bluuebunny/crossref_metadata_2025 huggingface dataset:
BLEND: Probabilistic Cellular Deconvolution with Automated Reference Selection
Authors: Huang Penghui , Cai Manqi , McKennan Christopher , Wang Jiebiao
Published: August 2024

Cellular deconvolution aims to estimate cell type fractions from bulk transcriptomic and other omics data. Most existing deconvolution methods fail to account for the heterogeneity in cell type-specific (CTS) expression across bulk samples, ignore discrepancies between CTS expression in bulk and cell type reference data, and provide no guidance on cell type reference selection or integration. To address these issues, we introduce BLEND, a hierarchical Bayesian method that leverages multiple reference datasets. BLEND learns the most suitable references for each bulk sample by exploring the convex hulls of references and employs a "bag-of-words" representation for bulk count data for deconvolution. To speed up the computation, we provide an efficient EM algorithm for parameter estimation. Notably, BLEND requires no data transformation, normalization, cell type marker gene selection, or reference quality evaluation. Benchmarking studies on both simulated and real human brain data highlight BLEND's superior performance in various scenarios. The analysis of Alzheimer's disease data illustrates BLEND's application in real data and reference resource integration.
Fallow deer approaching humans are also more likely to be seropositive forToxoplasma gondii
Authors: Ryan Andrew R. , Zintl Annetta , Griffin Laura L. , Quinn Matthew , Haigh Amy , Sabbatini Pietro , Amin Bawan , Ciuti Simone
Published: August 2024

Toxoplasma gondii(T. gondii) is a trophically-transmitted protozoan parasite that has been suggested to facilitate its transmission by altering intermediate hosts’ anti-predator behaviour, thus increasing the likelihood of completing the cycle inside its definitive host i.e. domestic and wild felines.T. gondiihas been linked to reduced risk-aversion, slower reaction times, and more exploratory behaviours in intermediate hosts, including most famously weakened aversion to the scent of feline predators in mice. Studies examining this phenomenon, however, have almost exclusively been carried out in laboratory conditions with small mammals, whereas little is known about the role ofT. gondiiwithin more complex ecological contexts involving large mammals in the wild. Under such scenario, the goals of our study were three-fold. Firstly, to determine the prevalence ofT. gondiiinfection in a population of free-living fallow deer (Dama dama) living in a park at the edge of a metropolis. Secondly, to find a link between deer seropositivity and space use in the park, namely proximity to buildings with domestic cats, where deer may have been more likely to contract the disease. Finally, to determine whether infection withT. gondiiwas linked to risk taking behaviour in these free ranging large mammals, namely likelihood to approach park visitors. To achieve our goals, we estimated seropositivity and combined it with spatial distribution and behavioural data of individually-recognizable deer ranging from those that avoid humans (risk-avoiders) to those who beg for food (risk-takers). We foundT. gondiito be quite widespread in this population with a seropositive of 20% (24 out of 120 individuals). Contrary to our expectations, we found no correlation betweenT. gondiiseropositivity and space use in the park, therefore not allowing us to engage with the dynamics of disease contraction. We did however find that fallow deer taking the risk of approaching humans were also more likely to be seropositive. Are risk taking individuals more likely to contract the disease? Or, alternatively, do they take more risk because they have contracted the disease? The causal mechanism behind our result has yet to be disentangled, opening new scenarios in research aimed at tackling host manipulation in this parasite. It is a fact, however, that those animals that were more likely to be in contact with the public were also those more likely to be seropositive, adding key empirical evidence to the study of zoonotic diseases. Our study is a significant contribution on the transmission and maintenance dynamics ofT. gondii, offering new insights on the need to conduct longitudinal studies able to disentangle the causal mechanism andT. gondii’s ability to manipulate its intermediate host.
Movement responses to lethal risk: an integrative analysis of proactive and reactive antipredator behaviours in a large herbivore
Authors: Vanderlocht Charlotte , Robira Benjamin , Corradini Andrea , Farra Simone Dal , Ossi Federico , Righetti Davide , Hauffe Heidi C. , Pedrotti Luca , Cagnacci Francesca
Published: August 2024

Prey species can display antipredation movement behaviours to reduce predation risk including proactive responses to chronic or predictable risk, and reactive responses to acute or unpredictable risk. Thus, at any given time, prey movement choice may reflect the trade-off between proaction and reaction. In previous studies, proaction and reaction have generally been considered separately, which neglects their simultaneous influence on animal decisions. In this study, we analysed how proaction and reaction interact to shape the movements of GPS-collared red deer (Cervus elaphus), in response to human hunting of conspecifics. Our results show that red deer proactively selected canopy cover where and when risk was predictably high. However, when they were unable to avoid risk, canopy cover was no longer selected, but only modulated a reactive response along a freeze-to-escape continuum. This reaction was even more evident when the environment was unfamiliar, underlining the importance of memory in such reaction patterns. Therefore, to our knowledge, for the first time, we describe how proaction and reaction fuse in anantipredation sequenceof interconnected movement decisions in a large herbivore, and we lay the foundations for further investigations into the evolutionary origins of similarities and differences between proactive and reactive behaviours.
UniPTM: Multiple PTM site prediction on full-length protein sequence
Authors: Meng Lingkuan , Lin Jiecong , Cheng Ke , Xu Kui , Sun Hongyan , Wong Ka-Chun
Published: August 2024

Abstract

Post-translational modifications (PTMs) enrich the functional diversity of proteins by attaching chemical groups to the side chains of amino acids. In recent years, a myr-iad of AI models have been proposed to predict many specific types of PTMs. However, those models typically adopt the sliding window approach to extract short and equal-length protein fragments from full-length proteins for model training. Unfortunately, such a subtle step results in the loss of long-range information from distal amino acids, which may impact the PTM formation process. In this study, we introduce UniPTM, a window-free model designed to train and test on natural and full-length protein sequences, enabling the prediction of multiple types of PTMs in a holistic manner. Moreover, we established PTMseq, the first comprehensive dataset of full-length pro-tein sequences with annotated PTMs, to train and validate our model. UniPTM has undergone extensive validations and significantly outperforms existing models, eluci-dating the influence of protein sequence completeness on PTM. Consequently, UniPTM offers interpretable and biologically meaningful predictions, enhancing our understand-ing of protein functionally and regulation. The source code and PTMseq dataset for UniPTM are available athttps://www.github.com/TransPTM/UniPTM.
3D histology reveals that immune response to pancreatic precancers is heterogeneous and depends on global pancreas structure
Authors: Kiemen Ashley L. , Almagro-Pérez Cristina , Matos Valentina , Forjaz Andre , Braxton Alicia M. , Dequiedt Lucie , Parksong Jeeun , Cannon Courtney D. , Yuan Xuan , Shin Sarah M. , Babu Jaanvi Mahesh , Thompson Elizabeth D. , Cornish Toby C. , Ho Won Jin , Wood Laura D. , Wu Pei-Hsun , Muñoz Barrutia Arrate , Hruban Ralph H. , Wirtz Denis
Published: August 2024

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer for which few effective therapies exist. Immunotherapies specifically are ineffective in pancreatic cancer, in part due to its unique stromal and immune microenvironment. Pancreatic intraepithelial neoplasia, or PanIN, is the main precursor lesion to PDAC. Recently it was discovered that PanINs are remarkably abundant in the grossly normal pancreas, suggesting that the vast majority will never progress to cancer. Here, through construction of 48 samples of cm3-sized human pancreas tissue, we profiled the immune microenvironment of 1,476 PanINs in 3D and at single-cell resolution to better understand the early evolution of the pancreatic tumor microenvironment and to determine how inflammation may play a role in cancer progression.

We found that bulk pancreatic inflammation strongly correlates to PanIN cell fraction. We found that the immune response around PanINs is highly heterogeneous, with distinct immune hotspots and cold spots that appear and disappear in a span of tens of microns. Immune hotspots generally mark locations of higher grade of dysplasia or locations near acinar atrophy. The immune composition at these hotspots is dominated by naïve, cytotoxic, and regulatory T cells, cancer associated fibroblasts, and tumor associated macrophages, with little similarity to the immune composition around less-inflamed PanINs. By mapping FOXP3+ cells in 3D, we found that regulatory T cells are present at higher density in larger PanIN lesions compared to smaller PanINs, suggesting that the early initiation of PanINs may not exhibit an immunosuppressive response.

This analysis demonstrates that while PanINs are common in the pancreases of most individuals, inflammation may play a pivotal role, both at the bulk and the microscopic scale, in demarcating regions of significance in cancer progression.
Metabolic Segregation and Functional Gene Clusters in Anaerobic Digestion Consortia
Authors: Wang Yubo , Zhang Ruoqun , Wang Chunxiao , Yan Weifu , Zhang Tong , Ju Feng
Published: August 2024

Enrichment experiment integrated with genome-centric meta-omics analysis revealed that metabolic specificity, rather than metabolic flexibility, governs the anaerobic digestion (AD) ecosystem. This study provides new insights into interspecies electron transfer in the AD process, highlighting a segregation in the metabolism of H₂ and formate. Our findings indicate that H₂ serves as the primary electron sink for recycling redox cofactors, NAD⁺ and oxidized ferredoxin (Fdox), during primary fermentation. In contrast, formate predominates in the co-occurring secondary fermentation, particularly under conditions of elevated H₂ concentrations. Notably, no evidence of biochemical interconversion between H₂ and formate was identified in the primary fermenting bacteria or in syntrophs enriched in this study. This segregation of H₂ and formate metabolism likely benefit the anaerobic oxidation of butyrate and propionate with a higher tolerance to H₂ accumulation. Furthermore, this study underscores the functional partitioning among microbial populations within key niches of the AD bioprocess: primary fermentation, secondary fermentation (syntrophic acetogenesis), hydrogenotrophic methanogenesis, and acetoclastic methanogenesis. Through genome-centric analysis of the AD microbiome, we identified several key functional gene clusters, highlighting the potential for improving genome-centric genotype-phenotype correlations, which is particularly valuable for strict anaerobes that remain challenging to isolate and characterize in pure culture.
Pertpy: an end-to-end framework for perturbation analysis
Authors: Heumos Lukas , Ji Yuge , May Lilly , Green Tessa , Zhang Xinyue , Wu Xichen , Ostner Johannes , Peidli Stefan , Schumacher Antonia , Hrovatin Karin , Müller Michaela , Chong Faye , Sturm Gregor , Tejada Alejandro , Dann Emma , Dong Mingze , Bahrami Mojtaba , Gold Ilan , Rybakov Sergei , Namsaraeva Altana , Moinfar Amir , Zheng Zihe , Roellin Eljas , Mekki Isra , Sander Chris , Lotfollahi Mohammad , Schiller Herbert B. , Theis Fabian J.
Published: August 2024

Advances in single-cell technology have enabled the measurement of cell-resolved molecular states across a variety of cell lines and tissues under a plethora of genetic, chemical, environmental, or disease perturbations. Current methods focus on differential comparison or are specific to a particular task in a multi-condition setting with purely statistical perspectives. The quickly growing number, size, and complexity of such studies requires a scalable analysis framework that takes existing biological context into account. Here, we present pertpy, a Python-based modular framework for the analysis of large-scale perturbation single-cell experiments. Pertpy provides access to harmonized perturbation datasets and metadata databases along with numerous fast and user-friendly implementations of both established and novel methods such as automatic metadata annotation or perturbation distances to efficiently analyze perturbation data. As part of the scverse ecosystem, pertpy interoperates with existing libraries for the analysis of single-cell data and is designed to be easily extended.
Circular RNAs exhibit exceptional stability in the aging brain and serve as reliable age and experience indicators
Authors: Kirio Ken , Patop Ines , Anduaga Ane Martin , Harris Jenna , Pamudurti Nagarjuna , Martel Claire , Kadener Sebastian
Published: August 2024

Circular RNAs (circRNAs) comprise a large class of stable RNAs produced through backsplicing. While circRNAs have been shown to be very stable in cell culture, it is unknown how stable they arein vivo. Interestingly, studies across various animal systems demonstrated that circRNAs levels increase with age in neural tissue. However, the underlying reasons for this age-related accumulation are still unclear. To address these questions, we profiled circRNAs from fly heads at six timepoints across their lifespan. We found that circRNA levels increase linearly with age, independent of changes in mRNA levels, overall transcription, intron retention, or host genes splicing. This indicates that the age-related accumulation is attributed to their extraordinary stability in neural tissue rather than changes in biosynthesis. Furthermore, exposure to environmental stimuli like different temperatures, resulted in the increase but not decrease of circRNAs subsets, further confirming their stabilityin vivo. This exceptional stability implies that circRNAs can serve as markers of environmental experience. Indeed, flies subjected to a ten-day regimen at 29°C exhibit higher levels of specific brain circRNAs even six weeks after returning to standard conditions, indicating that circRNAs can reveal past environmental stimuli. Additionally, circRNA half-life measurements revealed values exceeding 20 days, with some showing no degradation over the animal’s lifetime. These findings demonstrate the extreme stability of circRNAsin vivoand their use as markers for aging, stress and life experiences.
Quantifying irreversibility of ecological systems
Authors: Li Junang , Munch Stephan B. , Tan Tzer Han , Song Chuliang
Published: August 2024

Irreversibility—the asymmetry of population dynamics when played forward versus backward in time—is a fundamental property of ecological dynamics. Despite its early recognition in ecology, irreversibility has remained a high-level and unquantifiable concept. Here, we introduce a quantitative framework rooted in non-equilibrium statistical physics to measure irreversibility in general ecological systems. Through theoretical analyses, we demonstrate that irreversibility quantifies the degree to which a system is out of equilibrium, a property not captured by traditional ecological metrics. We validate this prediction empirically across diverse ecological systems structured by different forces, such as rapid evolution, nutrient availability, and temperature. In sum, our study provides a rigorous formalism for quantifying irreversibility in ecological systems, with the potential to integrate dynamical, energetic, and informational perspectives in ecology.
Nanopore sequencing from protozoa to phages: decoding biological information on a string of biochemical molecules into human-readable signals
Authors: Hunter Branden , Cromwell Timothy , Shim Hyunjin
Published: August 2024

Biological information is encoded in a sequence of biochemical molecules such as nucleic acids and amino acids, and nanopore sequencing is a long-read sequencing technology capable of directly decoding these molecules into human-readable signals. The long reads from nanopore sequencing offer the advantage of obtaining contiguous information, which is particularly beneficial for decoding complex or repetitive regions in a genome. In this study, we investigated the efficacy of nanopore sequencing in decoding biological information from distinctive genomes in metagenomic samples, which pose significant challenges for traditional short-read sequencing technologies. Specifically, we sequenced blood and fecal samples from mice infected withTrypanosoma brucei, a unicellular protozoan known for its hypervariable and dynamic regions that help it evade host immunity. Such characteristics are also prevalent in other host-dependent parasites, such as bacteriophages. The taxonomic classification results showed a high proportion of nanopore reads identified asT. bruceiin the infected blood samples, with no significant identification in the control blood samples and fecal samples. Furthermore, metagenomic de novo assembly of these nanopore reads yielded contigs that mapped to the reference genome ofT. bruceiin the infected blood samples with over 96% accuracy. This exploratory work demonstrates the potential of nanopore sequencing for the challenging task of classifying and assembling hypervariable and dynamic genomes from metagenomic samples.
Chronic cigarette smoke exposure masks pathological features ofHelicobacter pyloriinfection while promoting tumor initiation
Authors: Morris Maeve T. , Piazuelo M Blanca , Olfert I. Mark , Xu Xiaojiang , Hussain Salik , Peek Richard M. , Busada Jonathan T.
Published: August 2024

Gastric cancer is the fifth most common cancer and the fifth leading cause of cancer deaths worldwide. Chronic infection by the bacteriumHelicobacter pyloriis the most prominent gastric cancer risk factor, but only 1-3% of infected individuals will develop gastric cancer. Cigarette smoking is another independent gastric cancer risk factor, andH. pylori-infected smokers are at a 2-11-fold increased risk of gastric cancer development, but the direct impacts of cigarette smoke onH. pyloripathogenesis remain unknown. In this study, male C57BL/6 mice were infected withH. pyloriand began smoking within one week of infection. The mice were exposed to cigarette smoke (CS) five days/week for 8 weeks. CS exposure had no notable impact on gross gastric morphology or inflammatory status compared to filtered-air (FA) exposed controls in mock-infected mice. However, CS exposure significantly bluntedH. pylori-induced gastric inflammatory responses, reducing gastric atrophy and pyloric metaplasia development. Despite blunting these classic pathological features ofH. pyloriinfection, CS exposures increased DNA damage within the gastric epithelial cells and acceleratedH. pylori-induced dysplasia onset in the INS-GAS gastric cancer model. These data suggest that cigarette smoking may clinically silence classic clinical symptoms ofH. pyloriinfection but enhance the accumulation of mutations and accelerate gastric cancer initiation.
Delineating In-Vivo T1-Weighted Intensity Profiles Within the Human Insula Cortex Using 7-Tesla MRI
Authors: Dalby Connor , Dibble Austin Jon , Carvalheiro Joana , Queirazza Filippo , Sevegnani Michele , Harvey Monika , Svanera Michele , Fracasso Alessio
Published: August 2024

The integral role of the insula cortex in sensory and cognitive function has been well documented in humans, and fine anatomical details characterising the insula have been extensively investigated ex-vivo in both human and non-human primates. However, in-vivo studies of insula anatomy in humans (in general), and within-insula parcellation (in particular) have been limited. The current study leverages 7 tesla magnetic resonance imaging to delineate T1-weighted intensity profiles within the human cortex, serving as an indirect proxy of myelination. Our analysis revealed two separate clusters of relatively high and low T1-weighted signal intensity across the insula cortex located in three distinct cortical locations within the posterior, anterior, and middle insula. The posterior and anterior cortical locations are characterised by elevated T1-weighted signal intensities, contrasting with lower intensity observed in the middle insular cortical location, compatible with ex-vivo studies. Importantly, the detection of the high T1-weighted anterior cluster is determined by the choice of brain atlas employed to define the insular ROI. We obtain reliable in-vivo within-insula parcellation at the individual and group levels, across two separate cohorts acquired in two separate sites (n1 = 21, Glasgow, UK; n2 = 101, Amsterdam, NL). These results reflect new insights into the insula anatomical structure, in-vivo, while highlighting the use of 7 tesla in neuroimaging. Specifically, the current study also paves the way to study within-insula parcellation at 7 tesla and above, and discusses further implications for individualised medicine approaches.
A hidden mark of a troubled past: neuroimaging and transcriptomic analyses reveal interactive effects of maternal immune activation and adolescent THC exposure in the absence of overt behavioural disruptions
Authors: Moreno-Fernández Mario , Luján Víctor , Baliyan Shishir , Poza Celia , Capellán Roberto , de las Heras Natalia , Morcillo Miguel Ángel , Oteo Marta , Ambrosio Emilio , Ucha Marcos , Higuera-Matas Alejandro
Published: August 2024

Maternal exposure to infections during gestation has been shown to predispose individuals to the development of schizophrenia. Additionally, clinical data suggest that cannabis use could trigger the onset of schizophrenia in vulnerable individuals. However, the direction of causality remains unclear. To elucidate this issue, we utilised a rat model of maternal immune activation, combined with exposure to increasing doses of THC during adolescence, in both male and female rats. We investigated several behaviours in adulthood that resemble specific symptoms of schizophrenia, including impairments in working memory, deficits in sensorimotor gating, alterations in social behaviour, anhedonia, and potential changes in implicit learning (conditioned taste aversion). Furthermore, we conducted a longitudinal positron emission tomography (PET) study to identify affected brain regions and subsequently collected brain samples from one of these regions (the orbitofrontal cortex) for RNA sequencing analyses. These analyses were also performed on peripheral blood mononuclear cells to identify peripheral biomarkers. Notably, while no overt behavioural disruptions were observed, our PET scans revealed several brain alterations dependent on the combination of both exposures. Additionally, the transcriptomic studies demonstrated that maternal immune activation affected glutamatergic and serotoninergic genes, with the combination of both exposures shifting the expression from down-regulation to up-regulation. In peripheral cells, interactive effects were observed on inflammatory pathways, and some genes were proposed as biomarkers of the disease. These results suggest that the combination of these two vulnerability factors leaves a lasting mark on the body, potentially predisposing individuals to the disease even before behavioural alterations manifest.
Selective epigenetic regulation of IFN-γ signature genes by JAK inhibitor in inflammatory diseases
Authors: Kwon Geunho , Park Yebin , Kang Keunsoo , Kang Kyuho
Published: August 2024

This study addresses the molecular mechanisms behind JAK inhibitors (JAKi)' epigenetic regulation of IFN-γ-induced genes in macrophages, key players in controlling inflammation in chronic diseases such as rheumatoid arthritis (RA) and COVID-19. Utilizing transcriptomic and epigenomic approaches, we reveal that JAKi selectively regulate gene programs in IFN-γ-activated human macrophages. Our single-cell analysis identified high expression of IFN-γ signature genes in macrophages from RA and severe COVID-19 patients. JAKi suppressed some inflammatory genes, while a subset remained unresponsive to JAK-STAT inhibition. We discovered that JAKi selectively target IRF-STAT-dependent open chromatin regions, leaving AP-1-C/EBP-regulated genes with open chromatin unaffected. Some JAKi-insensitive genes could be inhibited by JNK inhibitors in IFN-γ-primed macrophages. Our analysis also identified JAKi-sensitive and -insensitive IFN-γ signature genes in RA patients resistant to MTX treatments and COVID-19 vaccinated donors, highlighting JAKi's therapeutic potential and risks. These findings uncover new JAKi responsiveness mechanisms through epigenomic changes in IFN-γ-primed macrophages, advancing our understanding of inflammation regulation in chronic diseases.
Scalable spatial single-cell transcriptomics and translatomics in 3D thick tissue blocks
Authors: Sui Xin , Lo Jennifer A. , Luo Shuchen , He Yichun , Tang Zefang , Lin Zuwan , Zhou Yiming , Wang Wendy Xueyi , Liu Jia , Wang Xiao
Published: August 2024

Characterizing the transcriptional and translational gene expression patterns at the single-cell level within their three-dimensional (3D) tissue context is essential for revealing how genes shape tissue structure and function in health and disease. However, most existing spatial profiling techniques are limited to 5-20 µm thin tissue sections. Here, we developed Deep-STARmap and Deep-RIBOmap, which enable 3Din situquantification of thousands of gene transcripts and their corresponding translation activities, respectively, within 200-µm thick tissue blocks. This is achieved through scalable probe synthesis, hydrogel embedding with efficient probe anchoring, and robust cDNA crosslinking. We first utilized Deep-STARmap in combination with multicolor fluorescent protein imaging for simultaneous molecular cell typing and 3D neuron morphology tracing in the mouse brain. We also demonstrate that 3D spatial profiling facilitates comprehensive and quantitative analysis of tumor-immune interactions in human skin cancer.
Endogenous Retrovirus Loci and Induced Changes in Gene Expression in Japanese Indigenous Chickens
Authors: Ishihara Shinya , Shiraishi Jun-ichi , Shimamoto Saki , Ijiri Daichi
Published: August 2024

When retroviruses infect germ cells and are transmitted to offspring, they become endogenous retroviruses (ERVs), whose insertions influence the expression of nearby genes. This study aimed to identify the genomic loci of ERVs in commercial broiler (Ross308), Tosa-Jidori, and Yakido chickens as well as to elucidate their impact on neighboring gene expression. Whole-genome data were obtained using next-generation sequencing, and candidate ERV loci were identified using the RetroSeq software. The Integrative Genomics Viewer tool was used to confirm target site duplications (TSDs) as evidence of ERV insertions. All reads within 200 bp of these TSDs were extracted to create contigs, confirming the presence of ERV sequences in the contigs using BLASTN. Gene expression levels were estimated by focusing on genes located near the 172 identified ERV loci. Among these, 119 loci were detected in broiler chickens, 80 in Tosa-Jidori chickens, and 86 in Yakido chickens, with 28 loci shared among them. Moreover, of these 172 loci, 75 were located within or near genes. Significant differences in gene expression were observed for N-acetylated alpha-linked acidic dipeptidase 2, glypican 6, and phospholipid scramblase family member 5 depending on the presence of ERV insertions. These results suggest that ERV insertions may influence the expression of certain genes, providing insights into the genetic diversity and evolutionary background of commercial and indigenous chickens. Understanding the effects of ERV insertions on gene expression can inform future genetic research and poultry breeding programs aimed at improving health and productivity.
Ice Finder: Few-Shot Learning for Non-Vitrified Ice Segmentation
Authors: Vivas-Lago Alma , Castaño-Díez Daniel
Published: August 2024

This study introduces Ice Finder, a novel tool for quantifying crystalline ice in tomography, filling a crucial gap in existing methodologies. We establish the first application of the meta-learning paradigm to tomography, demonstrating that various tomographic tasks across datasets can be unified under a single meta-learning framework. Our approach utilizes few-shot learning to enhance domain generalization and adaptability to domain shifts, facilitating rapid adaptation to new datasets with minimal examples. Ice Finder’s performance is evaluated on a comprehensive set of in situ datasets from EMPIAR, proving its ease of use and fast processing capabilities, with inference times in the milliseconds. This tool not only accelerates workflows but also enhances the precision of structural studies in structural biology.
GOLEM: A tool for visualizing the distribution of Gene regulatOry eLEMents within the plant promoters with a focus on male gametophyte
Authors: Nevosád Lukáš , Klodová Božena , Raček Tomáš , Přerovská Tereza , Kusová Alžbeta , Svobodová Radka , Honys David , Schrumpfová Petra Procházková
Published: August 2024

Background

The regulation of gene expression during tissue development is very complex. A key mechanism of gene regulation is the recognition of regulatory motifs, also known as cis-regulatory elements (CREs), by various proteins in gene promoter regions. Localization of these motifs near the transcription start site (TSS) or translation start site (ATG) is crucial for transcription initiation and rate. Transcription levels of individual genes, regulated by these motifs, can vary significantly across tissues and developmental stages, especially in processes like sexual reproduction. However, the precise localization and visualization of regulatory motifs in relation to gene expression in specific tissues can be challenging.

Results

Here, we introduce a program called GOLEM (Gene regulatOry eLEMents) which enables users to precisely locate any motif of interest with respect to TSS or ATG within the relevant plant genomes across the plant Tree of Life (Marchantia, Physcomitrium, Amborella, Oryza, Zea, SolanumandArabidopsis). The visualization of the motifs is performed with respect to the transcript levels of particular genes in leaves and male reproductive tissues and can be compared with genome-wide distribution regardless of the transcription level. Additionally, genes with specific CREs at defined positions and high expression in selected tissues can be exported for further analysis. GOLEM’s functionality is illustrated by its application to conserved motifs (e.g. TATA-box, ABRE, I-box, and TC-element), as well as to male gametophyte-related motifs (e.g. LAT52, MEF2, ARR10_core, and DOF_core).

Conclusion

GOLEM is a freely available tool (https://golem.ncbr.muni.cz) for tracking the precise localization and distribution of any CREs of interest in plant gene promoters.

Graphical abstract
Slow-wave sleep and REM sleep differentially contribute to memory representational transformation
Authors: Liu Jing , Chen Danni , Xia Tao , Zeng Shengzi , Xue Gui , Hu Xiaoqing
Published: August 2024

Memory transforms over time, gradually becoming less idiosyncratic and more gist-like. While sleep contributes to memory transformation, how different sleep stages and EEG activity influence memory transformation is far from clear. Applying representational similarity analysis to electroencephalogram (EEG) recordings, we examined memory representational transformation at both the idiosyncratic “item-level” and the generic “category-level”. Our findings revealed that after an overnight sleep, item-level neural representations for post-sleep remembered items were abolished. In contrast, category-level representations remained prominent, but they became distinctive from pre-sleep. Across participants, more rapid eye movement (REM) sleep relative to slow-wave sleep (SWS) was associated with reduced item-level neural representational strength, increased category-level representational strength, as well as the decreased item-level representational similarity between pre-sleep learning and post-sleep retrieval sessions. Moreover, the theta and beta EEG power during REM sleep, and delta power during SWS differentially supported these representational transformations. These findings suggest that post-learning REM sleep and SWS play differential roles in supporting overnight memory transformation.
Gene Expression Prediction from Histology Images via Hypergraph Neural Networks
Authors: Li Bo , Zhang Yong , Wang Qing , Zhang Chengyang , Li Mengran , Wang Guangyu , Song Qianqian
Published: August 2024

Spatial transcriptomics reveals the spatial distribution of genes in complex tissues, providing crucial insights into biological processes, disease mechanisms, and drug development. The prediction of gene expression based on cost-effective histology images is a promising yet challenging field of research. Existing methods for gene prediction from histology images exhibit two major limitations. First, they ignore the intricate relationship between cell morphological information and gene expression. Second, these methods do not fully utilize the different latent stages of features extracted from the images. To address these limitations, we propose a novel hypergraph neural network model, HGGEP, to predict gene expressions from histology images. HGGEP includes a gradient enhancement module to enhance the model’s perception of cell morphological information. A lightweight backbone network extracts multiple latent stage features from the image, followed by attention mechanisms to refine the representation of features at each latent stage and capture their relations with nearby features. To explore higher-order associations among multiple latent stage features, we stack them and feed into the hypergraph to establish associations among features at different scales. Experimental results on multiple datasets from disease samples including cancers and tumor disease, demonstrate the superior performance of our HGGEP model than existing methods.

Key Points

We develop a novel histology image-based gene prediction model named HGGEP, which demonstrates high accuracy and robust performance.

To reveal the intricate relationship between cell morphology and gene expression in images, we propose a gradient enhancement module, which effectively improves the model’s capability in perceiving cell morphology in images.

HGGEP includes a hypergraph module that efficiently models higher-order associations among features across multiple latent stages, resulting in significant performance improvement.
High-grade serous ovarian cancer development and anti-PD-1 resistance is driven by IRE1α activity in neutrophils
Authors: Emmanuelli Alexander , Salvagno Camilla , Min-Hwang Sung , Awasthi Deepika , Sandoval Tito A. , Chae Chang-Suk , Cheong Jin-Gyu , Tan Chen , Iwawaki Takao , Cubillos-Ruiz Juan R.
Published: August 2024

High-grade serous ovarian cancer (HGSOC) is an aggressive malignancy that remains refractory to current immunotherapies. While advanced stage disease has been extensively studied, the cellular and molecular mechanisms that promote early immune escape in HGSOC remain largely unexplored. Here we report that primary HGSO tumors program neutrophils to inhibit T cell anti-tumor function by activating the endoplasmic reticulum (ER) stress sensor IRE1α. We found that intratumoral neutrophils exhibited overactivation of ER stress response markers compared with their counterparts at non-tumor sites. Selective deletion of IRE1α in neutrophils delayed primary ovarian tumor growth and extended the survival of mice with HGSOC by enabling early T cell-mediated tumor control. Notably, loss of IRE1α in neutrophils sensitized tumor-bearing mice to PD-1 blockade, inducing HGSOC regression and long-term survival in ∼50% of treated hosts. Hence, neutrophil-intrinsic IRE1α facilitates early adaptive immune escape in HGSOC and targeting this ER stress sensor might be used to unleash endogenous and immunotherapy-elicited immunity that controls metastatic disease.
Transcranial focused ultrasound modulates visual thalamus in a nonhuman primate model
Authors: Yu Kai , He Bin
Published: August 2024

The thalamus plays a pivotal role as a neural hub, integrating and distributing visual information to cortical regions responsible for visual processing. Transcranial focused ultrasound (tFUS) has emerged as a promising non-invasive brain stimulation technology, enabling modulation of neural circuits with high spatial precision. This study investigates the tFUS neuromodulation at visual thalamus and characterizes the resultant effects on interconnected visual areas in a nonhuman primate model. Experiments were conducted on a rhesus macaque trained in a visual fixation task, combining tFUS stimulation with simultaneous scalp electroencephalography (EEG) and intracranial recordings from area V4, a region closely linked to the thalamus. Ultrasound was delivered through a 128-element random array ultrasound transducer operating at 700 kHz, with the focus steered onto the pulvinar of the thalamus based on neuroanatomical atlas and individual brain model. EEG source imaging revealed localized tFUS-induced activities in the thalamus, midbrain, and visual cortical regions. Critically, tFUS stimulation of the pulvinar can elicit robust neural responses in V4 without visual input, manifested as significant modulations in local field potentials, elevated alpha and gamma power, corroborating the functional thalamocortical connectivity. Furthermore, the tFUS neuromodulatory effects on visually-evoked V4 activities were region-specific within the thalamus and dependent on ultrasound pulse repetition frequency. This work provides direct electrophysiological evidence demonstrating the capability of tFUS in modulating the visual thalamus and its functional impact on interconnected cortical regions in a large mammalian model, paving the way for potential investigations for tFUS treating visual, sensory, and cognitive impairments.
CqHKT1 and CqSOS1 mediate genotype-dependent Na+exclusion under high salt stress in quinoa
Authors: Kobayashi Yasufumi , Sugita Ryohei , Fujita Miki , Yasui Yasuo , Murata Yoshinori , Ogata Takuya , Nagatoshi Yukari , Fujita Yasunari
Published: August 2024

Salinity threatens crop production worldwide, and salinized areas are steadily increasing. As most crops are sensitive to salt, there is a need to improve the salt tolerance of major crops and promote the cultivation of under-utilized salt-tolerant crops. Quinoa, a pseudocereal and leafy vegetable from the Andean region of South America, is highly salt-tolerant, thrives in marginal environments, and has excellent nutritional properties. Research has often focused on epidermal bladder cells, a feature of quinoa thought to contribute to salt tolerance; however recent evidence suggests that these cells are not directly involved. The salt tolerance mechanism in quinoa remains unclear. Here, we show genotype-dependent differences in Na+and K+accumulation mechanisms using representative 18 lines of three genotypes by focusing on young quinoa seedlings at a stage without epidermal bladder cells. High salinity (600 mM NaCl) did not affect the early growth of all three quinoa genotypes. Under high salinity, lowland quinoa lines accumulated the most Na+in the aerial parts, whereas southern highland lines accumulated the least. By contrast, K+accumulation was slightly reduced in the aerial parts but significantly decreased in roots of all the genotypes. Resequencing of 18 quinoa lines supports the notion that genotype determines aboveground Na+uptake and gene expression in response to salt stress. Using virus-induced gene silencing, we further demonstrated that CqHKT1 and CqSOS1 mediate Na+exclusion in quinoa. These findings provide insight into salt tolerance mechanisms, serving as a basis for improving crop production under salt stress.
Inhibitory basal ganglia nuclei differentially innervate pedunculopontine nucleus subpopulations and evoke opposite motor and valence behaviors.
Authors: Fallah Michel , Udobi Kenea C , Swiatek Aleksandra E , Scott Chelsea B , Evans Rebekah C
Published: August 2024

The canonical basal ganglia model predicts that the substantia nigra pars reticulata (SNr) and the globus pallidus externa (GPe) will have specific effects on locomotion: the SNr inhibiting locomotion and the GPe enhancing it. In this manuscript, we use in vivo optogenetics to show that a projection-defined neural subpopulation within each structure exerts non-canonical effects on locomotion. These non-canonical subpopulations are defined by their projection to the pedunculopontine nucleus (PPN) and mediate opposing effects on reward. To understand how these structures differentially modulate the PPN, we use ex vivo whole-cell recording with optogenetics to comprehensively dissect the SNr and GPe connections to regionally- and molecularly-defined populations of PPN neurons. The SNr inhibits all PPN subtypes, but most strongly inhibits caudal glutamatergic neurons. The GPe selectively inhibits caudal glutamatergic and GABAergic neurons, avoiding both cholinergic and rostral cells. This circuit characterization reveals non-canonical basal ganglia pathways for locomotion and valence.
Models of microbiome evolution incorporating host resource provisioning
Authors: Xiao Yao , Li Teng , Rodrigo Allen
Published: August 2024

Multicellular hosts and their associated microbial partners (i.e., microbiomes) often interact in mutually beneficial ways. Consequently, hosts may choose to allocate resources to regulate and recruit appropriate microbes. In doing so, hosts may incur an energetic cost, and in turn, these costs can affect host fitness. It remains unclear how hosts have evolved to balance the costs of expending resources to manage their microbiomes against the benefits that might accrue by doing so. We extended a previously-developed agent-based computational model of hostmicrobiome evolution by incorporating a resource provisioning process, whereby hosts provide resources to support beneficial microbes and suppress harmful microbes, with attendant fitness costs. Our results indicate that the ways and sources from which a host acquires microbes are crucial factors influencing the host’s willingness to provide resources, to regulate microbiome composition. The intensity of resource provisioning will depend, in part, on how much of their microbiome hosts contribute to, and obtain from, their environment: when hosts that engage in resource provisioning contribute a high percentage of their microbiome to the environment, then there is less evolutionary imperative for other hosts to also provide resources. Since resource provisioning incurs a fitness cost to the host, over evolutionary time, resource provisioning will not be favored. Additionally, if selection at the microbial level is not sufficiently strong, and the host obtains a high proportion of microbes from the environment, then the higher the proportion of beneficial microbes in the environment, the less the host is willing to provide resources.
A COVID-19 Rapid Antigen Test Employing Upconversion Nanoparticles
Authors: Zhang Le , Zhou Jiajia , Shimoni Olga , Wen Shihui , Alghalayini Amani , Liu Yuan , Rezaeishahmirzadi Meysam , Liao Jiayan , Maddahfar Mahnaz , Hunt Roger , Black Murdo , Johansen Matt D. , Hansbro Phil M. , Zhang Lin , Stenzel Martina , Warkiani Majid , Valenzuela Stella M , Jin Dayong
Published: August 2024

The COVID-19 pandemic has underscored the critical need for rapid and accurate diagnostic tools. Current methods, including PCR and rapid antigen tests (RAT), have limitations in speed, sensitivity, and the requirement for specialized equipment and trained personnel. Nanotechnology, particularly upconversion nanoparticles (UCNPs), offer a promising alternative due to their unique optical properties. UCNPs can convert low-energy near-infrared (NIR) light into higher-energy visible light, making them ideal for use as optical probes in single molecule detection and point of care applications. This study, initiated in early 2020, explores the opportunity of using highly doped UCNPs (40%Yb3+/4%Er3+) in lateral flow assay (LFA) for the early diagnosis of COVID-19. The UCNPs-based LFA testing demonstrated a minimum detection concentration of 100 pg/mL for SARS-CoV-2 antigen and 105CCID50/mL for inactivated virus. Clinical trials, conducted in Malaysia and Western Australia independently, showed that the technique was at least 100 times more sensitive than commercial RAT kits, with a sensitivity of 100% and specificity of 91.34%. The development process involved multidisciplinary collaborations, resulting in the Virulizer device, an automated strip reader for point-of-care testing. This work sets a reference for future development of highly sensitive and quantitative rapid antigen tests, aiming for the Limits of Detection (LoD) in the range of sub-ng/mL.
Evaluation of High-Affinity Monoclonal Antibodies and Antibody-Drug Conjugates by Homogenous Time-Resolved FRET
Authors: Greenway Harmon , Wang Jin
Published: August 2024

The rapid growth of therapeutic monoclonal antibodies demands greater accessibility to scalable methods of evaluating antigen binding. Homogenous TR-FRET is ideal for preliminary screening but has not been reported to assay these interactions due to their high-affinity and complex solution-phase kinetics. Here we report the development of a competition assay to rank-order the relative affinities of these drugs for a common antigen. The assay is compatible with automation, requires no modification of the analytes, and measures affinities as low as single-digit picomolar. We further demonstrate applications to inform the development of antibody-drug conjugates. The assay may aid discovery and manufacturing of therapeutic antibodies as a low-cost, high-throughput alternative to existing technologies.
PCL-seq: enhanced high-resolution transcriptomic profiling of region of interest in fresh frozen and FFPE tissues
Authors: Dong Xue , Cui Xiaonan , Hu Mengzhu , Zhou Wenjian , Shi Weiyang
Published: August 2024

The spatial heterogeneity of gene expression has propelled the development of multiple spatial transcriptomics technologies. Here, we presentphotocleavage andligation sequencing (PCL-seq), an method for spatial indexing using a light-controlled DNA labeling strategy on tissue section. PCL-seq uses photocleavable oligonucleotides and ligation adapters to construct transcription profiles of region of interest (ROI), selected by microscopically controlled photo illumination apparatus in tissue sections. Applied to mouse embryos, PCL-seq obtains gene expression matrices that align with spatial locations and competitive data quality, featuring around 1.7×105UMIs and 8,600 genes (irradiation diameter=100µm). PCL-seq can also apply to formalin fixation and paraffin embedding (FFPE) mouse embryo sections, whereas obtained competitive data output and recovered thousands of differentially enriched transcripts from limb and skeleton. Additionally, PCL-seq can achieve subcellular resolution, which was demonstrated for differential expression between nuclear and cytoplasmic. Thus, PCL-seq provides an accessible workflow for spatial transcriptomic analysis in frozen and FFPE tissue at subcellular resolution.