bluuebunny/crossref_metadata_2025 huggingface dataset:
Lactococcus lactissubsp.cremorisC60 promotes immunoglobulin A production from B cells through functional modification of dendritic cells in intestinal environment
Authors: Saito Suguru , Okuno Alato , Kakizaki Nanae , Maekawa Toshio , Tsuji Noriko M.
Published: October 2024

Probiotics utilizing lactic acid bacteria (LAB) have gained considerable attention in recent trends promoting self-managed health. Specifically, LAB-mediated immune modulation has been a key focus due to its potential to reduce the risk of pathogenic invasion and enhance host immunity. Immunoglobulin A (IgA) plays a crucial role in innate defense against various pathogens. Although only a limited number of probiotic LAB strains have been shown to increase IgA production, this capability remains of great interest. Here, we report a new strain,Lactococcus lactissubsp.cremorisC60 (C60), which promotes IgA production through functional modulation of intestinal B cells and dendritic cells (DCs). Heat-killed (HK)-C60 increased both pro-inflammatory and anti-inflammatory cytokine productions in DCs via the Toll-like receptor (TLR)-Myeloid differentiation primary response 88 (MyD88) signaling pathway, as demonstrated in both a physiological mouse model andin vitrocultures using bone marrow-derived dendritic cells (BMDCs). Notably, intragastric administration of HK-C60 significantly increased systemic IgA production, which was associated with the functional modification of B cells in the Peyer’s patches (PPs) of the small intestine. Immunophenotyping of PP cells from HK-C60-administered mice revealed both an expansion and functional upregulation of B cells. Mechanistically, we identified that DC-derived interleukin-6 (IL-6) and IL-10 play essential roles in the C60-mediated increase in IgA production by B cells. Finally, we evaluated the effect of C60 on IgA production using human peripheral blood mononuclear cells (PBMCs). Consistent with our findings in the mouse model, PBMCs produced IgA upon HK-C60 stimulation in an IL-6- and IL-10-dependent manner. Our results suggest that C60 is a novel probiotic strain capable of promoting intestinal immune homeostasis by upregulating IgA production, underscoring its potential for probiotic applications focused on immune conditioning.
Bioinformatics of combined nuclear and mitochondrial phylogenomics to define key nodes for the classification of Coleoptera
Authors: Creedy Thomas J. , Ding Yinhuan , Gregory Katherine M. , Swaby Luke , Zhang Feng , Vogler Alfried P.
Published: October 2024

Nuclear genome sequencing is resource-intensive and not practical for building densely sampled phylogenetic trees of the most species rich lineages of animals, while mitochondrial genomes can be sequenced and analysed with relative ease. Here, we develop a conceptual approach and bioinformatics workflow for combining nuclear single-copy orthologs with less informative but densely sampled mitochondrial genomes, for a detailed tree of Coleoptera (beetles). Basal relationships of Coleoptera were first inferred from >2,000 BUSCO loci mined from GenBank’s Short Read Archive for 119 exemplars of all major lineages under various substitution models and levels of matrix completion, to reveal universally supported nodes. Second, the corresponding mitogenomes were extracted and combined with an additional 373 species selected for broad taxonomic and biogeographic coverage, roughly in proportion to the known global species diversity of Coleoptera. Bioinformatic processing of mitogenomes was conducted with a novel pipeline for rapid, accurate annotation of protein-coding genes. Finally, phylogenetic trees from all 492 mitogenomes were generated under a backbone constraint from the universal basal nodes, which produced a well-supported tree of the major lineages at family and superfamily level. Being genetically unlinked and showing unique character variation, mitogenomes provide a unique perspective of the phylogeny. Comparison with three recent nuclear phylogenomic studies resulted in the recognition of >80 nodes universally present across all analyses. These may now support the higher classification of Coleoptera and serve as backbone of further studies, as numerous full mitogenomes and mitochondrial DNA barcodes are added to an increasingly complete phylogenetic tree of this super-diverse insect order.
Host genotype shapes root mycobiota in durum wheat
Authors: Margot Trinquier , Michel Colombo , Hélène Fréville , Jacques David , Aline Rocher , Benoit Lefebvre , Christophe Roux
Published: October 2024

In addition to environmental factors, plant genetics play a key role in shaping the root microbiota; however, the extent of this genetic control remains underexplored. Using a collection of 181 wheat lines derived from a genetically diverse population, we investigated the influence of wheat genotypes on the composition of the root endophytic mycobiota and explored the genetic determinants driving these relationships.

We first characterized the mycobiota associated with the roots of field-grown lines from the Evolutionary Prebreeding pOpulation (EPO) using Internal Transcribed Spacer 2 (ITS2) barcoding. Fungal diversity was then correlated with wheat genetics by quantitative methods, including heritability analysis and Genome Wide Association Studies (GWAS), to identify novel genetic determinants influencing the mycobiota composition.

Fungal species richness showed a positive correlation across most fungal clades, except betweenMortierellomycotinaandGlomeromycotina. Some specific fungal clades, such asOlpidiomycotaorChytridiomycota, underscored their potential as root endophytes. Additionally, we observed higher heritability in fungal clades (i.e.at the phylum or subphylum rank) that exhibit a homogenous trophic mode, such as the biotrophic Arbuscular Mycorrhizal Fungi (AMF).

This study identifies 11 QTLs associated with mycobiota composition at the clade level. By shedding light on the genetic control of fungal diversity and uncovering key fungal associations, this work enhances our understanding of plant-microbiota interactions and highlights the potential for breeding strategies to optimize these relationships.
Directing cellular transitions on gene graph-enhanced cell state manifold
Authors: Wang Tianze , Pan Yan , Ju Fusong , Zheng Shuxin , Liu Chang , Min Yaosen , Liu Xinwei , Xia Huanhuan , Liu Guoqing , Liu Haiguang , Deng Pan
Published: October 2024

A select few genes act as pivotal drivers in the process of cell state transitions. However, finding key genes involved in different transitions is challenging. To address this problem, we present CellNavi, a deep learning-based framework designed to predict genes that drive cell state transitions. CellNavi builds a driver gene predictor upon a cell state manifold, which captures the intrinsic features of cells by learning from large-scale, high-dimensional transcriptomics data and integrating gene graphs with causal connections. Our analysis shows that CellNavi can accurately predict driver genes for transitions induced by genetic modifications and chemical treatments across diverse cell types, conditions, and studies. It is proficient in tasks involving critical transitions such as cellular differentiation, disease progression, and drug response by leveraging a biologically meaningful cell state manifold. CellNavi represents a substantial advancement in the methodology for predicting driver genes and manipulating cell states, opening up new research opportunities in disease biology and therapeutic innovation.
Brassinosteroids and Flavonols Confer Temperature Stress Tolerance to Pollen Tube Germination and Growth
Authors: Matsuura-Tokita Kumi , Sakai Ayaka , Suzuki Takamasa , Nakano Akihiko , Higashiyama Tetsuya
Published: October 2024

Successful reproduction is a prerequisite for the maintenance of species in the era of climate change. In agriculture, temperature has a significant impact on pollen tube elongation and attraction, and consequently, on the efficiency of fruiting and crop yields. Brassinosteroids (BRs) are plant steroid hormones involved in pollen tube germination, elongation, and capacitation. To elucidate the effect of BR signaling in pistils during the reproductive process, transcriptome analysis of BR receptor (BRI1) mutant pistils was performed, which indicated that genes involved in flavonol biosynthesis were downregulated inbri1pistils. Flavonols are essential for pollen tube growth in some plants and facilitate pollen tube elongation under high-temperature conditions. To investigate the effects of BR and flavonols on pollen tubes under temperature stress,in vitroassays were performed using both the compounds. Brassinolide (BL), which is the most active BR, promoted pollen tube germination at high, low, and optimal temperatures. Germination was further enhanced by the flavonol, quercetin, in the presence of BL especially at low temperatures.in vivoanalysis supported the observation that when BL and quercetin were supplied concurrently, the pollen tube guidance rate was rescued at low temperatures. Quercetin enhanced pollen tube elongation under all the conditions tested at an optimal concentration of 15 μM. BL elevated reactive oxygen species (ROS) under all temperature conditions, whereas quercetin regulated ROS synergistically with BR. Thus, BRs and flavonols supplied by pistils are suggested to function in pollen tube germination and elongation through the maintenance of ROS homeostasis.
Probabilistic Fine-mapping of Putative Causal Genes
Authors: Okamoto Jeffrey , Yin Xianyong , Ryan Brady , Chiou Joshua , Luca Francesca , Pique-Regi Roger , Im Hae Kyung , Morrison Jean , Burant Charles , Fauman Eric B. , Laakso Markku , Boehnke Michael , Wen Xiaoquan
Published: October 2024

Integrative genetic analysis of molecular and complex trait data, including colocalization analysis and transcriptome-wide association studies (TWAS), has shown promise in linking GWAS findings to putative causal genes (PCGs) underlying complex diseases. However, existing methods have notable limitations: TWAS tend to produce an excess of false-positive PCGs, while colocalization analysis often lacks sufficient statistical power, resulting in many false negatives. This paper introduces a probabilistic fine-mapping method, INTERFACE, which is designed to identify putative causal genes while accounting for direct variant-to-trait effects within genomic regions harboring multiple gene candidates. INTERFACE lever-ages interpretable, data-informed priors that incorporate both colocalization and TWAS evidence, enhancing the sensitivity and specificity of PCG inference and setting it apart from existing methods. Additionally, INTERFACE implements analytical measures to improve the accuracy of gene-to-trait effect estimation. We apply INTERFACE to METSIM plasma metabolite GWASs and UK Biobank pQTL data to identify causal genes regulating blood metabolite levels and demonstrate the unique biological insights INTERFACE provides.
Obesity induces phenotypic switching of gastric smooth muscle cells through the activation of the PPARD/PDK4/ANGPTL4 pathway
Authors: Dekkar Sanaa , Mahloul Kamilia , Falco Amandine , Konate Karidia , Pisteur Romane , Maurel Sarah , Maimoun Laurent , Chauvet Norbert , Boisguérin Prisca , Nocca David , Sultan Ariane , Pallot Florian , Walther Guillaume , Cenac Nicolas , Breuker Cyril , Faure Sandrine , de Santa Barbara Pascal
Published: October 2024

Objective

Clinical research has identified stomach dysmotility as a common feature of obesity. However, the specific mechanisms driving gastric emptying dysfunction in patients with obesity remain largely unknown. In this study, we investigated potential mechanisms by focusing on the homeostasis of gastric smooth muscle, using tissue samples from both patient and mice, as well as human cell culture system.

Design

Tissue samples were collected from patients who underwent sleeve gastrectomy for obesity, as well as from control subjects with standard weight who were undergoing treatment for gastric or esophageal carcinoma. Stomach tissues were harvested from mice after 12 weeks on a High-Fat Diet (HFD). Differentiated human gastric smooth muscle cells (SMCs) were treated with lipids, siRNA-peptide-based nanoparticles and/or pharmaceutical compounds. All experimental conditions were analyzed for their effects on SMC differentiation using stage-specific smooth muscle markers. Additionally, lipidomic and RNA sequencing analyses were performed on human gastric SMC cultures. The findings were assessed in patients with obesity to evaluate their clinical relevance.

Results

The smooth muscle layers in gastric tissue from both patients with obesity and mice fed on a HFD exhibited altered differentiation status. Treatment of differentiated human gastric SMCs with lipids phenocopies these alterations and is associated with increased expression ofPDK4andANGPTL4. Inhibition of PDK4 or ANGPTL4 upregulation prevents these lipid-induced modifications. Mechanistically, lipid treatment activates PPARD, which regulatesPDK4andANGPTL4upregulation, leading to SMC dedifferentiation. Notably,PDK4andANGPTL4levels correlate with immaturity and alteration of gastric smooth muscle in patients with obesity.

Conclusion

Obesity triggers a phenotypic change in gastric SMCs, driven by the activation of the PPARD/PDK4/ANGPTL4 pathway. These mechanistic insights offer potential biomarkers for diagnosing stomach dysmotility in patients with obesity.
scMultiNODE: Integrative Model for Multi-Modal Temporal Single-Cell Data
Authors: Zhang Jiaqi , Chakravarthy Manav , Singh Ritambhara
Published: October 2024

Measuring single-cell genomic profiles at different timepoints enables our understanding of cell development. This understanding is more comprehensive when we perform an integrative analysis of multiple measurements (or modalities) across various developmental stages. However, obtaining such measurements from the same set of single cells is resource-intensive, restricting our ability to study them integratively. We propose an unsupervised integration model, scMultiNODE, that integrates gene expression and chromatin accessibility measurements in developing single cells while preserving cell type variations and cellular dynamics. scMultiNODE uses autoencoders to learn nonlinear low-dimensional cell representation and optimal transport to align cells across different measurements. Next, it utilizes neural ordinary differential equations to explicitly model cell development with a regularization term to learn a dynamic latent space. Our experiments on four real-world developmental single-cell datasets show that scMultiNODE can integrate temporally profiled multi-modal single-cell measurements better than existing methods that focus on cell type variations and tend to ignore cellular dynamics. We also show that scMultiNODE’s joint latent space helps with the downstream analysis of single-cell development.

Availability

The data and code are publicly available athttps://github.com/rsinghlab/scMultiNODE.
Dynamic Kidney Organoid Microphysiological Analysis Platform
Authors: Hong SoonGweon , Song Minsun , Miyoshi Tomoya , Morizane Ryuji , Bonventre Joseph V. , Lee Luke P.
Published: October 2024

Kidney organoids, replicating human development, pathology, and drug responses, are a promising model for advancing bioscience and pharmaceutical innovation. However, reproducibility, accuracy, and quantification challenges hinder their broader utility for advanced biological and pharmaceutical applications. Herein, we present a dynamic kidney organoid microphysiological analysis platform (MAP), designed to enhance organoid modeling and assays within physiologically relevant environments, thereby expanding their utility in advancing kidney physiology and pathology research. First, precise control of the dynamic microenvironment in MAP enhances the ability to fine-tune nephrogenic intricacies, facilitating high-throughput and reproducible human kidney organoid development. Also, MAP’s miniaturization of kidney organoids significantly advances pharmaceutical research by allowing for detailed analysis of entire nephron segments, which is crucial for assessing the nephrotoxicity and safety of drugs. Furthermore, the MAP’s application in disease modeling faithfully recapitulates pathological development and functions as a valuable testbed for therapeutic exploration in polycystic kidney diseases. We envision the kidney organoid MAP enhancing pharmaceutical research, standardizing processes, and improving analytics, thereby elevating the quality and utility of organoids in biology, pharmacology, precision medicine, and education.
New proteomic signature in circulating extracellular vesicles from tumor-draining vein of lung adenocarcinomas patients
Authors: Tricard Jérémy , Durand Stéphanie , Gateau Amy , Negroni Luc , Chaunavel Alain , Bertin François , Conti Massimo , Akil Hussein , Lalloué Fabrice
Published: October 2024

Identification of noninvasive prognostic biomarkers, allowing monitoring of frequently developed relapse in patients with locally advanced non-small cell lung cancer (NSCLC), still of primary importance. Tumor-draining vein (TDV) plasma samples, are known to be enriched in circulating cancer biomarkers compared to samples from peripheral vein (PV). Thus, we thought to investigate the proteomic profile of extracellular vesicles (EVs) from TDV compared to those from PV plasma samples of patients operated for NSCLC.

Purified EVs from TDV and PV plasma samples were characterized for their size distribution and concentration using nanoparticles tracking analysis (NTA). Proteomic profiling of TDV-derived EVs and PV-derived EVs were further done using mass spectrometry (nanoLC-MS/MS) analysis. In parallel, proteomic profile of tumoral and non-tumoral adjacent counterpart tissues from patients with NSCLC were investigated.

Twenty patients with NSCLC, treated by surgery with curative intent, were enrolled in this study. We showed that EVs from TDV plasma samples were significantly smaller than those from PV plasma samples. Interestingly, the concentration of TDV-derived EVs were significantly higher than PV-derived EVs. However, EVs concentration and size were not associated with tumor size or other clinical characteristics. Proteomic profiling showed that 9 of the 10 most overexpressed proteins in EVs from TDV samples compared to those from PV, were associated with lung cancer diagnosis and prognosis. Remarkably, 1 protein (SRPRB) was commonly upregulated in lung tumor tissues (as compared to non-tumoral counterparts) and in TDV-derived EVs (as compared to PV-derived EVs). In contrast, 12 proteins were found to be upregulated in TDV-derived EVs and downregulated in tumor tissues.

In conclusion, all of these identified proteins, carried by EVs from TDV plasma samples, might represent promising novel biomarkers for NSCLC prognosis and predicting recurrences at early stages.
Assessing Technical College Students’ Biology Proficiency as Related to Gender and Performance in Biology in Nigeria
Authors: Sowunmi Kehinde , Enoch Ajoa Iyanu , Uchenna Ogbonnaya
Published: October 2024

This study investigated biology proficiency in relation to gender and performance among 350 Nigerian technical college students from 5 elitist technical colleges in Lagos State, employing a quantitative research method within a descriptive survey design. Data collected were analysed using descriptive statistics of frequency, percentage, mean, and standard deviation, alongside inferential statistics including independent samples t-test and multiple regression analysis. Findings revealed that technical college students from elitist schools displayed a high level of biology proficiency. Significant correlations were found among students conceptual understanding, procedural knowledge, strategic competence, adaptive reasoning, productive disposition, and overall performance in biology. While gender differences in biology proficiency appear to be diminishing across most subscales, subtle gender differences were observed in performance in biology in this study. Gender, conceptual understanding, productive disposition, adaptive reasoning, strategic competence, and procedural knowledge made statistically significant contributions to the variance in technical college students performance in biology. Based on this baseline study, it is recommended that future research in Nigeria should explore the biology proficiency of non-elitist schools, which constitute the majority of educational institutions in the country, to enable broader generalization of these findings.
Temperate phages increase antibiotic effectiveness in aCaenorhabditis elegansinfection model
Authors: Fatima Rabia , MacNeil Lesley T. , Hynes Alexander P.
Published: October 2024

The bactericidal nature of obligately lytic bacterial viruses (phages) is of increasing interest for the treatment of drug-resistant bacterial infections, either administered alone or in combination with antibiotics. In contrast, temperate phages are largely ignored in a therapeutic context due to their ability to lie dormant within the bacterial host. However, these phages often undergo a lytic cycle. Furthermore, even in their dormant state their carriage can be a considerable burden to the bacterium – most famously by their ability to switch to lytic replication in response to environmental triggers, such as antibiotics, that stress the bacterial host. Recent reports of antibiotics synergizing uniquely with temperate phagesin vitro, termed “temperate phage antibiotic synergy” (tPAS), present a potentially scalable opportunity to make use of these abundant entities for the treatment of bacterial infections. Here we employCaenorhabditis elegansas a robustin vivoanimal model for testing the efficacy of temperate phages as adjuvants to antibiotics.In vivo, the antibiotic ciprofloxacin can abolish dormancy of temperate phage Hali - infecting a ciprofloxacin resistantPseudomonas aeruginosaclinical strain - while in the absence of the antibiotic dormancy events explain 60% of the bacterial survivors. The Phage Hali-ciprofloxacin pairing increased the lifespan ofP. aeruginosainfected worms to that of the uninfected control, at doses where neither the phage nor the antibiotic had any effect alone. Complete rescue was also observed in worms infected with a phage-carrying strain treated with the otherwise ineffective antibiotic, supporting that the phage - even in its dormant form - can greatly enhance antibiotic effectiveness. This illustrates potential “accidental” phage therapy when antibiotics are normally prescribed. Our work establishesC. elegansas a suitable model for studying thein vivoefficacy of tPAS and is the firstin vivodemonstration of this synergy, greatly expanding the therapeutic potential of temperate phages.
Age, sex, and mitochondrial-haplotype influence gut microbiome composition and metabolites in a genetically diverse rat model
Authors: Nguyen Hoang Van M. , Cabello Eleana , Dyer David , Fender Chloe , Garcia-Jaramillo Manuel , Hord Norman G. , Austad Steven , Richardson Arlan , Unnikrishnan Archana
Published: October 2024

We evaluated the impact of sex and mitochondrial-haplotype on the age-related changes in the fecal gut microbiome of the genetically heterogeneous rodent model, the OKC-HETB/Wrat. Alpha-diversity, measuring richness and evenness of gut microbiome composition, did not change with age or mitochondrial-haplotype. However, beta-diversity, a measure of microbial differences among samples, was significantly modulated by age in male and female rats in both mitochondrial-haplotypes. The age-related changes in the microbiome differed markedly between male and female rats. Five microbial species changed significantly with age in male rats compared to nine microbial species in female rats. Only three of these microbes changed with age in both male and female rats. The mitochondrial-haplotype of the rats also affected how aging altered the microbiome. Interestingly, most of the microbial species that changed significantly with age were mitochondrial-haplotype and sex specific, i.e., changing in one sex and not the other. We also discovered that sex and mitochondrial-haplotype significantly affected the age-related variations in content of fecal short-chain fatty acids and plasma metabolites that influence or are regulated by the microbiome, e.g., tryptophan derived metabolites and bile acids. This study demonstrates that the host’s sex plays a significant role in how the gut microbiome evolves with age, even within a genetically diverse background. Importantly, this is the first study to show that the mitochondrial-haplotype of a host impacts the age-related changes in the microbiome and supports previous studies suggesting a bidirectional interaction between the gut microbiome and host mitochondria.

Highlights

Most age-related changes in microbial species occurred in one sex but not the other

Mitochondrial-haplotype altered the microbiome and was generally sex dependent

Microbiome associated metabolites differed by age, sex, and mitochondria-haplotype
Health outcomes after national acute sleep deprivation events among the American public
Authors: Kelly Neil J. , Chaudhary Rahul , El Khoury Wadih , Kalepalli Nishita , Wang Jesse , Patel Priya , Chan Irene N. , Rahman Haris , Saiyed Aisha , Shah Anisha N. , McClung Colleen A. , Okawa Satoshi , Nouraie Seyed Mehdi , Chan Stephen Y.
Published: October 2024

Background

Sleep is increasingly recognized as essential to human health, yet the adverse health consequences of acute sleep deprivation are unknown. Using actigraphic, genomic, and health data from theAll of Us(AoU) Research Program, we characterized the detrimental health consequences of acute sleep deprivation in the American public.

Methods

LOESS smoothing was performed on sleep estimates from Fitbit users (N = 14,681) between June 1, 2016 and July 1, 2022. Dates when population minutes slept were less than the 90% confidence interval of the LOESS regression were named acute sleep deprivation events (ASDEs). Phenome-wide disease incidence among theAoUpopulation (N = 287,012) in the 10 days post-ASDE was compared to a preceding reference period by McNemar test. Circadian rhythm and sleep duration-associated SNPs were screened to identify genotypes associated with shorter ASDE sleep duration. Influences of sleep and circadian genotype on post-ASDE influenza risk were modeled using binomial family generalized estimating equations.

Findings

We identified 32 ASDEs spanning political and non-political events. A phenome-wide screen found increased risk of influenza (OR = 1.54 [1.40, 1.70],P-value = 1.00 x 10-18) following ASDEs. 56 SNPs were associated with decreased sleep duration on ASDEs. Higher quantiles of ASDE-related SNP genotype burden were associated with less ASDE sleep duration and a greater risk of influenza-associated healthcare visits.

Interpretation

National political and non-political events are associated with acute sleep deprivation and greater influenza risk which is amplified by sleep genotypes. These findings should inform public health vigilance surrounding major national events.
Essential role of Hepcidin in host resistance to disseminated candidiasis
Authors: Arekar Tanmay , Katikaneni Divya , Kasem Sadat , Desai Dhruv , Acharya Thrisha , Cole Augustina , Khodayari Nazli , Vaulont Sophie , Hube Bernhard , Nemeth Elizabeta , Drakesmith Alexander , Lionakis Michail S , Mehrad Borna , Scindia Yogesh
Published: October 2024

Candida albicansis a leading cause of life-threatening invasive infections with up to 40% mortality rates in hospitalized individuals despite antifungal therapy. Patients with chronic liver disease are at an increased risk of candidemia, but the mechanisms underlying this susceptibility are incompletely defined. One consequence of chronic liver disease is attenuated ability to produce hepcidin and maintain organismal control of iron homeostasis. To address the biology underlying this critical clinical problem, we demonstrate the mechanistic link between hepcidin insufficiency and candida infection using genetic and inducible hepcidin knockout mice. Hepcidin deficiency led to unrestrained fungal growth and increased transition to the invasive hypha morphology with exposed 1,3, β-glucan that exacerbated kidney injury, independent of the fungal pore-forming toxin candidalysin in immunocompetent mice. Of translational relevance, the therapeutic administration of PR-73, a hepcidin mimetic, improved the outcomes of infection. Thus, we identify hepcidin deficiency as a novel host susceptibility factor againstC. albicansand hepcidin mimetics as a potential intervention.
Task-irrelevant features in working memory alter current visual processing
Authors: Shi Hongqiao , Zhang Qiqi , Zhou Jieyudong , Ding Yue , Wang Yonghui , Li Ya
Published: October 2024

Abstract

Higher-level cognition depends on visual working memory (VWM), the ability of our brain to maintain and manipulate internal representations of images that are no longer presented to us. An important question in this field is whether VWM is represented in a sensory or nonsensory manner. Progress has been made in understanding the features to be remembered, but the representational nature of the memory-irrelevant features is unclear. Here, we used a dual-task paradigm to investigate how and when the memory-irrelevant features interact with the concurrent visual information. In a series of experiments, participants were asked to perform a visual search task (Experiment 1) or a perceptual discrimination task (Experiments 2 and 3) involving a memory- irrelevant feature while simultaneously holding the other feature for later retrieval. Experiment 1 showed that VWM biases the allocation of attention to color matching to the memory-irrelevant color. More importantly, the degree of VWM-biased attention decreased monotonically with decreasing feature similarity, and this behavioral monotonic gradient profile resembled the tuning curve of feature-selective neurons in the early visual cortex. Experiment 2 revealed that irrelevant features biased ongoing perception, as indicated by the shifted discrimination threshold. Experiment 3 further demonstrated that VWM-biased perception occurs only at short delays but not at prolonged delays. Our results suggest that the memory-irrelevant feature is represented as a sensory analog for a limited period of time in the visual areas where it was initially processed. Our results extend sensory recruitment theory to memory-irrelevant features in VWM.
Resistance of E2F4DN to p38MAPKphosphorylation attenuates DNA damage-induced neuronal death via Cited2
Authors: Llabrés-Mas Aina María , Garrido-García Alberto , Cano-Daganzo Vanesa , Frade José M.
Published: October 2024

E2F4, a transcription factor with a prominent role in cell homeostasis, can be phosphorylated by the stress kinase p38MAPKat the Thr248/Thr250 motif, while the Thr248Ala/Thr250Ala E2F4 mutant (E2F4DN) triggers multifactorial therapeutic effects in a murine model of Alzheimer’s disease. We hypothesized that the mechanism of action of this therapy relays on the phosphorylation of the Thr248/Thr250 motif under stress conditions, which prevents the homeostatic function of E2F4, while exogenous E2F4DN expression can restore this function. To provide support to this hypothesis, we have focused on genotoxicity induced by camptothecin (CPT) in N2a neuroblastoma-derived neurons, as a paradigm of cell stress followed by cell death. Here we show that, in these cells, p38MAPKbecomes activated 6 h after CPT treatment, followed by E2F4 phosphorylation in the Thr248/Thr250 motif. The effect of this phosphorylation in apoptosis was tested by overexpressing wild-type E2F4 (E2F4WT), its Thr248Glu/Thr250Glu phosphomimetic (E2F4CA) or E2F4DN in CPT-treated N2a neurons, followed by quantification of procaspase-3 cleavage. E2F1, which was used as a positive control, induced a statistically-significant increase of procaspase-3 cleavage 32 h after CPT treatment. This was mimicked by either E2F4WT or E2F4CA, while E2F4DN expression inhibited this effect through a Cited2-dependent mechanism. Pharmacological p38MAPKinhibition prevented cell death by E2F4WT but not by E2F4CA, confirming the requirement of E2F4 phosphorylation for cell death in these cells. We conclude that the phosphorylation of E2F4 facilitates the death of N2a neurons carrying DNA damage, while E2F4DN maintains the homeostatic function of E2F4 under stress conditions.
A Nostalgia Brain-Music Interface for Enhancing Nostalgia, Well-Being, and Memory Vividness in Young and Elderly Individuals
Authors: Sakakibara Yuna , Kusutomi Tomohiro , Kondoh Sotaro , Etani Takahide , Shimada Saori , Imamura Yasuhiko , Naruse Yasushi , Fujii Shinya , Ibaraki Takuya
Published: October 2024

Music-evoked nostalgia has the potential to assist in recalling autobiographical memories and enhancing well-being. However, nostalgic music preferences vary from person to person, presenting challenges for applying nostalgia-based music interventions in clinical settings, such as a non-pharmacological approach. To address these individual differences, we developed the Nostalgia Brain-Music Interface (N-BMI), a neurofeedback system that recommends nostalgic songs tailored to each individual. This system is based on prediction models of nostalgic feelings, developed by integrating subjective nostalgia ratings, acoustic features and in-ear electroencephalographic (EEG) data during song listening. To test the effects of N-BMI on nostalgic feelings, well-being, and memory recall, seventeen elderly and seventeen young participants took part in the study. The N-BMI was personalized for each individual, and songs were recommended under two conditions: the "nostalgia condition", where songs were selected to enhance nostalgic feelings, and the "control condition", to reduce nostalgic feelings. We found nostalgic feelings, well-being, and memory vividness were significantly higher after listening to the recommended songs in the nostalgia condition compared to the control condition in both groups. This indicates that the N-BMI enhanced nostalgic feelings, well-being, and memory recall across both groups. The N-BMI paves the way for innovative therapeutic interventions, including non-pharmacological approaches.
Pup defence in lactating rats: The underlying neuropeptide signalling and their interactions in the nucleus accumbens shell
Authors: Sanson Alice , Köck Annika , Demarchi Luisa , Ebner Karl , Bosch Oliver J.
Published: October 2024

Maternal aggression is a core feature of rodent maternal behaviour to defend their offspring from potential threats and is modulated by corticotropin-releasing factor (CRF) and oxytocin (OXT) systems signalling. Here, we investigated the involvement of those neuropeptide systems in maternal aggression within the nucleus accumbens shell (NAcSh), a central region of the reward and maternal circuits. Infusion of CRF or Urocortin3 (CRF-receptor 2 agonist), as well as an OXT receptor antagonist, reduced maternal aggression, suggesting a role in pup defence. Furthermore, the effects of CRF infusion in the NAcSh continued beyond the maternal defence test (MDT), reducing nursing and increasing self-grooming. Corroborating the involvement of the stress system in maternal aggression, colocalization of CRF and cFos immunoreactive cells were increased in response to the MDT, regardless of pup presence. In addition, MDT exposure increased intra-NAc OXT release in lactating rats, which could be also triggered by local retrodialysis of CRF, but not Urocortin3. However, both ligands of the CRF system elicited dopamine (DA) release in different dynamics.Crh-r1 werepredominantly expressed in the medial NAc on medium-sized spiny neurons (MSN), but also in the rostral part on GABAergic interneurons.Crh-r2were mainly expressed in the rostral NAc and its expression on GABAergic interneurons increased towards the caudal pole. Lastly, we identified CRF-enriched projections to the NAcSh descending from the prefrontal cortex, the amygdala, and the paraventricular thalamus, among others.

In conclusion, intra-NAcSh dampened CRF system activity and enhanced OXT system transmission are indispensable for successful pup defence. Any perturbations like increased CRF system signalling might activate compensatory mechanisms to ensure adequate maternal behaviour.
Novel hepatocyte-like liver organoids recapitulate crucial mature hepatic functions
Authors: Ardisasmita A. I. , Joore I. P. , Levy N. , Myszczyszyn A. , Marsee A. , Sinnige T. , Ruiter J. , Ferdinandusse S. , Dudaryeva O. , Gruber E. , Daive V. , Levato R. , Spee B , Verstegen M.M.A. , van der Laan L.J.W. , Nieuwenhuis E. E. S. , Schene I. F. , Fuchs S. A.
Published: October 2024

Accurate liver disease modeling and drug toxicity testing still remain challenging as liver cellsin vitropoorly resemble adult hepatocytes, as we previously demonstrated using whole transcriptome and cell identity analysis. To address this, we used our insights into hepatic modeling to develop hepatocyte-like liver organoids (HeLLOs), a novel human organoid model with mature hepatocyte functions superior to existing models. HeLLOs are easily established from (small) healthy or diseased liver tissues and rapidly expanded for an extended period in optimized culture conditions. Transcriptomic and functional analyses revealed that differentiated HeLLOs closely resemble fresh primary human hepatocytes (PHHs) and perform key hepatic functions such as gluconeogenesis, drug metabolism, and bile acid synthesis. We developed a HeLLO-based toxicity assay with higher sensitivity in predicting liver toxicity of known liver-toxic drugs compared to the gold-standard PHHs. By modeling disease-related mechanisms, such as bile acid transport, HeLLOs uncover transport-inhibition toxicity mechanisms of known liver toxic drugs. Single cell sequencing analysis of HeLLOs identified a heterogeneous cluster of cells with cholangiocyte-like and hepatocyte-like cells, overall resembling liver regenerative cells. As such, HeLLOs hold great promise for advancing liver disease modeling and drug testing. To our knowledge, HeLLOs are the best expandable liver model for predicting adverse drug reactions as well as modeling various liver disease mechanisms.
Mechanochemical Patterning Localizes the Organizer of a Luminal Epithelium
Authors: Weevers Sera Lotte , Falconer Alistair D. , Mercker Moritz , Sadeghi Hajar , Ferenc Jaroslav , Ott Albrecht , Oelz Dietmar B. , Marciniak-Czochra Anna , Tsiairis Charisios D.
Published: October 2024

The spontaneous emergence of tissue patterns is often attributed to biochemical reaction-diffusion systems. InHydratissue regeneration, the formation of a Wnt signaling center serves as a well-known example of such a process. However, despite extensive research, a strictly biochemical mechanism for self-organization inHydraremains elusive. In this study, we investigated mechanical stimuli and identified a positive feedback loop between Wnt signaling and tissue stretching. We developed a mathematical model of mechanochemical pattern formation in a closed elastic shell, representing regeneratingHydraepithelial spheroids. Our model explains how mechanical forces drive axis formation and predicts the organizer’s location under various perturbations, providing a more comprehensive understanding of the spatial dynamics involved. Validation by partially confining regenerating tissues showed that the organizer indeed forms in regions with the greatest stretching potential. This work highlights a novel mechanochemical mechanism for luminal epithelium patterning, suggesting that mechanical forces, in addition to biochemical signals, play a crucial role in tissue regeneration and axis specification. Our findings offer broader implications for the role of mechanical forces in tissue organization in various biological systems, opening new avenues for investigating mechanochemical feedback in development and regeneration.
Dynamic imbalances in cell-type specific striatal ensemble activity during visually guided locomotion
Authors: Fearey Brenna , Tong Yuxin , Alexander Andrew , Graham Ben , Howe Mark
Published: October 2024

Locomotion is continuously regulated by an animal’s position within an environment relative to goals. Direct and indirect pathway striatal output neurons (dSPNs and iSPNs) influence locomotion, but how their activity is naturally coordinated by changing environments is unknown. We found, in head-fixed mice, that the relative balance of dSPN and iSPN activity was dynamically modulated with respect to position within a visually-guided locomotor trajectory to retrieve reward. Imbalances were present within ensembles of position-tuned SPNs which were sensitive to the visual environment. Our results suggest a model in which competitive imbalances in striatal output are created by learned associations with sensory input to shape context dependent locomotion.
Directed evolution of the multicopper oxidase laccase for cell surface proximity labeling and electron microscopy
Authors: Lee Song-Yi , Roh Heegwang , Gonzalez-Perez David , Mackey Mason R. , Kim Keun-Young , Hoces Daniel , McLaughlin Colleen N. , Adams Stephen R. , Nguyen Khanh , Luginbuhl David J. , Luo Liqun , Udeshi Namrata D. , Carr Steven A. , Hernández-López Rogelio A. , Ellisman Mark H. , Alcalde Miguel , Ting Alice Y.
Published: October 2024

Enzymes that oxidize aromatic substrates have shown utility in a range of cell-based technologies including live cell proximity labeling (PL) and electron microscopy (EM), but are associated with drawbacks such as the need for toxic H2O2. Here, we explore laccases as a novel enzyme class for PL and EM in mammalian cells. LaccID, generated via 11 rounds of directed evolution from an ancestral fungal laccase, catalyzes the one-electron oxidation of diverse aromatic substrates using O2instead of toxic H2O2, and exhibits activity selective to the surface plasma membrane of both living and fixed cells. We show that LaccID can be used with mass spectrometry-based proteomics to map the changing surface composition of T cells that engage with tumor cells via antigen-specific T cell receptors. In addition, we use LaccID as a genetically-encodable tag for EM visualization of cell surface features in mammalian cell culture and in the fly brain. Our study paves the way for future cell-based applications of LaccID.
Memory System Maladaptation Impairs CA1-Dependent Temporal Binding and Declarative Memory in the Cntnap2 Knockout Mouse Model of Autism
Authors: Rawlinson Elise C. , McCullough Michael H. , Sellami Azza , Marighetto Aline , Al Abed A. Shaam , Dehorter Nathalie
Published: October 2024

Growing evidence implicates the hippocampus in the pathophysiology of autism spectrum disorder, particularly in the domains of social interactions and cognition. Yet, the mechanisms driving hippocampal-dependent cognitive atypicalities in autism remain poorly defined. Here, we characterize how dysfunction of the CA1 subfield of the dorsal hippocampus (dCA1) impacts critical components of declarative memory. Using trace fear conditioning combined within vivofiber photometry in theCntnap2knockout mouse model of autism, we found that capabilities to bridge temporally distant stimuli, i.e. temporal binding capabilities, were reduced relative to wildtype mice. This impairment was associated with decreased dCA1 activity during temporal gaps. Using a relational/declarative memory task, we also revealed a deficit in flexible spatial memory, a preferential use of egocentric learning strategy. This unflexible learning strategy resulted from the imbalance between memory system activity, promoting frontostriatal-dependent procedural learning instead of dorsal dCA1/hippocampus-dependent relational/declarative memory. Overall, this study elucidates how memory systems are mistuned in theCntnap2knockout mouse model, opening new avenues for understanding and addressing atypical learning in autism.
Neural dynamics in the orbitofrontal cortex reveal cognitive strategies
Authors: Schiereck Shannon S. , Pérez-Rivera Danilo Trinidad , Mah Andrew , DeMaegd Margaret L. , McMahon Ward Royall , Hocker David , Savin Cristina , Constantinople Christine M.
Published: October 2024

Behavior is sloppy: a multitude of cognitive strategies can produce similar behavioral read-outs. An underutilized approach is to combine multifaceted behavioral analyses with neural recordings to resolve cognitive strategies. Here we show that rats performing a decision-making task exhibit distinct strategies over training, and these cognitive strategies are decipherable from orbitofrontal cortex (OFC) neural dynamics. We trained rats to perform a temporal wagering task with hidden reward states. While naive rats passively adapted to reward statistics, expert rats inferred reward states. Electrophysiological recordings and novel methods for characterizing population dynamics identified latent neural factors that reflected inferred states in expert but not naive rats. In experts, these factors showed abrupt changes following single trials that were informative of state transitions. These dynamics were driven by neurons whose firing rates reflected single trial inferences, and OFC inactivations showed they were causal to behavior. These results reveal the neural signatures of inference.
Structural landscape of engineered multivalent antibody fragments and their application as crystallization scaffolds
Authors: Kedari Ashwini , Hannula Liina , Jayachandran Rupesh Balaji , Rissanen Ilona
Published: October 2024

Multivalent recombinant antibody fragments, “multibodies”, are produced by fusing antibody VH and VL domains and provide the ability to bind multiple antigens simultaneously. The oligomeric state of a multibody is believed to be determined by the length of the linker region between the V-domains, with longer linkers resulting in diabodies (60 kDa) and shorter linkers leading to the formation of triabodies (90 kDa), tetrabodies (120 kDa), and larger oligomers. In this work, we investigate this design space by engineering multibodies from the sequences of human mAbs CR57 and Imdevimab, and resolve their crystal structures at 2.25 Å and 2.55 Å resolution, respectively. Our results show that despite minimizing the length of the hinge region between the V-domains, these constructs form diabodies. This indicates that linker length is not the sole determinant of a multibody’s oligomeric state, and additional factors such as the mAb origin species and light chain type must also be taken into account when designing multibodies. Moreover, we confirmed that the native paratope of the antibody is well- maintained in the diabody format, and conducted a proof-of-concept trial comparing the crystallization propensity of a diabody versus a Fab in antibody-antigen complex crystallization. Our results show that a diabody can promote crystallization more effectively than a Fab, demonstrating the potential of diabodies as crystallization scaffolds for antibody- antigen complexes.
Markers, Mechanisms and Metrics of Biological Aging: A Scoping Review
Authors: Ziesel Alison , Reeves Jennifer , Mallidou Anastasia , Newton Lorelei , Rhodes Ryan , Zhang Jie , Paterson Theone , Jabbari Hosna
Published: October 2024

Biological aging is a rapidly growing area of research, which entails characterizing the rate of aging independent of an individual’s chronological age. In this review, we analyze the results of biological aging research in 435 papers published in a twelve year window, revealing changing patterns of molecular markers of biological aging use over time, and the development of novel metrics of biological aging. We further identify consistent and discordant research findings, as well as areas of potential future research focusing on questions of measurement with methylation or biomarker-based assessment and other variables relevant to the study of biological age.