circadian periods observed among populations from differing environments.
Lateral Entorhinal Cortex Dysfunction in Alzheimer’s disease Mice
Authors: Raghuraman Radha , Aoun Andrew , Herman Mathieu , Shetler Oliver , Nahmani Eden , Hussaini S. Abid
Published: April 2024

In Alzheimer’s disease (AD), the formation of amyloid beta (Aβ) and neurofibrillary tangles (NFTs) leads to neuronal loss in entorhinal cortex (EC), a crucial brain region for memory and navigation. These pathological changes are concurrent with the onset of memory impairments in AD patients with symptoms of forgetfulness such as misplacing items, disorientation in familiar environments etc. The lateral EC (LEC) is associated with non-spatial memory processing including object recognition. Since some LEC neurons fire in response to objects (object cells) while others fire at locations previously occupied by objects (trace cells), pathology in this region could lead to dysfunction in object-location coding. In this paper we show that a transgenic AD mouse model, EC-App/Tau, which expresses both APP and tau primarily in the EC region, have deficits in LEC-specific memory tasks. Using in vivo single-unit electrophysiology recordings we show that LEC neurons are hyperactive with low information content and high sparsity compared to the controls indicating poor firing fidelity. We finally show that object cells and trace cells fire less precisely in the EC-App/Tau mice compared to controls indicating poor encoding of objects. Overall, we show that AD pathology causes erratic firing of LEC neurons and object coding defects leading to LEC-specific memory impairment.
A nutrient-dependent foraging phenotype ofS. coelicolorexhibits enhanced antimicrobial activity and is common across the genus
Authors: Söderholm Niklas , Tanner Hugh , Sandblad Linda
Published: April 2024

Species of the genusStreptomycesare filamentous bacteria mainly residing in soils. The capacity of streptomycetes to adapt to various environments is reflected in the sheer size of their genomes and the number of encoded regulatory proteins. The nutrient-rich laboratory conditions significantly differ from the natural habitat of streptomycetes and fail to stimulate their full range of adaptive behaviors; as a result, the majority of biosynthetic gene clusters remain silent. Moreover, the use of rich media has led to the assumption that nutrient depletion ultimately promotes sporulation. However, we demonstrate thatS. coelicolorcolonies can respond to nutrient depletion by undergoing a previously unidentified phenotypic transition termed “foraging” due to its submerged and continuous growth on depleted media. The foraging phenotype is distinctly different from conventional phenotypes in terms of colony morphology, genomic stability, and metabolomic profile. This adaptation to nutrient deprivation through foraging is found throughout theStreptomycesphylogeny, indicating that the phenotype is highly conserved. Furthermore, foragingS. coelicolorgains the ability to inhibit molds and enhanced competitive activity against both gram-negative and gram-positive bacteria is detected in other species. These findings highlight how morphological adaptations of streptomycetes in nutrient-limited environments alter secondary metabolite production, enabling the screening of novel antimicrobial activities. These discoveries have implications ranging from the basic biology of streptomycetes to drug discovery and microbial ecology.
Genetic properties underlying transcriptional variability across different perturbations
Authors: Tsuru Saburo , Furusawa Chikara
Published: April 2024

Abstract

The rate and direction of phenotypic evolution depend on the availability of phenotypic variants induced genetically or environmentally. It is widely accepted that organisms do not display uniform phenotypic variation, with certain variants arising more frequently than others in response to genetic or environmental perturbations. Previous studies have suggested that gene regulatory networks channel both environmental and genetic influences. However, how the gene regulatory networks influence phenotypic variation remains unclear. To address this, we characterize transcriptional variations inEscherichia coliunder environmental and genetic perturbations. Based on the current understanding of transcriptional regulatory networks, we identify genetic properties that explain gene-to-gene differences in transcriptional variation. Our findings highlight the role of gene regulatory networks in shaping the shared phenotypic variability across different perturbations.
Proteome of human glioblastoma and meningioma tissue small extracellular vesicles
Authors: Su Huaqi , Purnianto Adityas , Kaye Andrew , Morokoff Andrew , Drummond Katherine j , Stylli Stanley , Vella Laura J
Published: April 2024

Small extracellular vesicles have gained attention in neuroscience due to their role in cell-to-cell communication and their potential diagnostic and therapeutic applications. Despite progress in the field, there remains a gap in our understanding of the composition and function of extracellular vesicles with regards to brain tumours. Previous studies have primarily evaluated extracellular vesicles obtained from patient fluids or cell culture medium, rather than directly from tumour tissue. Here we successfully isolated small extracellular vesicles from surgical tissue biopsies of glioblastomas or meningiomas, marking, marking the first report of in situ extracellular vesicle isolation from brain tumours. The protein content of the tumour tissue and their extracellular vesicles was characterized using tandem mass spectrometric proteomics, revealing proteins exclusively detected or enriched in extracellular vesicles relative to the tumour tissue. While our study confirmed proteins previously identified in glioblastoma and meningioma extracellular vesicles from various sources, it also identified novel proteins and pathways associated with extracellular vesicles from these tumour types. This study underscores the benefit of analysing in situ extracellular vesicles derived directly from brain tissue for insights into tumour biology and highlights the need for further research comparing extracellular vesicles from various types and grades of brain tumours.
Transcriptome-wide mRNA condensation precedes stress granule formation and excludes stress-induced transcripts
Authors: Glauninger Hendrik , Bard Jared A.M. , Wong Hickernell Caitlin J. , Airoldi Edo M. , Li Weihan , Singer Robert H. , Paul Sneha , Fei Jingyi , Sosnick Tobin R. , Wallace Edward W. J. , Drummond D. Allan
Published: April 2024

Stress-induced condensation of mRNA and proteins into stress granules is conserved across eukaryotes, yet the function, formation mechanisms, and relation to well-studied conserved transcriptional responses remain largely unresolved. Stress-induced exposure of ribosome-free mRNA following translational shutoff is thought to cause condensation by allowing new multivalent RNA-dependent interactions, with RNA length and associated interaction capacity driving increased condensation. Here we show that, in striking contrast, virtually all mRNA species condense in response to multiple unrelated stresses in budding yeast, length plays a minor role, and instead, stress-induced transcripts are preferentially excluded from condensates, enabling their selective translation. Using both endogenous genes and reporter constructs, we show that translation initiation blockade, rather than resulting ribosome-free RNA, causes condensation. These translation initiation-inhibited condensates (TIICs) are biochemically detectable even when stress granules, defined as microscopically visible foci, are absent or blocked. TIICs occur in unstressed yeast cells, and, during stress, grow before the appearance of visible stress granules. Stress-induced transcripts are excluded from TIICs primarily due to the timing of their expression, rather than their sequence features. Together, our results reveal a simple system by which cells redirect translational activity to newly synthesized transcripts during stress, with broad implications for cellular regulation in changing conditions.