bluuebunny/crossref_metadata_2025 huggingface dataset:
Advancements in Ligand-Based Virtual Screening through the Synergistic Integration of Graph Neural Networks and Expert-Crafted Descriptors
Authors: Liu Yunchao (Lance) , Moretti Rocco , Wang Yu , Dong Ha , Yan Bailu , Bodenheimer Bobby , Derr Tyler , Meiler Jens
Published: April 2023

The fusion of traditional chemical descriptors with Graph Neural Networks (GNNs) offers a compelling strategy for enhancing ligand-based virtual screening methodologies. A comprehensive evaluation revealed that the benefits derived from this integrative strategy vary significantly among different GNNs. Specifically, while GCN and SchNet demonstrate pronounced improvements by incorporating descriptors, SphereNet exhibits only marginal enhancement. Intriguingly, despite SphereNet’s modest gain, all three models-GCN, SchNet, and SphereNet-achieve comparable performance levels when leveraging this combination strategy. This observation underscores a pivotal insight: sophisticated GNN architectures may be substituted with simpler counterparts without sacrificing efficacy, provided that they are augmented with descriptors. Furthermore, our analysis reveals a set of expert-crafted descriptors’ robustness in scaffold-split scenarios, frequently outperforming the combined GNN-descriptor models. Given the critical importance of scaffold splitting in accurately mimicking real-world drug discovery contexts, this finding accentuates an imperative for GNN researchers to innovate models that can adeptly navigate and predict within such frameworks. Our work not only validates the potential of integrating descriptors with GNNs in advancing ligand-based virtual screening but also illuminates pathways for future enhancements in model development and application. Our implementation can be found athttps://github.com/meilerlab/gnn-descriptor.
Melt electrowritten scaffold architectures to mimic vasculature mechanics and control neo-tissue orientation
Authors: Federici Angelica S. , Tornifoglio Brooke , Lally Caitríona , Garcia Orquidea , Kelly Daniel J. , Hoey David A.
Published: April 2023

Cardiovascular disease is one of the leading causes of death worldwide, commonly associated with the development of an arteriosclerotic plaque and impairment of blood flow in arteries. Current adopted grafts to bypass the stenosed vessel fail to recapitulate the unique mechanical behaviour of native vessels, particularly in the case of small diameter vessels (<6 mm), leading to graft failure. Therefore, in this study, melt-electrowriting (MEW) was adopted to produce a range of fibrous grafts to mimic the extracellular matrix (ECM) architecture of the tunica media of vessels, in an attempt to match the mechanical and biological behaviour of the native tissue. Initially, the range of collagen architectures within the native vessel was determined, and subsequently replicated using MEW (winding angles (WA) 45°, 26.5°, 18.4°, 11.3°). These scaffolds recapitulated the anisotropic, non-linear mechanical behaviour of native carotid blood vessels. Moreover, these grafts facilitated human mesenchymal stromal/stem cell (hMSC) infiltration, differentiation, and ECM deposition that was independent of WA. The bioinspired MEW fibre architecture promoted cell alignment and preferential neo-tissue orientation in a manner similar to that seen in native tissue, particularly for WA 18.4° and 11.3°, which is a mandatory requirement for long-term survival of the regenerated tissue post-scaffold degradation. Lastly, the WA 18.4° was translated to a tubular graft and was shown to mirror the mechanical behaviour of small diameter vessels within physiological strain. Taken together, this study demonstrates the capacity to use MEW to fabricate bioinspired grafts to mimic the tunica media of vessels and recapitulate vascular mechanics which could act as a framework for small diameter graft development and functional long-term tissue regeneration.
Climate, host and geography shape insect and fungal communities of trees
Authors: Franić Iva , Allan Eric , Prospero Simone , Adamson Kalev , Attorre Fabio , Auger-Rozenberg Marie Anne , Augustin Sylvie , Avtzis Dimitrios , Baert Wim , Barta Marek , Bauters Kenneth , Bellahirech Amani , Boroń Piotr , Bragança Helena , Brestovanská Tereza , Brurberg May Bente , Burgess Treena , Burokienė Daiva , Cleary Michelle , Corley Juan , Coyle David R , Csóka György , Černý Karel , Davydenko Kateryna , de Groot Maarten , Diez Julio Javier , Doğmuş Lehtijärvi H. Tuğba , Drenkhan Rein , Edwards Jacqueline , Elsafy Mohammed , Eötvös Csaba Béla , Falko Roman , Fan Jianting , Feddern Nina , Fürjes-Mikó Ágnes , Gossner Martin M. , Grad Bartłomiej , Hartmann Martin , Havrdova Ludmila , Horáková Miriam Kádasi , Hrabětová Markéta , Justesen Mathias Just , Kacprzyk Magdalena , Kenis Marc , Kirichenko Natalia , Kovač Marta , Kramarets Volodymyr , Lacković Nikola , Lantschner Maria Victoria , Lazarević Jelena , Leskiv Marianna , Li Hongmei , Madsen Corrie Lynne , Malumphy Chris , Matošević Dinka , Matsiakh Iryna , May Tom W. , Meffert Johan , Migliorini Duccio , Nikolov Christo , O’Hanlon Richard , Oskay Funda , Paap Trudy , Parpan Taras , Piškur Barbara , Ravn Hans Peter , Richard John , Ronse Anne , Roques Alain , Ruffner Beat , Santini Alberto , Sivickis Karolis , Soliani Carolina , Talgø Venche , Tomoshevich Maria , Uimari Anne , Ulyshen Michael , Vettraino Anna Maria , Villari Caterina , Wang Yongjun , Witzell Johanna , Zlatković Milica , Eschen René
Published: April 2023

Non-native pests, climate change, and their interactions are likely to alter relationships between trees and tree-associated organisms with consequences for forest health. To understand and predict such changes, factors structuring tree-associated communities need to be determined. Here, we analysed the data consisting of records of insects and fungi collected from dormant twigs from 155 tree species at 51 botanical gardens or arboreta in 32 countries. Generalized dissimilarity models revealed similar relative importance of studied climatic, host-related and geographic factors on differences in tree-associated communities. Mean annual temperature, phylogenetic distance between hosts and geographic distance between locations were the major drivers of dissimilarities. The increasing importance of high temperatures on differences in studied communities indicate that climate change could affect tree-associated organisms directly and indirectly through host range shifts. Insect and fungal communities were more similar between closely related vs. distant hosts suggesting that host range shifts may facilitate the emergence of new pests. Moreover, dissimilarities among tree-associated communities increased with geographic distance suggesting that human-mediated transport may facilitate the introductions of new pests. The results of this study highlight the need to limit the establishment of tree pests and increase the resilience of forest ecosystems to changes in climate.
Spatially repeatable components from ultrafast ultrasound are associated with motor unit activity in human isometric contractions
Authors: Rohlén Robin , Carbonaro Marco , Cerone Giacinto L. , Meiburger Kristen M. , Botter Alberto , Grönlund Christer
Published: April 2023

Objective

Ultrafast ultrasound imaging has been used to measure intramuscular mechanical dynamics associated with single motor unit (MU) activations. Detecting MU activity from ultrasound sequences requires decomposing a displacement velocity field into components consisting of spatial maps and temporal displacement signals. These components can be associated with putative MU activity or spurious movements (noise). The differentiation between putative MUs and noise has been accomplished by comparing the temporal displacement signals with MU firings obtained from needle EMG. Here, we examined whether the repeatability of the spatial maps over brief time intervals can serve as a criterion for distinguishing putative MUs from noise in low-force isometric contractions.

Approach

In five healthy subjects, ultrafast ultrasound images and high-density surface EMG (HDsEMG) were recorded simultaneously from biceps brachii. MUs identified through HDsEMG decomposition were used as a reference to assess the outcomes of the ultrasound-based decomposition. For each contraction, displacement velocity sequences from the same eight-second ultrasound recording were separated into consecutive two-second epochs and decomposed. The Jaccard Similarity Coefficient (JSC) was employed to evaluate the repeatability of components’ spatial maps across epochs. Finally, the association between the ultrasound components and the MUs decomposed from HDsEMG was assessed.

Main results

All the MU-matched components had JSC > 0.38, indicating they were repeatable and accounted for about one-third of the HDsEMG-detected MUs (1.8 ± 1.6 matches over 4.9 ± 1.8 MUs). The repeatable components (with JSC over the empirical threshold of 0.38) represented 14% of the total components (6.5 ± 3.3 components). These findings align with our hypothesis that intra-sequence repeatability can differentiate putative MUs from spurious components and can be used for data reduction.

Significance

The results of our study provide the foundation for developing stand-alone methods to identify MU in ultrafast ultrasound sequences and represent a step forward towards real-time imaging of active MU territories. These methods are relevant for studying muscle neuromechanics and designing novel neural interfaces.
The genomic landscape of adaptation to a new host plant
Authors: Steward Rachel A. , Nilsson Kalle J. , Ortega Giménez Jesús , Nolen Zachary J. , Yan Chao , Huang Yajuan , Ayala López Julio , Runemark Anna
Published: April 2023

Adaptation to novel ecological niches is known to be rapid. However, how the loci underlying ecological divergence are coupled to traits reproductively isolating populations, ultimately enabling the formation of persistent species, remains a consequential question in speciation research. Here, we investigated the genomic differences underpinning colonization of a new niche and formation of two partly sympatric host races ofTephritis conurapeacock flies. We took advantage of two independent sympatric zones west and east of the Baltic Sea, where host plant specialists using the thistle speciesCirsium heterophyllumandC. oleraceumco-occur, and address what regions of the genome maintain the host races in parallel. Using genome-wide association, differentiation and divergence statistics, we identified a large, highly divergent region associated with host use among western and eastern populations. Within this region, we identified unique haplotypes associated with each host race, indicative of a large inversion, adding to the growing body of evidence that structural changes to the genome are important for adaptations to persist in the face of gene flow. We further showed strong signatures of selection in this region, especially in populations of the derivedC. oleraceumspecialist host race. The region also had reduced introgression, especially in western populations, while the rest of the genome showed signs of extensive gene flow. Genes within highly differentiated windows within the putative inversion were not only enriched for functions involved in host adaptation, including phenology and metabolic responses to different metabolites in the two host plants, but also enriched for gametogenesis, fertilization and embryological development, all of which suggest sequence divergence could have large consequences on reproductive isolation between the host races. In conclusion, this study suggests that structural changes in the genome may facilitate the formation of persistent host races, and ultimately speciation, in face of gene flow.
NucleosomeDB - a database of 3D nucleosome structures and their complexes with comparative analysis toolkit
Authors: Armeev Grigoriy A. , Gribkova Anna K. , Shaytan Alexey K.
Published: April 2023

Nucleosomes are basic building blocks of chromatin, comprising DNA wrapped around an octamer of eight histone proteins. They play key roles in DNA compaction, epigenetic mark up of the genome and actively participate in chromatin dynamics. X-ray and later cryo-EM studies have contributed greatly to our understanding of nucleosome structure, their interactions and dynamics. With over 470 nucleosome containing structures in the Protein Data Bank there is a wealth of information to be gleaned from these structures, especially through comparative analysis. However, due to the variability in their representation (chain naming, residue numbering, other artifacts), these structures cannot be systematically analyzed “as is”. To address this issue, we developed a framework for analyzing and classifying nucleosome structures and their complexes, resulting in the creation of the NucleosomeDB database and the corresponding web-service. NucleosomeDB allows researchers to search, explore, and compare nucleosomes with each other, despite differences in composition and peculiarities of their representation. By utilizing the information contained within the NucleosomeDB, researchers can gain valuable insights into how nucleosomes interact with DNA and other proteins, assess the implications of mutations and protein binding on nucleosome structure. The detailed information contained within NucleosomeDB can contribute to a better understanding of the structure and function of nucleosomes, and ultimately, the functioning of chromatin and gene regulation. NucleosmeDB is freely available athttps://nucldb.intbio.org.
Identifying variants associated with dwarfism via long read sequencing of theDdw1locus in winter rye
Authors: Haardt Rowena C. , Schmiedchen Brigitta , Gordillo-Rodriguez Andres , Eifler Jakob
Published: April 2023

Dwarfism or semi-dwarfism is an established characteristic in the European cereal market, for example semi-dwarf barley and wheat are commonplace. However, dwarf winter rye is still atypical commercially and fundamental research into the underlying genes influencing plant height is still in its relative infancy. In this study, association between two independent dwarf donors are established asDdw1carriers and variants within theDdw1locus are identified using long read sequencing. Here over 20,000 variants are identified as having putative association with the dwarf phenotype by using twoDdw1genotypes and four representative (non-dwarf) elite lines for exclusion. Consequently, the sequence data presented here provides rye breeders and researchers a resource to develop KASP markers to track the allelic status ofDdw1and to select for dwarf material.
A single-dose of intranasal vaccination with a live-attenuated SARS-CoV-2 vaccine candidate promotes protective mucosal and systemic immunity
Authors: Adam Awadalkareem , Kalveram Birte , Chen John Yun-Chung , Yeung Jason , Rodriguez Leslie , Singh Ankita , Shi Pei-Yong , Xie Xuping , Wang Tian
Published: April 2023

An attenuated SARS-CoV-2 virus with modified viral transcriptional regulatory sequences and deletion of open-reading frames 3, 6, 7 and 8 (∆3678) was previously reported to protect hamsters from SARS-CoV-2 infection and transmission. Here we report that a single-dose intranasal vaccination of ∆3678 protects K18-hACE2 mice from wild-type or variant SARS-CoV-2 challenge. Compared with wild-type virus infection, the ∆3678 vaccination induces equivalent or higher levels of lung and systemic T cell, B cell, IgA, and IgG responses. The results suggest ∆3678 as an attractive mucosal vaccine candidate to boost pulmonary immunity against SARS-CoV-2.
Transcriptome Complexity Disentangled: A Regulatory Molecules Approach
Authors: Asiaee Amir , Abrams Zachary B. , Pua Heather H. , Coombes Kevin R.
Published: April 2023

Transcription factors (TFs) and microRNAs (miR-NAs) are fundamental regulators of gene expression, cell state, and biological processes. This study investigated whether a small subset of TFs and miRNAs could accurately predict genome-wide gene expression. We analyzed 8895 samples across 31 cancer types from The Cancer Genome Atlas and identified 28 miRNA and 28 TF clusters using unsupervised learning. Medoids of these clusters could differentiate tissues of origin with 92.8% accuracy, demonstrating their biological relevance. We developed Tissue-Agnostic and Tissue-Aware models to predict 20,000 gene expressions using the 56 selected medoid miR-NAs and TFs. The Tissue-Aware model attained anR2of 0.70 by incorporating tissue-specific information. Despite measuring only 1/400th of the transcriptome, the prediction accuracy was comparable to that achieved by the 1000 landmark genes. This suggests the transcriptome has an intrinsically low-dimensional structure that can be captured by a few regulatory molecules. Our approach could enable cheaper transcriptome assays and analysis of low-quality samples. It also provides insights into genes that are heavily regulated by miRNAs/TFs versus alternative mechanisms. However, model transportability was impacted by dataset discrepancies, especially in miRNA distribution. Overall, this study demonstrates the potential of a biology-guided approach for robust transcriptome representation.
Cysteine tRNA acts as a stop codon readthrough-inducing rti-tRNA in the human HEK293T cell line
Authors: Valášek Leoš Shivaya , Kučerová Michaela , Zeman Jakub , Beznosková Petra
Published: April 2023

Under certain circumstances, any of the three termination codons can be read through by its near-cognate tRNA; i.e. a tRNA whose two out of three anticodon nucleotides base-pair with those of the stop codon. Unless programmed to synthetize C-terminally extended protein variants with expanded physiological roles, readthrough represents an undesirable translational error. On the other side of a coin, a significant number of human genetic diseases is associated with the introduction of nonsense mutations (premature termination codons - PTCs) into coding sequences, where stopping is not desirable. Here, the tRNA’s ability to induce readthrough opens up the intriguing possibility of mitigating the deleterious effects of PTCs on human health. In yeast, the UGA and UAR stop codons were described to be read through by four readthrough-inducing rti-tRNAs – tRNATrpand tRNACys, and tRNATyrand tRNAGln, respectively. The readthrough-inducing potential of tRNATrpand tRNATyrwas also observed in human cell lines. Here, we investigated the readthrough-inducing potential of human tRNACysin the HEK293T cell line. The tRNACysfamily consists of two isoacceptors, one with ACA and the other with GCA anticodons. We selected nine representative tRNACysisodecoders (differing in primary sequence and expression level) and tested them using dual luciferase reporter assays. We found that at least two tRNACyscan significantly elevate UGA readthrough when overexpressed. This indicates a mechanistically conserved nature of rti-tRNAs between yeast and human, supporting the idea that they could be utilized in the PTC-associated RNA therapies.
Separating phases of allopolyploid evolution with resynthesized and naturalCapsella bursa-pastoris
Authors: Duan Tianlin , Sicard Adrien , Glémin Sylvain , Lascoux Martin
Published: April 2023

Allopolyploidization is a frequent evolutionary transition in plants that combines whole-genome duplication (WGD) and interspecific hybridization. The genome of an allopolyploid species results from initial interactions between parental genomes and long-term evolution. Telling apart the contributions of these two phases is essential to understanding the evolutionary trajectory of allopolyploid species. Here, we compared phenotypic and transcriptomic changes in natural and resynthesizedCapsellaallotetraploids with their diploid parental species. We focused on phenotypic traits associated with the selfing syndrome and on transcription-level phenomena such as expression level dominance, transgressive expression, and homoeolog expression bias.

We found that selfing syndrome, high pollen and seed quality in natural allotetraploids likely resulted from long-term evolution. Similarly, transgressive expression and most down-regulated expression-level dominance were only found in natural allopolyploids. Natural allotetraploids also had more expression-level dominance toward the self-fertilizing parental species than resynthesized allotetraploids, mirroring the establishment of the selfing syndrome. However, short-term changes mattered, and 40% of the cases of expression-level dominance in natural allotetraploids were already observed in resynthesized allotetraploids. Resynthesized allotetraploids showed striking variation of homoeolog expression bias among chromosomes and individuals. Homoeologous synapsis was its primary source and may still be a source of genetic variation in natural allotetraploids.

In conclusion, both short- and long-term mechanisms contributed to transcriptomic and phenotypic changes in natural allotetraploids. However, the initial gene expression changes were largely reshaped during long-term evolution leading to further morphological changes.
Do people with disabilities experience disparities in cancer care? A systematic review
Authors: Tosetti Irene , Kuper Hannah
Published: April 2023

Background

Over 1.3 billion people, or 16% of the world’s population, live with some form of disability. Recent studies have reported that people with disabilities (PwD) might not be receiving state-of-the-art treatment for cancer as their non-disabled peers; our objective was to systematically review this topic.

Methods

A systematic review was undertaken to compare cancer outcomes and quality of cancer care between adults with and without disabilities (NIHR Prospero register ID number: CRD42022281506). A search of the literature was performed in July 2022 across five databases: EMBASE, Medline, Cochrane Library, Web of Science and CINAHL databases. Peer-reviewed quantitative research articles, published in English from 2000 to 2022, with interventional or observational study designs, comparing cancer outcomes between a sample of adult patients with disabilities and a sample without disabilities were included. Studies focused on cancer screening and not treatment were excluded, as well as editorials, commentaries, opinion papers, reviews, case reports, case series under 10 patients and conference abstracts Studies were evaluated by one reviewer for risk of bias based on a set of criteria according to the SIGN 50 guidelines. A narrative synthesis was conducted according to the Cochrane SWiM guidelines, with tables summarizing study characteristics and outcomes. This research received no external funding.

Results

Thirty-one studies were included in the systematic review. Compared to people without disabilities, PwD had worse cancer outcomes, in terms of poorer survival and higher overall and cancer-specific mortality. There was also evidence that PwD received poorer quality cancer care, including: lower access to state-of-the-art care or curative-intent therapies, treatment delays, undertreatment or excessively invasive treatment, worse access to in-hospital services, less specialist healthcare utilization, less access to pain medications and inadequate end-of-life quality of care.

Discussion

Limitations of this work include the exclusion of qualitative research, no assessment of publication bias, selection performed by only one reviewer, results from high-income countries only, no meta-analysis and a high risk of bias in 15% of included studies. In spite of these limitations, our results show that PwD often experience severe disparities in cancer care with less guideline-consistent care and higher mortality than people without disabilities. These findings raise urgent questions about how to ensure equitable care for PwD; in order to prevent avoidable morbidity and mortality, cancer care programs need to be evaluated and urgently improved, with specific training of clinical staff, more disability inclusive research, better communication and shared decision-making with patients and elimination of physical, social and cultural barriers.
Faithful AI in Medicine: A Systematic Review with Large Language Models and Beyond
Authors: Xie Qianqian , Schenck Edward J. , Yang He S. , Chen Yong , Peng Yifan , Wang Fei
Published: April 2023

Artificial intelligence (AI), especially the most recent large language models (LLMs), holds great promise in healthcare and medicine, with applications spanning from biological scientific discovery and clinical patient care to public health policymaking. However, AI methods have the critical concern for generating factually incorrect or unfaithful information, posing potential long-term risks, ethical issues, and other serious consequences. This review aims to provide a comprehensive overview of the faithfulness problem in existing research on AI in healthcare and medicine, with a focus on the analysis of the causes of unfaithful results, evaluation metrics, and mitigation methods. We systematically reviewed the recent progress in optimizing the factuality across various generative medical AI methods, including knowledge-grounded LLMs, text-to-text generation, multimodality-to-text generation, and automatic medical fact-checking tasks. We further discussed the challenges and opportunities of ensuring the faithfulness of AI-generated information in these applications. We expect that this review will assist researchers and practitioners in understanding the faithfulness problem in AI-generated information in healthcare and medicine, as well as the recent progress and challenges in related research. Our review can also serve as a guide for researchers and practitioners who are interested in applying AI in medicine and healthcare.
Computer vision, causal inference and public health modelling approaches to generate evidence on the impacts of urban planning in non-communicable disease and health inequalities in UK and Australian cities: A proposed collaborative approach
Authors: Hunter Ruth F. , Garcia Leandro , Stevenson Mark , Nice Kerry , Wijnands Jasper S. , Kee Frank , Ellis Geraint , Anderson Neil , Seneviratne Sachith , Moeinaddini Mehdi , Godic Branislava , Akaraci Selin , Thompson Jason
Published: April 2023

Background

Given that the majority of the world’s population live in cities, it is essential to global health efforts that we design them in ways that both reduce non-communicable diseases (NCDs) risk and that facilitate adoption and maintenance of healthy lifestyles. Current approaches tend to focus on the relationship between urban design-related factors that affect health at the local or neighbourhood level but few studies have explored this relationship both within and across entire cities, nor explored the causal pathways between urban-designed related factors and NCDs. The aim of this research program is to use computer vision, causal inference, and public health modelling methods for understanding the causal relationship between urban design and health at the neighbourhood level, and to explore intervention approaches at the city scale.

Methods

Phase 1 will use machine learning and computer vision techniques to analyse gridded, local-level aerial images (with an optical resolution of <20cm), of all UK and Australian cities with populations over 100,000. It will identify a variety of urban features within these images and derive associations between them and NCD incidence and risk factors identified through location-based health surveys. Phase 2, using data from prospective health cohorts and linked objective built environment data, will apply Bayesian networks to investigate the possible causal pathways between built environment, lifestyle factors, and NCD incidence. Phase 3 will estimate the health impacts of actionable changes in urban design. Using health impact assessment modelling, we will calculate the NCD burden that could be prevented if cities were to adopt urban features of healthier counterparts. A similar approach will be applied on finer-grained scale within all case study cities, enabling assessment of health impacts of changes in individual locations. Phase 4 will develop an interactive web-based toolkit to enable urban designers, planners and policymakers to inform the decision-making cycle, co-designed with intended users involving participatory workshops.

Discussion

We use state-of-the-art approaches to: (i) generate evidence on the impacts of urban planning and design in NCDs and health inequalities in UK and Australian cities, and (ii) provide stakeholders with tools for advocacy and designing healthier cities.

Trial registration

Not applicable.
How AlphaFold shaped the structural coverage of the human transmembrane proteome
Authors: Jambrich Márton A. , Tusnady Gabor E. , Dobson Laszlo
Published: April 2023

AlphaFold2 (AF2) provides structures for every protein, opening up prospects for virtually every field in structural biology. However, transmembrane proteins pose a challenge for experimental scientists, resulting in a limited number of solved structures. Consequently, algorithms trained on this finite training set also face difficulties. To address this issue, we recently launched the TmAlphaFold database, where predicted AlphaFold2 structures are embedded into the membrane and a quality assessment is provided for each prediction using geometrical evaluation. In this paper, we analyze how AF2 has changed the structural coverage of membrane proteins compared to earlier years when only experimental structures were available, and high-throughput structure prediction was greatly limited. We also evaluate how AF2 can be used to search for (distant) homologs in highly diverse protein families. By combining quality assessment and homology search, we can pinpoint protein families where AF2 accuracy is limited, and experimental approaches are still desired.
Single-cell and spatial transcriptomics identify a macrophage population associated with skeletal muscle fibrosis
Authors: Coulis Gerald , Jaime Diego , Guerrero-Juarez Christian , Kastenschmidt Jenna M. , Farahat Philip K. , Nguyen Quy , Pervolarakis Nicholas , McLinden Katherine , Thurlow Lauren , Movahedi Saba , Duarte Jorge , Sorn Andrew , Montoya Elizabeth , Mozaffar Izza , Dragan Morgan , Othy Shivashankar , Joshi Trupti , Hans Chetan P. , Kimonis Virginia , MacLean Adam L. , Nie Qing , Wallace Lindsay M. , Harper Scott Q. , Mozaffar Tahseen , Hogarth Marshall W. , Bhattacharya Surajit , Jaiswal Jyoti K. , Golann David R. , Su Qi , Kessenbrock Kai , Stec Michael , Spencer Melissa J. , Zamudio Jesse R. , Villalta S. Armando
Published: April 2023

The monocytic/macrophage system is essential for skeletal muscle homeostasis, but its dysregulation contributes to the pathogenesis of muscle degenerative disorders. Despite our increasing knowledge of the role of macrophages in degenerative disease, it still remains unclear how macrophages contribute to muscle fibrosis. Here, we used single-cell transcriptomics to determine the molecular attributes of dystrophic and healthy muscle macrophages. We identified six novel clusters. Unexpectedly, none corresponded to traditional definitions of M1 or M2 macrophage activation. Rather, the predominant macrophage signature in dystrophic muscle was characterized by high expression of fibrotic factors, galectin-3 and spp1. Spatial transcriptomics and computational inferences of intercellular communication indicated that spp1 regulates stromal progenitor and macrophage interactions during muscular dystrophy. Galectin-3+macrophages were chronically activated in dystrophic muscle and adoptive transfer assays showed that the galectin-3+phenotype was the dominant molecular program induced within the dystrophic milieu. Histological examination of human muscle biopsies revealed that galectin-3+macrophages were also elevated in multiple myopathies. These studies advance our understanding of macrophages in muscular dystrophy by defining the transcriptional programs induced in muscle macrophages, and reveal spp1 as a major regulator of macrophage and stromal progenitor interactions.
Quantitative mechanistic model reveals key determinants of placental IgG transfer and informs prenatal immunization strategies
Authors: Erdogan Remziye R , Dolatshahi Sepideh
Published: April 2023

Transplacental antibody transfer is crucially important in shaping neonatal immunity. Recently, prenatal maternal immunization has been employed to boost pathogen-specific immunoglobulin G (IgG) transfer to the fetus. Multiple factors have been implicated in antibody transfer, but how these key dynamic regulators work together to elicit the observed selectivity is pertinent to engineering vaccines for mothers to optimally immunize their newborns. Here, we present the first quantitative mechanistic model to uncover the determinants of placental antibody transfer and inform personalized immunization approaches. We identified placental FcγRIIb expressed by endothelial cells as a limiting factor in receptor-mediated transfer, which plays a key role in promoting preferential transport of subclasses IgG1, IgG3, and IgG4, but not IgG2. Integrated computational modeling andin vitroexperiments reveal that IgG subclass abundance, Fc receptor (FcR) binding affinity, and FcR abundance in syncytiotrophoblasts and endothelial cells contribute to inter-subclass competition and potentially inter-and intra-patient antibody transfer heterogeneity. We developed anin silicoprenatal vaccine testbed by combining a computational model of maternal vaccination with this placental transfer model using the tetanus, diphtheria, and acellular pertussis (Tdap) vaccine as a case study. Model simulations unveiled precision prenatal immunization opportunities that account for a patient’s anticipated gestational length, placental size, and FcR expression by modulating vaccine timing, dosage, and adjuvant. This computational approach provides new perspectives on the dynamics of maternal-fetal antibody transfer in humans and potential avenues to optimize prenatal vaccinations that promote neonatal immunity.
Development and calibration of the FSPM CPlantBox to represent the interactions between water and carbon fluxes in the soil-plant-atmosphere continuum
Authors: Giraud M. , Le Gall S. , Harings M. , Javaux M. , Leitner D. , Meunier F. , Rothfuss Y. , van Dusschoten D. , Vanderborght J. , Vereecken H. , Lobet G. , Schnepf A.
Published: April 2023

A plant’s development is strongly linked to the water and carbon flows in the soil-plant-atmosphere continuum. Expected climate shifts will alter the water and carbon cycles and will affect plant phenotypes. Comprehensive models which simulate mechanistically and dynamically the feedback loops between a plant’s three-dimensional development and the water and carbon flows are useful tools to evaluate the sustainability of genotype-environment-management combinations which do not yet exist. In this study, we present the latest version of the open-source three-dimensional Functional-Structural Plant Model CPlantBox with PiafMunch and DuMuxcoupling. We simulated semi-mechanistically the development of generic C3 monocots from 10 to 25 days after sowing and undergoing an atmospheric dry spell of one week (no precipitation). We compared the results for dry spells starting on different days (day 11 or 18) and with different climates (wetter and colder against drier and warmer atmospheric and initial soil conditions). Compared with the wetter and colder climate, the dry spell with the drier and warmer climate led to a lower instantaneous water use efficiency. Moreover, the lower symplasm turgor for the drier and warmer climate limited the growth, which made the sucrose available for other processes, such as maintenance respiration. Both of these effects were stronger for the later dry spell compared with the early dry spell under the drier and warmer climate. We could thus use CPlantBox to simulate diverging emerging processes (like carbon partitioning) defining the plants’ phenotypic plasticity response to their environment.
Anti-diarrheal drug loperamide induces dysbiosis in zebrafish microbiota via bacterial inhibition
Authors: Stevick Rebecca J. , Bedu Sébastien , Dray Nicolas , Ghigo Jean-Marc , Pérez-Pascual David
Published: April 2023

Background

Perturbations of animal-associated microbiomes from chemical stress can affect host physiology and health. While dysbiosis induced by antibiotic treatments and disease are well known, chemical, non-antibiotic drugs have recently been shown to induce changes in microbiome composition, warranting further exploration. Loperamide is an opioid-receptor agonist drug widely prescribed drug for treating acute diarrhea in humans. Loperamide is also used as a tool to study the impact of bowel dysfunction in animal models by inducing constipation, but its effect on host-associated microbiota is poorly characterized.

Results

We used conventional and gnotobiotic larval zebrafish models to show that in addition to host-specific effects, loperamide also has anti-bacterial activities that directly induce changes in microbiota diversity. This dysbiosis is due to changes in bacterial colonization, since germ-free zebrafish mono-reconventionalized with bacterial strains sensitive to loperamide are colonized up to 100-fold lower when treated with loperamide. Consistently, the bacterial diversity of gnotobiotic zebrafish colonized by a mix of representative bacterial strains is affected by loperamide treatment.

Conclusion

Our results demonstrate that loperamide, in addition to host effects, also induces dysbiosis in a vertebrate model, highlighting that established treatments can have underlooked secondary effects on microbiota structure and function. This study further provides a insights for future studies exploring how common medications directly induce changes in host-associated microbiota.

Graphical Abstract
DMC1stabilizes synapsis and crossover at high and low temperatures during wheat meiosis
Authors: Draeger Tracie N. , Rey María-Dolores , Hayta Sadiye , Smedley Mark , Martín Azahara C. , Moore Graham
Published: April 2023

Effective chromosome synapsis and crossover during meiosis are essential for fertility, especially in grain crops such as wheat. These processes function most efficiently in wheat at temperatures between 17-23 °C, although the genetic mechanisms for such temperature dependence are unknown. In a previously identified mutant of the hexaploid wheat reference variety ‘Chinese Spring’ lacking the long arm of chromosome 5D, exposure to low temperatures during meiosis resulted in asynapsis and crossover failure. In a second mutant (ttmei1), containing a 4 Mb deletion in chromosome 5DL, exposure to 13 °C led to similarly high levels of asynapsis and univalence. Moreover, exposure to 30 °C led to a significant, but less extreme effect on crossover. Previously, we proposed that, of 41 genes deleted in this 4 Mb region, the major meiotic geneTaDMC1-D1was the most likely candidate for preservation of synapsis and crossover at low (and possibly high) temperatures. In the current study, using RNA-guided Cas9, we developed a new Chinese Spring CRISPR mutant, containing a 39 bp deletion in the 5D copy ofDMC1, representing the first reported CRISPR-Cas9 targeted mutagenesis in Chinese Spring, and the first CRISPR mutant forDMC1in wheat. In controlled environment experiments, wild-type Chinese Spring, CRISPRdmc1-D1and backcrossedttmei1mutants were exposed to either high or low temperatures during the temperature-sensitive period from premeiotic interphase to early meiosis I. After 6-7 days at 13 °C, crossover decreased by over 95% in thedmc1-D1mutants, when compared with wild-type plants grown under the same conditions. After 24 hours at 30 °C,dmc1-D1mutants exhibited a reduced number of crossovers and increased univalence, although these differences were less marked than at 13 °C. Similar results were obtained forttmei1mutants, although their scores were more variable, possibly reflecting higher levels of background mutation. These experiments confirm our previous hypothesis thatDMC1-D1is responsible for preservation of normal synapsis and crossover at low and, to a certain extent, high temperatures. Given that reductions in crossover have significant effects on grain yield, these results have important implications for wheat breeding, particularly in the face of climate change.

Key message

The meiotic recombination geneDMC1on wheat chromosome 5D preserves normal chromosome synapsis and crossover during periods of high and low temperature.
Growth balance analysis models of cyanobacteria for understanding resource allocation strategies
Authors: Ghaffarinasab Sajjad , Lercher Martin J. , Dourado Hugo
Published: April 2023

Cyanobacteria have emerged as attractive microbial cell factories, as they can convert atmospheric CO2and sunlight into valuable chemicals. To increase their growth and productivity, one should aim to optimize the allocation of limited cellular resources across different metabolic processes. Here, we developed two growth balance analysis (GBA) models for the cyanobacteriumSynechocystissp. PCC 6803. In its biological assumptions, the models closely related to an existing coarse-grained model, while its mathematical formulation is heavily streamlined. We show that the GBA models provide virtually identical predictions about cellular resource allocation among photosynthesis, carbon metabolism, and the protein translation machinery under different environmental conditions as the previous, mathematically more involved model. Our model also captures the effects of photodamage on proteome allocation and the resulting growth rates. We further show how the GBA model can be easily extended to include more reactions, leading to a second GBA model capable of new predictions about the cellular resource allocation. Balanced growth models of the type presented here can easily expanded to include more biological details, providing a useful toolbox for the understanding of the physiological capabilities of cyanobacteria, their allocation of cellular resources, and the potential of their bioengineering for optimized biomass production.
Using artificial intelligence to document the hidden RNA virosphere
Authors: Hou Xin , He Yong , Fang Pan , Mei Shi-Qiang , Xu Zan , Wu Wei-Chen , Tian Jun-Hua , Zhang Shun , Zeng Zhen-Yu , Gou Qin-Yu , Xin Gen-Yang , Le Shi-Jia , Xia Yin-Yue , Zhou Yu-Lan , Hui Feng-Ming , Pan Yuan-Fei , Eden John-Sebastian , Yang Zhao-Hui , Han Chong , Shu Yue-Long , Guo Deyin , Li Jun , Holmes Edward C , Li Zhao-Rong , Shi Mang
Published: April 2023

Current metagenomic tools can fail to identify highly divergent RNA viruses. We developed a deep learning algorithm, termed LucaProt, to discover highly divergent RNA-dependent RNA polymerase (RdRP) sequences in 10,487 metatranscriptomes generated from diverse global ecosystems. LucaProt integrates both sequence and predicted structural information, enabling the accurate detection of RdRP sequences. Using this approach we identified 161,979 potential RNA virus species and 180 RNA virus supergroups, including many previously poorly studied groups, as well as RNA virus genomes of exceptional length (up to 47,250 nucleotides) and genomic complexity. A subset of these novel RNA viruses were confirmed by RT-PCR and RNA/DNA sequencing. Newly discovered RNA viruses were present in diverse environments, including air, hot springs and hydrothermal vents, and both virus diversity and abundance varied substantially among ecosystems. This study advances virus discovery, highlights the scale of the virosphere, and provides computational tools to better document the global RNA virome.
TDP-1 and FUST-1 co-inhibit exon inclusion and control fertility together with transcriptional regulation
Authors: Taylor Morgan , Marx Olivia , Norris Adam
Published: April 2023

Gene expression is a multistep, carefully controlled process, and crosstalk between regulatory layers plays an important role in coordinating gene expression. To identify functionally relevant coordination between transcriptional and post-transcriptional gene regulation, we performed a systematic reverse-genetic interaction screen inC. elegans. We combined RNA binding protein (RBP) and transcription factor (TF) mutants, creating over 100 RBP; TF double mutants. This screen identified a variety of unexpected double mutant phenotypes, including two strong genetic interactions between the ALS-related RBPs,fust-1andtdp-1, and the homeodomain TFceh-14. Losing any one of these genes alone has no significant effect on the health of the organism. However,fust-1; ceh-14andtdp-1; ceh-14double mutants both exhibit strong temperature-sensitive fertility defects. Both double mutants exhibit defects in gonad morphology, sperm function, and oocyte function. RNA-seq analysis of double mutants identifiesceh-14as the main controller of transcript levels, whilefust-1andtdp-1control splicing through a shared role in exon inhibition. We identify a cassette exon in the polyglutamine-repeat proteinpqn-41whichtdp-1inhibits. Loss oftdp-1causes thepqn-41exon to be aberrantly included, and forced skipping of this exon intdp-1; ceh-14double mutants rescues fertility. Together our findings identify a novel shared physiological role forfust-1andtdp-1in promotingC. elegansfertility in aceh-14mutant background and reveal a shared molecular function offust-1andtdp-1in exon inhibition.
The small RNA component of Arabidopsis phloem sap and its response to iron deficiency
Authors: Bakirbas Ahmet , Castro-Rodriguez Rosario , Walker Elsbeth L.
Published: April 2023

In order to discover sRNA that might function during iron deficiency stress, RNA was prepared from phloem exudates ofArabidopsis thaliana. Bioanalyzer results indicate that abundant RNA from phloem is small in size—less than 200 nt. Moreover, typical rRNA bands were not observed. Sequencing of eight independent phloem RNA samples indicated that that tRNA-derived fragments, specifically 5’ tRFs and 5’ tRNA halves, are highly abundant in phloem sap, comprising about 46% of all reads. In addition, a set of miRNAs that are present in phloem sap was defined, and several miRNA and sRNAs were identified that are differentially expressed during iron deficiency.

Highlight

Preparation of RNA from Arabidopsis phloem sap revealed that

most of the RNA is small (less than 200 nt)

tRNA fragments (tRFs) are highly abundant

a set of miRNAs present in phloem sap can be defined
Optogenetic control of kinesins -1, -2, -3 and dynein reveals their specific roles in vesicular transport
Authors: Nagpal Sahil , Wang Samuel , Swaminathan Karthikeyan , Berger Florian , Hendricks Adam G.
Published: April 2023

Each cargo in a cell employs a unique set of motor proteins for its transport. Often multiple types of kinesins are bound to the same cargo. It is puzzling why several types of motors are required for robust transport. To dissect the roles of each type of motor, we developed optogenetic inhibitors of kinesin-1, -2, -3 and dynein. This system allows us to control the activity of the endogenous set of motor proteins that are bound to intracellular cargoes. We examined the effect of optogenetic inhibition of kinesins-1, -2, and -3 and dynein on the transport of early endosomes, late endosomes, and lysosomes. While kinesin-1, kinesin-3, and dynein transport vesicles at all stages of endocytosis, kinesin-2 primarily drives late endosomes and lysosomes. In agreement with previous studies, sustained inhibition of either kinesins or dynein results in reduced motility in both directions. However, transient, optogenetic inhibition of kinesin-1 or dynein causes both early and late endosomes to move more processively by relieving competition with opposing motors. In contrast, optogenetic inhibition of kinesin-2 reduces the motility of late endosomes and lysosomes, and inhibition of kinesin-3 reduces the motility of endosomes and lysosomes. These results suggest that the directionality of transport is likely controlled through regulating kinesin-1 and dynein activity. On vesicles transported by several kinesin and dynein motors, motility can be directed by modulating the activity of a single type of motor on the cargo.