bluuebunny/crossref_metadata_2025 huggingface dataset:
Interindividual variability in flower pickiness by foraging bumblebees
Authors: Armand Mélissa , Beckenbauer Christoph , Avarguès-Weber Aurore , Lihoreau Mathieu , Czaczkes Tomer J.
Published: December 2024

Pollinators navigate complex and heterogeneous “flower markets”, where floral resources vary in quality, availability, and distribution. Bumblebees, as generalist foragers, visit numerous flowers during their foraging bouts. Yet, the factors influencing their flower choices and the notable individual differences in foraging behaviour among bees are still not well understood. We hypothesised that early foraging experiences influence bees’ subsequent flower choices. To test this, we observed individualBombus terrestrisworkers forage for three consecutive bouts in two artificial flower arrays. One array simulated a favourable environment with patches alternating high- and low-quality flowers (40% vs. 20% w/w sucrose solution), while the other array presented a more challenging environment with patches of high-quality flowers alongside unrewarded flowers (40% w/w sucrose solution vs. plain water). In both arrays, bees rapidly improved their foraging efficiency, increasing sucrose intake per unit time across bouts. In the favourable array, most bees became highly selective for high-quality flowers, while some continued visiting both flower types. Their degree of pickiness was influenced by early experiences: bees initially exposed to high-quality flowers became more selective, whereas those encountering low-quality flowers first were less selective in subsequent foraging. Despite differences in pickiness and array conditions, bees achieved comparable sucrose intake rates within three bouts. This study highlights the adaptability of bee foraging behaviour and emphasizes the role of early foraging experiences in driving individual differences.

Significance statement

To forage efficiently, pollinators must navigate complex “flower markets”, where floral resources vary in quality and availability. We observedBombus terrestrisworkers forage across three bouts in two artificial flower arrays: a favourable array with flower patches alternating high- and low-quality flowers (40% vs. 20% w/w sucrose solution), and an extreme array with high-quality and non-rewarding flowers (40% w/w sucrose solution vs. plain water). We found that bees initially exposed to high-quality flowers became highly selective, whereas those encountering low-quality flowers first were less picky, collecting both flower types. Despite these differences, bees rapidly improved foraging efficiency over successive bouts, achieving similar sucrose intake rates within three bouts. This study highlights the foraging flexibility of bumblebees and suggests that early experiences can have lasting effects, influencing flower choices dozens of visits later.
The use of variational autoencoders to characterise the heterogeneous subpopulations that arise due to antibiotic treatment
Authors: Bersenev Dennis , Zhang Emily
Published: December 2024

Antimicrobial resistance (AMR) is a persistent threat to global agriculture and healthcare systems. One of the challenges towards development of robust antimicrobials to date has been the limitation posed by low resolution bacterial sequencing technologies. The recent development of Bacterial Single Cell RNA sequencing protocols has provided an unprecedented opportunity in AMR research as it now enables researchers to probe bacterial populations at single cell resolution. In this study, we apply a Bayesian Variational Autoencoder, MrVI, to data generated by one such Bacterial Single Cell RNA sequencing protocol, BacDrop, and use it characterise changes in gene expression levels before and after antibiotic perturbation. Through the use of MrVI, we were able to find distinct DNA damage and heat shock response subpopulations. We also determined that each of the subpopulations could be mapped back to its respective antibiotic treatments, providing more precise insight into their mechanisms of resistance. These preliminary results indicate the potential that this new window into intracellular bacterial communication provides, and motivate the continued exploration of models to unveil the mechanisms underlying AMR.
Environmental Mixtures Analysis (E-MIX) Workflow and Methods Repository
Authors: Joubert Bonnie R. , Palmer Glenn , Dunson David , Kioumourtzoglou Marianthi-Anna , Coull Brent A.
Published: December 2024

Human exposure to complex, changing, and variably correlated mixtures of environmental chemicals has presented analytical challenges to epidemiologists and human health researchers. There have been a wide variety of recent advances in statistical methods for analyzing mixtures data, with most of these methods having open-source software for implementation. However, there is no one-size-fits-all method for analyzing mixtures data given the considerable heterogeneity in scientific focus and study design. For example, some methods focus on predicting the overall health effect of a mixture and others seek to disentangle main effects and pairwise interactions. Some methods are only appropriate for cross-sectional designs, while other methods can accommodate longitudinally measured exposures or outcomes. This article focuses on greatly simplifying the daunting task of identifying which methods are most suitable for a particular study design, data type, and scientific focus. With this goal in mind, we present an organized workflow for statistical analysis considerations in environmental mixtures data. This systematic strategy builds on epidemiological and statistical principles, considering specific nuances for the mixtures’ context. We also describe an accompanying online methods repository in development to increase awareness of and inform application of existing methods and new methods as they are developed and identify gaps in existing methods warranting further development.
Acquisition of an immunosuppressive microenvironment after CAR-T therapy drives T-cell dysfunction and resistance
Authors: Ponzo Marianna , Drufuca Lorenzo , Buracchi Chiara , Sindoni Marco M. , Nucera Silvia , Bugarin Cristina , Bason Ramona , Rossetti Grazisa , Bonnal Raoul , Meli Cristian , Rambaldi Benedetta , Lussana Federico , Ferrari Silvia , Moretti Alex , Risca Giulia , Pellegrino Christian , Manz Markus G. , Galimberti Stefania , Rambaldi Alessandro , Gaipa Giuseppe , Biondi Andrea , Pagani Massimiliano , Magnani Chiara F.
Published: December 2024

Chimeric antigen receptor (CAR) T cells targeting CD19 induce durable responses in B-cell acute lymphoblastic leukemia (B-ALL). However, the contribution of the tumor microenvironment to the therapeutic response after CAR-T cell treatment remains incompletely understood. We performed single-cell RNA sequencing and spectral flow cytometry-based analyses of bone marrow-resident immune cells from B-ALL patients before and after CAR T-cell treatment. We observed profound changes in the microenvironment in response to CAR T cell-mediated inflammation, including an increase in myeloid cells. Significant induction of the IFN response, hypoxia, and TGF-β-signaling was associated with expansion of myeloid-derived suppressor cells (MDSCs) and endogenous exhausted CD8+ T cells. PD1 expression in endogenous T cells post-treatment was associated with a lack of durable response in the cohort of patients analyzed. Further, we revealed that HIF1α, VEGF, and TGFBR2 are key players in the intercellular communication between CAR T cells and the immune niche, driving widespread T-cell dysfunction. Infusion of anti-CD19 CAR T cells led to increased accumulation of human MDSCs, exacerbation of a hypoxic environment and T-cell exhaustion in HSPC-humanized mice bearing a human tumor. In conclusion, CAR T-cell-mediated myeloid activation is associated with pathways of immune dysregulation that may antagonize the effects of therapy.

Key points

The tumor immune context post-treatment affects CAR T-cell fate and endogenous immunity in B-cell acute lymphoblastic leukemia.

IFN response, hypoxia, and TGF-β-signaling result in endogenous T-cell exhaustion and compromise CAR T-cell efficacy.
Benchmarking AI Models forIn SilicoGene Perturbation of Cells
Authors: Li Chen , Gao Haoxiang , She Yuli , Bian Haiyang , Chen Qing , Liu Kai , Wei Lei , Zhang Xuegong
Published: December 2024

Understanding perturbations at the single-cell level is essential for unraveling cellular mechanisms and their implications in health and disease. The growing availability of biological data has driven the development of a variety ofin silicoperturbation methods designed for single-cell analysis, which offer a means to address many inherent limitations of experimental approaches. However, these computational methods are often tailored to specific scenarios and validated on limited datasets and metrics, making their evaluation and comparison challenging. In this work, we introduce a comprehensive benchmarking framework to systematically evaluatein silicoperturbation methods across four key scenarios: predicting effects of unseen perturbations in known cell types, predicting effects of observed perturbations in unseen cell types, zero-shot transfer to bulk RNA-seq of cell lines, and application to real-world biological cases. For each scenario, we curated diverse and abundant datasets, standardizing them into flexible formats to enable efficient analysis. Additionally, we developed multiple metrics tailored to each scenario, facilitating a thorough and comparative evaluation of these methods. Our benchmarking study assessed 10 methods, ranging from linear baselines to advanced machine learning approaches, across these scenarios. While some methods demonstrated surprising efficacy in specific contexts, significant challenges remain, particularly in zero-shot predictions and the modeling of complex biological processes. This work provides a valuable resource for evaluating and improvingin silicoperturbation methods, serving as a foundation for bridging computational predictions with experimental validation and real-world biological applications.
Conserved heavy/light contacts and germline preferences revealed by a large-scale analysis of natively paired human antibody sequences and structural data
Authors: Dudzic Pawel , Chomicz Dawid , Bielska Weronika , Jaszczyszyn Igor , Zieliński Michał , Janusz Bartosz , Wróbel Sonia , Pannérer Marguerite-Marie Le , Philips Andrew , Ponraj Prabakaran , Kumar Sandeep , Krawczyk Konrad
Published: December 2024

Antibody next-generation sequencing (NGS) datasets have become crucial to develop computational models addressing this successful class of therapeutics. Although antibodies are composed of both heavy and light chains, most NGS sequencing depositions provide them in unpaired form, reducing their utility. Here we introduce PairedAbNGS, a novel database with paired heavy/light antibody chains. To the best of our knowledge, this is the largest resource for paired natural antibody sequences with 58 bioprojects and over 14 million assembled productive sequences. We make the database accessible athttp://naturalantibody.com/paired-ngsas a valuable tool for biological and machine-learning applications. Using this dataset, we investigated heavy and light chain variable (V) gene pairing preferences and found significant biases beyond gene usage frequencies, possibly due to receptor editing favoring less autoreactive combinations. Analyzing the available antibody structures from the Protein Data Bank, we studied conserved contact residues between heavy and light chains, particularly interactions between the CDR3 region of one chain and the FWR2 region of the opposite chain. Examination of amino acid pairs at key contact sites revealed significant deviations of amino acids distributions compared to random pairings, in the heavy chain’s CDR3 region contacting the opposite chain, indicating specific interactions might be crucial for proper chain pairing. This observation is further reinforced by preferential IGHV-IGLJ and IGLV-IGHJ pairing preferences. We hope that both our resources and the findings would contribute to improving the engineering of biological drugs.
Black flying foxes in Australia harbor novelBorrelialineages adjacent to zoonotic clades
Authors: Verrett Taylor B. , Falvo Caylee A. , Benson Evelyn , Jones-Slobodian Devin N. , Crowley Daniel E. , Dale Adrienne S. , Lunn Tamika J. , Ruiz-Aravena Manuel ,   Bat One Health, McKee Clifton D. , Clark Kerry L. , Peel Alison J. , Plowright Raina K. , Becker Daniel J.
Published: December 2024

We explore the role of Australian black flying foxes (Pteropus alecto) as reservoir hosts of potentially zoonoticBorreliabacteria. Across six sites, 2% of 840 bats were infected with one of two novelBorreliahaplotypes. Phylogenetic reconstruction indicated these infections are distinct from Lyme or relapsing fever clades.
Modes of action and bio-fungicide potential of peptides derived from the bi-domain plant defensin MtDef5
Authors: Kalunke Raviraj M. , Pokhrel Ambika , Tetorya Meenakshi , Nath Vishnu Sukumari , Czymmek Kirk J. , Shah Dilip M.
Published: December 2024

Medicago truncatulabi-domain defensin MtDef5 exhibits antifungal activity at sub-micromolar concentrations against some fungal pathogens. It comprises two single-domain defensins, MtDef5A and MtDef5B, connected with a linker APKKVEP. MtDef5B is a more potent antifungal defensin than MtDef5A. We identified amino acid residues important for antifungal activity of MtDef5B and elucidated its modes of action (MoA). MtDef5B inhibited spore germination ofBotrytis cinerea (Bc)at low micromolar concentrations. However, it did not inhibit spore germination ofColletotrichum gloeosporioides (Cg). MtDef5B permeabilized the plasma membrane, induced reactive oxygen species and traveled to the nucleoli in germlings ofBc. Furthermore, a carboxy-terminal MtDef5A-derived GMA5AC peptide was selected for mutagenesis because of its lower cationicity than the corresponding MtDef5B-derived peptide. GMA5AC inhibited spore germination ofBc, but not ofCg. However, GMA5AC_V2, a variant of GMA5AC, inhibited spore germination ofCgand exhibited multi-faceted MoA. Spray-application of GMA5AC_V2 on the leaves of pepper plants demonstrated preventive and curative control of the gray mold disease. Furthermore, when applied topically on tomato fruits pre-inoculated with the pathogenCg, this peptide reduced anthracnose disease symptoms. This study highlights the potential of short chain defensin-derived peptides for management of fungal diseases.

Highlights

The bi-domain MtDef5-derived antifungal peptides exhibit multiple modes of action and confer resistance against the gray mold and anthracnose diseases in pepper plants and tomato fruits, respectively.
Genetic and behavioral analyses suggest that larval and adult stages ofLucilia cuprinaemploy different sensory systems to detect rotten beef
Authors: Wulff Juan P. , Laminack Rachel K. , Scott Maxwell J.
Published: December 2024

Background

The blowflyLucilia cuprinais a destructive parasite of sheep that causes flystrike or myiasis. Larvae consume the animal’s living flesh, producing large wounds that can lead to death. Growing resistance to conventional control methods has prompted the analysis of alternative strategies.

Methods

An RNA-Seq analysis was used to identify sensory receptors and other genes relevant to the physiology ofL. cuprinalarvae. Adult females and larvae of the same species carrying a loss-of-function mutation for theL. cuprinaodorant coreceptor gene (LcupOrco) were obtained by gene editing. Their response to fresh and rotten meat at different temperatures was evaluated.

Results

The RNA-Seq analysis of whole larvae at different stages and third instar head and gut tissues, suggested that odorant (OR), gustatory, ionotropic andpickpocket receptors may not play a central role in theL. cuprinalarval sensory signaling and digestive systems. Rather, ATP-binding cassettes (ABCs) were highly enriched in head and gut RNA, and odorant-binding proteins (OBPs) only in the head. To confirm that ORs are not essential for larval detection of rotten beef, diet-choice assays were performed including larvae and adults homozygous for a null mutation inLcupOrco. While the attraction of adult females to rotten beef was fully disrupted,LcupOrcomutant larvae showed no change in diet preference.

Conclusions

The expression pattern of the ABC and OBP gene families suggests a central role in the sensory system of theL. cuprinalarva for these receptors. Behavioral assays showed that ORs are essential for the adult female response to rotten beef, but not for larval behavior. These findings are consistent with high levels of expression ofLcupOrcoin the adult female antenna but very low expression in larvae.
Trans-regulatory loci shape natural variation of gene expression plasticity in Arabidopsis
Authors: Lensink Mariele , Monroe Grey , Kliebenstein Dan
Published: December 2024

Organisms regulate gene expression in response to environmental cues, a process known as plasticity, to adjust to changing environments. Research into natural variation and the evolution of plasticity frequently studiescis-regulatory elements with theory suggesting they are more important evolutionarily thantrans-regulatory elements. Genome-wide association studies have supported this idea, observing a predominance ofcis-loci affecting plasticity. However, studies in structured populations provide a contrasting image, raising questions about the genetic architecture of natural variation in plasticity. To circumvent potential statistical difficulties present in genome-wide association studies, we mapped loci underlying transcriptomic plasticity in response to salicylic acid using recombinant inbred lines generated from two randomArabidopsis thalianaaccessions. We detected extensive transgressive segregation in the salicylic acid response, suggesting that plasticity to salicylate in Arabidopsis is polygenic. Most loci (>75%) underlying this variation act intrans, especially for loci influencing plasticity.Trans-acting loci were enriched in genome hotspots, with predominantly small effect sizes distributed across many genes. This could potentially explain their under-discovery in genome-wide association studies. This work reveals a potentially important role fortrans-acting loci in plastic expression responses, with implications for understanding plant adaptation to different environments.
Protocol for assessing DNA damage levelsin vivoin rodent testicular germ cells in the Alkaline Comet Assay
Authors: Olsen Ann-Karin , Ma Xiaoxiong , Zheng Congying , Dahl Hildegunn , Dirven Yvette , Boisen Anne-Mette Zenner , Sharma Anoop , Eide Dag. M. , Brunborg Gunnar
Published: December 2024

Few protocols are available for retrieving male germ cell-specific information on DNA damage dynamics or assessing the potential harmful effects of environmental contaminants, drugs, or lifestyle factors related to genotoxicity. Here, we present a protocol for evaluating testicular germ cell genotoxicity using a modified version of the alkaline comet assay in rodent testicular germ cells. The protocol includes experimental design, preparation of testicular cell suspensions, comet analysis, germ cell-specific scoring, and data curation methods to collect information on testicular male germ cells, specifically spermatids and spermatocytes.

For complete details on the use of this protocol please refer to Olsen et al., in preparation

Graphical abstract

Highlights

DNA damage levels can be specifically measured in testicular germ cells using the developed revised version of the alkaline comet assay

1C spermatids as well as 4C primary spermatocytes can be assessed

Both manual- and modeling-based approaches were developed that facilitate user-friendly protocols to select 1C spermatid comets.

This protocol expands the limited methodologies available to study germ cell DNA damage dynamics
Chemical Proteomics Identifies Protein Ligands for Monoacylglycerol Lipids
Authors: Shanbhag Karthik , Mhetre Amol B. , Saharan Ojal , Devarajan Archit , Rai Anisha , Madhusudhan M. S. , Chakrapani Harinath , Kamat Siddhesh S.
Published: December 2024

Signaling lipids are hormone-like small biomolecules that regulate many critical facets of physiology in mammals, including humans. Given their biomedical importance, the past few decades have seen a tremendous increase in our mechanistic understanding of the physiological processes regulated by a handful of such signaling lipids (e.g.: endocannabinoids, lysophospholipids, prostaglandins). However, a significant number of signaling lipid classes still remain poorly characterized, despite their direct associations to human pathophysiology and disease. Over the past decade, the advent of chemical proteomics technologies coupled with the development of multifunctional lipid probes has rapidly expanded our knowledge in terms of the protein ligands and biological pathways that the different signaling lipids interact with and modulate respectively. While the signaling pathways regulated by the endocannabinoid 2-arachidonoyl-glycerol in mammals are extensively characterized, the same cannot be said for the other members of the monoacylglycerol (MAG) family of signaling lipids. To understand this, here, we report the synthesis of a bifunctional MAG probe, containing a photoreactive group and a biorthogonal handle. Using established chemical proteomics approaches, we profile this bifunctional MAG probe in mouse brain and mammalian cell lysates, and leveraging probe competition experiments identify hitherto unknown protein ligands for MAG lipids. Finally, we biochemically validate the neuronal calcium sensor Hippocalcin as a putative MAG protein ligand, and show for the first time, that MAG may have a role to play in calcium sensing and downstream signaling in the mammalian brain.
Multi-Omic Atlas reveals cytotoxic phenotype and ROS-linked metabolic quiescence as key features of CTL-resistant HIV-infected CD4+T-cells
Authors: Herrera Alberto , Leyre Louise , Weiler Jared , Linden Noemi Luise , Huynh Tan Thinh , Wang Feng , Kovacs Colin , Caskey Marina , Zumbo Paul , Amiama Maider Astorkia , Terry Sandra , Ho Ya-Chi , Betel Doron , Jones R. Brad
Published: December 2024

Cytotoxic T-lymphocytes (CTL) exert sustained pressure on reservoirs of HIV-infected cells that persist through years of antiretroviral therapy (ART). This selects for latently infected cells, but also potentially for cells that express HIV but possess intrinsic CTL resistance. We demonstrate that such resistance exists in HIV-infected CD4+T-cells that survive rigorous CTL attack and map CTL susceptibility to cell identities and states defined by single-cell multi-omics and functional metabolic profiling. Cytotoxic CD4+T-cells were prominently overrepresented amongst survivors, as were cells with quiescent metabolic profiles and low levels of reactive oxygen species (ROS) production. The induction of ROS production by treatment with deferoxamine sensitized these cells to CTL-mediated elimination. Reservoir-harboring cells from clinical samples share the above transcriptional features, being enriched for quiescent states. Our results provide an atlas for elucidating features of CTL resistance in HIV reservoirs, and identify oxidative stress as a therapeutic target to facilitate reservoir elimination.
Structural Insights into the Activation and Inhibition of the ADAM17-iRhom2 Complex
Authors: Maciag Joseph J. , Slone Conner , Alnajjar Hala F. , Rich Maria F. , Guion Bryce , Blobel Carl P. , Seegar Tom C.M.
Published: December 2024

The endopeptidase activity of ADAM (a disintegrin and metalloprotease) -17, the primary processor of several EGFR ligands and tumor necrosis factor-alpha (TNF-α), is essential for proper embryonic development and immune regulation. Dysregulated ADAM17 activity is prevalent in a wide array of human diseases, including cancer, chronic inflammation, and SARS-CoV-2 viral progression. Initially translated as an inactive enzyme zymogen, ADAM17 maturation and enzymatic function are tightly regulated by its obligate binding partners, the inactive rhomboid proteins (iRhom) -1 and -2. Here, we present the cryo-EM structure of the ADAM17 zymogen bound to iRhom2. Our findings elucidate the interactions within the ADAM17-iRhom2 complex, the inhibitory mechanisms of the therapeutic MEDI3622 antibody and ADAM17 prodomain, and the previously unknown role of a membrane-proximal cytoplasmic re-entry loop of iRhom2 involved in the mechanism of activation. Importantly, we perform cellular assays to validate our structural findings and provide further insights into the functional implications of these interactions, paving the way for developing therapeutic strategies targeting this biomedically critical enzyme complex.
Circumferential actomyosin bundles drive endothelial cell deformations to constrict blood vessels
Authors: Chen Yan , Taberner Nuria , da Silva Jason , Kondrychyn Igor , Aswani Nitish , Chen Guihua , Okada Yasushi , Lagendijk Anne Karine , Okuda Satoru , Phng Li-Kun
Published: December 2024

Following the formation of new blood vessels, vascular remodelling ensues to generate a hierarchical network of vascular tubes with optimal connections and diameters for efficient blood perfusion of tissues. How transitions in endothelial cell (EC) number and shape are coordinated to define vessel diameter during development remains an open question. In this study, we discovered EC deformations, rearrangements and transient formation of self-seam junctions as key mechanisms that explain a negative relationship between cell number and vessel diameter. High-resolution analysis of actin cytoskeleton organization disclosed the generation of tension-bearing, circumferential actomyosin bundles in the endothelial cortex that drive EC deformation and vessel constriction. Importantly, the loss of circumferential actin bundles inkrit1/ccm1-deficient ECs causes cell enlargement and impaired vessel constriction that culminate in dilated vessels, characteristic of cerebral cavernous malformation. Our multiscale study therefore underpins circumferential actomyosin-driven EC deformations in controlling vessel size and in the prevention of vascular malformations.
Endocytic Patch Dynamics are Differentially Regulated at Distinct Cell Sites in Fission Yeast
Authors: Campbell Bethany F. , Patel Uma J. , Williams Ashlei R. , Das Maitreyi E.
Published: December 2024

Endocytosis promotes polarity and growth in eukaryotes. InSchizosaccharomyces pombefission yeast, endocytosis occurs at the polarized cell ends and division site and at the non-polarized cell sides. Our characterization of endocytic actin patches show that they are differentially regulated. The patches at the cell ends and division site internalize successfully while those at the sides are weak and erratic. The major regulator of cell polarity, Cdc42, and its target Pak1 kinase only localize to the cell ends and division site. We find that these proteins regulate assembly and internalization of patches at these sites but not at the cell sides. Moreover, Cdc42 specifically activated by the GEF Gef1 promotes proper patch dynamics. Endocytosis requires phosphorylation of the Type I Myosin Myo1 by the Pak1 kinase. Myo1 localizes to the cell ends, division site, and the cell sides. We find that unlike Cdc42 and Pak1, Myo1 also promotes patch assembly at the cell sides. Our data indicate that while Myo1 can globally promote branched actin assembly, successful endocytic patch dynamics and internalization at polarized sites require Cdc42 and Pak1 kinase.

SUMMARY STATEMENT

Endocytic patch dynamics are differentially regulated at distinct sites such as the cell ends, division site and the cell sides by Cdc42 and its downstream targets Pak1 kinase and the Type 1 myosin.
Spatiotemporal Regulatory Logics of Mouse Gastrulation
Authors: Yang Xianfa , Xie Bingbing , Shen Penglei , Chen Yingying , Li Chunjie , Tan Fengxiang , Yang Yumeng , Yang Yun , Song Rui , Mi Panpan , Liu Zhiwen , Wen Mingzhu , Tam Patrick P. L. , Suo Shengbao , Jing Naihe
Published: December 2024

Spatiotemporal coordination of cellular and molecular events is crucial for cell fate commitment during mouse gastrulation. However, the high-precision mechanisms governing the timing and spatial dynamics remain poorly understood. Here, we present a time-series single-cell multi-omic dataset from the mouse gastrulating embryos and construct a hierarchical gene regulatory landscape. Integrating this with real three-dimensional transcriptomic coordinate, we created ST-MAGIC and ST-MAGIC (+) atlas, dissecting the spatiotemporal logics of regulatory networks and signaling responsiveness underpinning the lineage commitment at gastrulation. Specifically, we delineated the multi-omic basis for left-right symmetry breaking events in the gastrula and also revealed the spatiotemporal molecular relay for axial mesendoderm lineage, where early and intermediate transcription factors first open the chromatin regions and setup the responsiveness to signaling, followed by terminal factors to consolidate the transcriptomic architecture. In summary, our study presents a spatiotemporal regulatory logic framework of mouse gastrulation, that advances our understanding of mammalian embryogenesis.
The plant pioneer factor LFY uses trans-kingdom chromatin remodeling mechanisms in vertebrates
Authors: Ribeiro Francisca , Teixeira Joana , Sottomayor Mariana , Bessa Jose
Published: December 2024

Multicellular complexity is thought to have evolved independently in animals and plants, but the molecular constraints driving this complexity are poorly understood. Genetic networks activated during animal and plant development both involve the regulation of nucleosome occupancy by chromatin remodelers. Pioneer factors, often specific to plants or animals, bind to nucleosome-occupied DNA in a sequence-specific manner, recruiting chromatin remodelers to control lineage-specific genetic networks. In this study, a plant-specific pioneer factor, LFY, when expressed in zebrafish cells, recruits the vertebrate chromatin remodeler Smarca4a to make DNA accessible at LFY binding sites. This allows a plant LFY-controlled promoter, introduced into the zebrafish genome, to become transcriptionally active in a Smarca4a-dependent manner. Our findings suggest that the protein-protein interaction between pioneer factors and chromatin remodelers is a trans-kingdom mechanism likely reflecting ancient eukaryotic events that became a key evolutionary constraint in the path to biological complexity.
Size-dependent temporal decoupling of morphogenesis and transcriptional programs in gastruloids
Authors: Bennabi Isma , Hansen Pauline , Merle Melody , Pineau Judith , Lopez-Delisle Lucille , Kolly Dominique , Duboule Denis , Mayran Alexandre , Gregor Thomas
Published: December 2024

Understanding the interplay between cell fate specification and morphogenetic changes remains a central challenge in developmental biology. Gastruloids, self-organizing stem cell-based models of post-implantation mammalian development, provide a powerful platform to address this question. Here, we show that physical parameters, particularly system size, critically influence the timing and outcomes of morphogenetic processes. Larger gastruloids exhibit delayed symmetry breaking, increased multipolarity, and prolonged axial elongation, with morphogenesis driven by system size. Despite these variations, transcriptional programs and cell fate composition remain remarkably stable across a broad size range. Notably, extreme sizes show distinct transcriptional modules and clear shifts in gene expression patterns. Intriguingly, size perturbation experiments rescued the morphogenetic and pattern phenotypes observed in extreme sizes, demonstrating the remarkable adaptability of gastruloids to their effective system size. These findings establish gastruloids as versatile models for studying spatiotemporal dynamics in mammalian embryogenesis and reveal how physical constraints decouple transcriptional from morphogenetic programs.
Fibrotic-like collagen matrices as innovative 3D in vitro models for investigating the impact of pathological ECM on muscle regeneration in muscular dystrophies
Authors: Camman Marie , Nieswic Naomi , Joanne Pierre , Brun Julie , Marcellan Alba , Agbulut Onnik , Helary Christophe
Published: December 2024

Muscular dystrophies are characterized by impaired skeletal muscle contraction due to genetic mutations. Beyond the disruption of muscle function, the extracellular matrix (ECM) surrounding muscle fibers becomes fibrotic, further impeding tissue repair and function. In this study, we designed both healthy and fibrotic matrices to examine the impact of persistent fibrosis on muscle cell behavior. Fibrotic matrices were synthesized by 3D printing of dense collagen solutions in air, followed by slow gelation to yield non-porous, isotropic hydrogels. These matrices were subsequently crosslinked using EDC/NHS chemistry, resulting in a Young’s modulus of approximately 50 kPa. The behavior of C2C12 myoblasts cultured within the fibrotic matrices was compared to cells grown in healthy matrices. Our results showed that the fibrotic matrix had a detrimental effect on cell behavior. Myoblasts were unable to differentiate into mature myotubes, exhibited poor alignment, and suffered from hypoxia. Furthermore, these cells failed to proliferate, secreted inflammatory cytokines, and were unable to remodel their ECM. Using matrices possessing a single characteristic of the fibrotic matrix (i.e stiff or non porous), the predominant factor for each feature of the cell phenotype was determined. These findings underscore the detrimental effects of a fibrotic persistent ECM on muscle homeostasis. The development of these two distinct 3D muscle models, one representing healthy muscle and the other fibrotic, offers a valuable tool for investigating the pathophysiology of muscular dystrophy.

Highlights

Stiff and non-porous dense collagen matrices synthesized by 3D printing recapitulate the key characteristics of fibrosis observed in muscular dystrophies

Fibrotic matrices negatively impact myoblast proliferation and differentiation into mature myocytes

Fibrotic matrices impede the 3D organotypic organization of myocytes

This 3D pathological model of skeletal muscle offers a valuable tool for investigating how persistent fibrosis influences the progression of muscular dystrophy

Graphical Abstract
The energy-saving metabolic switch underlies survival of extremophilic red microalgae in extremely high nickel levels
Authors: Santaeufemia Sergio , Marchetto Francesca , Romano Patrizia , Adamska Dorota , Goryca Krzysztof , Palatini Jeffrey , Kargul Joanna
Published: December 2024

The red microalgaCyanidioschyzon merolaeinhabits extreme environments of high temperature (40-56°C), high acidity (pH 0.05–4), and the presence of high concentrations of heavy metals and sulphites that are lethal to most other forms of life. However, information is scarce on the precise adaptation mechanisms of this extremophile to such hostile conditions. Gaining such knowledge is important for understanding the evolution of microorganisms in the early stages of life on Earth characterized by such extreme environments. By analyzing the re-programming of the global transcriptome upon long-term (up to 15 days) exposure ofC. merolaeto extremely high concentrations of nickel (1 and 3 mM), the key adaptive metabolic pathways and associated molecular components were identified. Our work shows that long-term Ni exposure ofC. merolaeleads to the lagged metabolic switch demonstrated by the transcriptional upregulation of the metabolic pathways critical for cell survival. DNA replication, cell cycle, and protein quality control processes were upregulated while downregulation occurred of energetically costly processes including assembly of the photosynthetic apparatus and lipid biosynthesis. This study paves the way for the multi-omicstudies of the molecular mechanisms of abiotic stress adaptation in phototrophs, as well as future development of the rational approaches for bioremediation of contaminated aquatic environments.

Importance

This study provides the first comprehensive analysis of the global transcriptome re-programming in the extremophilic red microalgaCyanidioschyzon merolaeduring its long-term adaptation to heavy metals. We show that the lagged metabolic switch, demonstrated by the transcriptional upregulation of the metabolic pathways critical for cell survival, underlies the long-term Ni adaptation of this model extremophile. The transcriptomic results shed light on how life may have adapted to some of the harshest abiotic stresses on Earth including high temperatures, extreme acidity, and high levels heavy metals that are prohibitive to most other organisms. Additionally, the differentially regulated genes identified in this work provide important clues on the rational development of effective bioremediation strategies of removing heavy metals from the heavily contaminated aquatic environments.
Computational exploration of a viable route to the Kitaev-quantum spin liquid phase in monolayer
OsCl3
Authors: Gu Qiangqiang , Pandey Shishir Kumar , Lin Yihao
Published: December 2024

In this computational study, we explore a viable route to access the Kitaev-quantum spin liquid (QSL) state in a recently synthesized monolayer of a so-called spin-orbit assisted Mott insulator OsCl3. In addition to other magnetic ground states in different regions, a substantial region of small JH/U in our Hubbard U–Hund's JH quantum phase diagram, obtained by combining second-order perturbation and pseudo-fermion functional renormalization group calculations, hosts Kitaev-QSL phase. Only the first neighbor Kitaev interaction of a smaller magnitude, nearly independent of the choice of U, is obtained in this region. Experimental tuning of the single parameter JH to access the QSL state can purportedly be achieved with epitaxial strain in advanced crystal growth techniques. Furthermore, negligibly small farther neighbor interactions appear as a distinct feature of monolayer OsCl3, suggesting this material to be a better candidate for the exploration of the possible Kitaev-QSL state than previously proposed materials.

Published by the American Physical Society
2024
The role of monetary policy in moderating the effect of international trade price on economic performance in non-WAEMU countries
Authors: Sedegah Kordzo , Odhiambo Nicholas M. , Asongu Simplice
Published: December 2024

Purpose

The present study complements the extant studies by empirically assessing the relevance of monetary policy in moderating the effect of oil price and terms of trade (TOT) on economic performance in non-WAEMU countries for the period 2000–2021.

Design/methodology/approach

Monetary policy is proxied by real interest rate (RIR), real effective exchange rate (REER) and bank credit while economic performance is understood in terms of real output, unemployment and inflation. The adopted empirical strategy is interactive fixed effects regressions.

Findings

The following main findings are established. First, RIR can be used to effectively moderate oil price and TOT in order to positively influence real output and the maximum or avoidable RIR policy thresholds are above policy range. Second, REER can be used to effectively moderate TOT for an overall positive effect on real output and the maximum or avoidable REER threshold of 150.142 REER index is within policy range. Third, bank credit does not effectively moderate the channels (i.e. oil price and TOT) for a significant incidence on real output. Fourth, only bank credit effectively moderates oil price for an overall negative effect on unemployment. However, for this to be possible, bank credit must exceed the threshold of 11.000 of private domestic credit (% GDP). Fifth, only REER effectively moderates TOT for a negative effect on inflation. However, the corresponding policy threshold is above the REER index policy range and hence, cannot be used by policy makers because it does not make economic/statistical sense. Policy implications are discussed.

Originality/value

This study extends the extant literature on potential monetary unions by assessing how monetary policy can be employed in order to moderate the manner in which international trade prices influence economic performance.
Does digital transformation matter for international diversification? The role of product market competition
Authors: Brahmana Rayenda Khresna , Kontesa Maria , Setiawan Doddy
Published: December 2024

Purpose

This study aims to investigate the impact of product market competition on the relationship between firm digital transformation and international diversification. It aims to uncover how competition moderates this relationship and to reveal the nonlinear dynamics between digital transformation and international diversification in strategic decision-making processes.

Design/methodology/approach

Using a panel logistic regression analysis, this study examines data from 235 Malaysian nonfinancial listed companies from 2012 to 2019. The analysis focuses on the manufacturing and technology industries due to the availability of digital transformation data, leading to a data set of 1,180 year-firm observations.

Findings

The results reveal a nonlinear relationship between digital transformation and international diversification, intensified by product market competition. Initially, digital transformation positively affects international diversification, but this effect turns negative as competition increases. Robustness checks validate these findings, indicating that competition’s impact varies with the level of digital transformation.

Research limitations/implications

This study’s findings are based on text analysis as a proxy for digital transformation, which may not fully capture organizational changes. Future research could use reported transformation costs or mandatory disclosures. In addition, this study focuses solely on international diversification, excluding other forms of diversification and financial constraints.

Practical implications

Policymakers should recognize that high product market competition can negate the benefits of digital transformation on internationalization. They need to balance promoting digital transformation with addressing competitive challenges. Managers should analyze the competitive landscape before pursuing international expansion, as high competition can diminish the advantages of digital transformation.

Originality/value

This research enriches agency and resource-based view theories by revealing the complex dynamics between digital transformation, competition and international diversification. It introduces a parabolic relationship between competition and diversification, challenging traditional assumptions and providing a comprehensive framework for understanding strategic decisions in competitive environments.
Closing the deal faster: the role of institutions and government involvement in cross-border M&A completions in Brazil
Authors: Cai Yingdan (Catherine) , Kamasak Rifat , Gorener Rifat
Published: December 2024

Purpose

This paper aims to reveal how institutional distance, institutional quality and government involvement may shorten M&A deal durations in Brazil. Therefore, t paper explains the determinants of M&A deal durations from the perspective of an emerging country acquirer.

Design/methodology/approach

The authors use a distinctive data set from the Thomson SDC Mergers and Acquisitions Database and Zephyr, covering both public and private M&As in Brazil. This sample includes all cross-border M&As in Brazil between 2000 and 2015. They used hierarchical ordinary least squares (OLS) regression to analyze the data set.

Findings

The findings show that informal institutional distance between Brazil and host countries does not impact deal durations when the target is from a developed host. Nonetheless, Brazilian deals involving developing country targets exhibit a positive association between institutional distance and deal durations. The results also reveal that stronger institutional quality reduces the duration of M&A deals executed by Brazilian firms in developed countries. However, no association was found in emerging countries. Finally, government involvement in Brazilian acquirers’ deals did not impact M&A completions in developed countries but prolonged the transactions in emerging countries. Therefore, the outcomes of government involvement occurred differently in developed and emerging host countries and did not manifest as a resource-based advantage.

Originality/value

The authors extend the literature by simultaneously explicating the country-, i.e. institutional distance and institutional quality, and firm-level, i.e. government involvement effects on M&A deal duration from an emerging country acquirer perspective. Second, the authors shed light on the unique impact of government involvement in cross-border M&As, including emerging-developed and emerging-emerging country pairs, on the speed of M&A completions.
An Afrocentric approach to climate change adaptation: indigenous seasonal predictors among Ndau people in Chimanimani in Zimbabwe
Authors: Tirivangasi Happy Mathew , Kontinen Tiina
Published: December 2024

Purpose

The effectiveness of scientific seasonal weather forecasts as a tool to help rural communities in Zimbabwe make decisions is under continuous debate. This persists due to rural communities' ongoing difficulty accessing scientific weather forecasts, early warning systems and remote sensing technologies. As a result, rural people continue to rely on the repository of their indigenous knowledge systems for decision-making, seasonal prediction tools and weather change measurement. This study employs Afrocentric lenses to explore the indigenous seasonal predictors used in rural Zimbabwe to forecast seasonal changes and weather patterns, as well as the climatic variations that these predictors can explain.

Design/methodology/approach

The study employed Afrocentric data generation tools such as transect walks and talking cycles. Thematic content analysis was used to analyze data.

Findings

The study identifies indigenous practices of naming months, typologizing rainfalls and weather forecasting based on fauna and flora, and discusses how climate change has been perceived by drawing on these practices. Moreover, the seasonal predictors were closely intertwined with food production and overall resilience in the face of changing climate. The paper concludes that both research and practical support for climate resilience should start with indigenous ideas and practices related to responding to changing climate conditions, along with scientific meteorological knowledge.

Originality/value

This study underscores the importance of Indigenous knowledge in addressing climate risks. It emphasizes the value of indigenous weather predictions, which predate modern weather stations and have long benefited rural communities. Integrating this knowledge into adaptation policies and practices can lead to more effective and resilient responses to climate change.