bluuebunny/crossref_metadata_2025 huggingface dataset:
PRESENCE OF A LARGE DASYPODIDAE GRAY, 1821 FROM THE CUVIERI CAVE, EASTERN BRAZIL
Authors: Chahud Artur
Published: January 2025

Cingulata represent a group of Xenarthra characterized by the presence of a carapace composed of bony plates (osteoderms). The Cuvieri Cave, located in the Lagoa Santa karst complex, presents a relevant quantity of vertebrate fossils, including extinct and extant species. Although several paleontological studies have been carried out, the material was reviewed from a taxonomic point of view, including Xenarthra material. Two osteoderms, initially attributed to the genusEuphractus, were found in Pleistocene deposits, but it was observed that the specimens did not belong to this genus. The aim of this study is to present the revision of these two specimens, now recognized as the first evidence of a large member of the family Dasypodidae in the Cuvieri Cave. The specimens were found in levels where both extant and extinct species from the Lagoa Santa region were found, but due to the paleoenvironmental changes of the Pleistocene-Holocene transition in Lagoa, it was not possible to determine the environment in which the specimen lived.
Fibroblast contractility drives network reorganization and epithelial proliferation in intestinal polyposis
Authors: Li Mei-Lan , Wang Yuying , Figetakis Maria , Gonzalez David , Jin Jason , McDonald Elizabeth S. , Ameen Nadia A. , Sumigray Kaelyn
Published: January 2025

Fibroblasts are critical regulators of epithelial homeostasis through mechanics and signaling. However, the regulatory principles governing fibroblast behaviors are largely unknown. Fibroblast dysregulation has emerged as a pathological contributor in epithelial diseases such as intestinal polyposis. Here, using an inducible Bmp-loss-of-function polyposis model, we define stepwise mechanisms unraveling how dysregulated signaling perturbs fibroblast behaviors, which in turn, disrupt their function to regulate epithelial homeostasis. Intriguingly, the first initiating event leading to epithelial polyps was architectural and impacted the fibroblasts, not the epithelium. Bmp signaling inhibition caused fibroblasts to become hypercontractile, leading to their reorganization from an elaborate network into collapsed clusters beneath crypts. Disrupted fibroblast mechanics and compartmentalization preceded epithelial hyperproliferation in polyps. Using in vitro models, we show that fibroblast hypercontractility not only disrupted fibroblast organization, but also enhanced the ability of fibroblasts to support epithelial growth, leading to epithelial dysregulation. Overall, our studies reveal stepwise regulatory mechanisms underlying fibroblast signaling, mechanics and organization critical for their function to regulate epithelial homeostasis.
Using a Pharmacokinetic Model to Design and Evaluate an Early ctDNA Biomarker for Response to Targeted Therapy
Authors: Li Aaron
Published: January 2025

Early prediction of response to therapy or lack thereof can help physicians plan treatment more efficiently. Biomarkers based on circulating tumor DNA (ctDNA) are promising. However, biomarkers beyond direct comparison to baseline have not been thoroughly explored. We develop a model for ctDNA shedding under targeted therapy that incorporates pharmacokinetics. Using a simulated cohort of virtual patients with varied parameters, we define and analyze a biomarker based on ctDNA samples at baseline, 12 hours, and 24 hours after initiation of treatment. The biomarker identified patients who would achieve partial or complete response with high sensitivity and specificity and was able to match the performance of a neural network classifier. Our result highlights the potential of ctDNA as a biomarker and underlines the importance of early ctDNA data collection.
A Machine Learning-based Approach for Quantification of Protein Secondary Structures from Discrete Frequency Infrared Images
Authors: Edmonds Harrison , Mukherjee Sudipta S. , Holcombe Brooke , Yeh Kevin , Bhargava Rohit , Ghosh Ayanjeet
Published: January 2025

Discrete frequency infrared (IR) imaging is an exciting experimental technique that has shown promise in various applications in biomedical science. This technique often involves acquiring IR absorptive images at specific frequencies of interest that enable pathologically relevant chemical contrast. However, certain applications, such as tracking the spatial variations in protein secondary structure of tissue specimens, necessary for the characterization of neurodegenerative diseases, require deeper analysis of spectral data. In such cases, the conventional analytical approach involves band fitting the hyperspectral data to extract the relative populations of different structures through their fitted areas under the curve (AUCs). While Gaussian spectral fitting for one spectrum is viable, expanding that to an image with millions of pixels, as often applicable for tissue specimens, becomes a computationally expensive process. Alternatives like Principal Component Analysis (PCA) are less structurally interpretable and incompatible with sparsely sampled data. Furthermore, this detracts from the key advantages of discrete frequency imaging by necessitating acquisition of a more finely sampled spectral data that is optimal for curve fitting, resulting in significantly longer data acquisition times, larger datasets and additional computational overhead. In this work we demonstrate that a simple two-step regressive neural network model can be utilized to mitigate these challenges and employ discrete frequency imaging for retrieving the results from band fitting without significant loss of fidelity. Our model reduces the data acquisition time nearly 6-fold by requiring only seven wavenumbers to accurately interpolate spectral information at a higher resolution, and subsequently using the upscaled spectra to accurate predict the component AUCs, which is more than 3000 times faster than spectral fitting. Our approach thus drastically cuts down the data acquisition and analysis time and predicts key differences in protein structure that can be vital towards broadening potential applications of discrete frequency imaging.
The influence of reproductive mode on resource competition and diversity patterns in Ediacaran early animal communities
Authors: Mitchell Emily G. , Manica Andrea
Published: January 2025

The appearance of the oldest known animals during the late Ediacaran (∼574 million years ago [Ma])1–4was followed by a phase of little change5. This period, which lasted ∼14 million years, ended with a burst of rapid diversification known as the Ediacaran “Second Wave”. The reasons for these diversity patterns are poorly understood. Here we investigate how reproductive mode mediated community dynamics, and in turn macroevolutionary change, in the Ediacaran. We show that widespread reproduction via stolon (namely via filaments connecting clones) in the first animals limited intra-specific competition among neighbours, leading to inter-specific competition acting at smaller-spatial scales than intra-specific competition, a phenomenon called heteromyopia6. Heteromyopia enables co-existence of sub-optimal competitors because the dispersal limitation of the dominant species means that they do not inhabit all the optimal habitat, so that lesser competitors can still exist within the same community, operating under reduced selection pressure. We explored the consequences of this dispersal limitation on community diversity using Approximate Bayesian Computation to estimate the posterior distributions of dispersal with a spatially explicit model fitted to the three Ediacaran assemblages and showed that the change from stoloniferous to sexual reproduction that coincided with the Second Wave could explain the sudden increase in alpha diversity observed in the fossil record. We conclude that widespread asexual reproduction via stolon likely constrained early animal evolution, limiting diversification until the onset of mobility and widespread sexual reproduction7–9.
Chromosomal inversions mediated by tandem insertions of transposable elements
Authors: Araya Robin Aasegg , Reinar William B , Tørresen Ole K , Goubert Clément , Daughton Tara J , Hoff Siv Nam Khang , Baalsrud Helle T , Brieuc Marine Servane Ono , Komisarczuk Anna , Jentoft Sissel , Cerca José , Jakobsen Kjetill S
Published: January 2025

Chromosomal inversions play a crucial role in evolution by influencing phenotypes through the linkage of co-adapted alleles. While inversions have been found across a large number of taxa, mapping and characterizing inversion breakpoint regions remains challenging, often due to the presence of complex tandem repeats and transposable elements (TEs). Here, we identify and quantify TEs in the breakpoints of the four large-scale inversions previously reported in Atlantic cod, leveraging on three high-quality long-read-based reference genome assemblies for the Norwegian Coastal cod, the Northeast Arctic cod and Celtic cod ecotypes. We detected a significant enrichment of TE orders and superfamilies with terminal inverted repeats (TIRs) within the inversion breakpoints of chromosomes 1, 7 and 12. Notably, we discovered a tandem accumulation of miniature inverted-repeat transposable elements (MITEs) belonging to a family ofhATtransposons, exclusively residing in the breakpoints of the inverted haplotype on chromosomes 1 and 7 found in the Northeast Arctic cod. The accumulation of tandemly arranged TEs in breakpoint regions suggests that they have driven the appearance of inversions through ectopic recombination, further supporting the potential of TEs in facilitating chromosomal reorganizations with large evolutionary implications.
30-Color Longitudinal Full-Spectrum Immunophenotyping and Sorting of Human Circulating Immune Cell Subsets Implicated in Systemic Autoimmune Rheumatic Diseases
Authors: Jiwrajka Nikhil , Tuluc Florin , Jaimes Maria C. , Murray Jennifer , Anguera Montserrat C.
Published: January 2025

Purpose and Appropriate Sample Types

This 30-color panel was developed to enable the enumeration and purification of distinct circulating immune cell subsets implicated in the pathogenesis of systemic autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc; scleroderma), Sjögren’s disease (SjD), idiopathic inflammatory myopathy (IIM), and others. While designed for application to peripheral blood mononuclear cells, the inclusion of CD45 coupled with the ability to extract cellular autofluorescence spectral signatures enables the application of this panel to other tissue types. Of the 30 total markers, this panel employs 18 markers to profile T cell subsets consisting of different memory subsets and T helper polarities,>10 markers to profile B cell subsets including double-negative B cells, and a total of 8 lineage markers to identify immune lineages including monocyte and natural killer cell subsets, conventional dendritic cells, plasmacytoid dendritic cells, and basophils. This panel reproducibly identifies target populations with excellent resolution over several months of data acquisition with minimal batch effects, offering investigators a practical approach to sort immune cell subsets of interest for downstream applications while simultaneously collecting high parameter immunophenotypic information using a limited sample quantity.
Palmitate-induced mitochondrial damage restricts histone acetylation in CD8+T cells to impair anti-tumor immunity
Authors: Tiberti Silvia , Romeo Martina , Rumiano Letizia , Nava Lauson Carina B , Sheraj Ilir , Catozzi Carlotta , Noberini Roberta , Olivari Davide , Dallavilla Tiziano , Galie’ Serena , Ballerini Mattia , Loffreda Alessia , Schaefer Martin H. , Bonaldi Tiziana , Nezi Luigi , Sdelci Sara , Manzo Teresa
Published: January 2025

Accumulation of lipids in the tumor microenvironment (TME) is a feature of several solid tumors and increased palmitate (PA) availability fosters tumor progression and metastases. The intrinsic effects of PA on cancer cells are well understood, but its role in modulating CD8+T cells (CTL) functional performances remains elusive. Here, we found that PA alters the mitochondrial metabolism of CTL and prevents their effector functions in an irreversible manner, resulting in impaired antitumoral immunity. Mechanistically, PA-induced mitochondrial block demotes histone acetylation and chromatin accessibility and decrease transcription of genes promoting DNA replication and production of effector molecules. We identified the metabolic enzyme Sphingosine Kinase 2 (SPHK2) as a molecular target of PA in establishing CTL dysfunction. Consistently, pharmacological inhibition of SPHK2 restored CTL mitochondrial fitness, effector functions and anti-tumor potential. Thus, we reveal a critical function of PA in tumor progression by undermining CTL antitumor immunity and highlight the therapeutic potential of inhibiting SPHK2 activity to optimize T cell functionality.
Determining off-target effects of splice-switching antisense oligonucleotides using short read RNAseq in neuronally differentiated human induced pluripotent stem cells
Authors: Kuijper EC , van der Graaf L , Pepers BA , Guimarães Ramos M , Korhorn S , Toonen LJA , Cats D , Buijsen RAM , Mina E , Mei H , van Roon-Mom WMC
Published: January 2025

Antisense oligonucleotides (AONs) are small pieces of chemically modified DNA or RNA that bind to RNA in a sequence-specific manner based on Watson-Crick base-pairing. Splice-switching AONs are designed to modulate pre-mRNA splicing, thereby for instance restoring protein expression or modifying the eventual protein to restore its function or reduce its toxicity. Given the current lack ofin silicomethods that adequately predict off-target splicing events, assessment of off-target effects of AONs in human cells using RNAseq could be a promising approach. The identification and prioritization of potential off-target effects for validation and further investigation into the biological relevance would contribute to the development of safe and effective AONs. In this study, we used three different splice-switching AONs targeting three different human transcripts to study their transcriptome-wide, hybridization-dependent off-target effects with short read RNAseq. Using the computational tools rMATS and Whippet, we identified differential splicing events of which only a minority could be explained by hybridization, illustrating the difficulty of predicting off-target effects based on sequence homology. The main splicing events could all be validated with RT-PCR. Furthermore, from the three AONs studied, one AON induced considerably more changes in gene expression and splicing compared to the two other AONs assessed, which was confirmed in a validation experiment. Our study demonstrates that the interpretation of short read RNAseq data to determine off-target effects is challenging. Nonetheless, we showed that valuable results can be obtained as it allows the comparison of toxicity between different AONs within an experiment and identification of AON-specific off-target profiles.
Applying a conservation-based approach for predicting novel phosphorylation sites in eukaryotes and evaluating their functional relevance
Authors: Kalyuzhnyy Anton , Eyers Patrick A , Eyers Claire E , Deutsch Eric W , Jones Andrew R
Published: January 2025

Protein phosphorylation, a key post-translational modification, is central to cellular signalling and disease pathogenesis. The development of high-throughput proteomics pipelines has led to the discovery of large numbers of phosphorylated protein motifs and sites (phosphosites) across many eukaryotic species. However, the majority of phosphosites are reported from human cellular sources, with most species having only a few experimentally confirmed or computationally predicted phosphosites. Furthermore, only a small fraction of the characterised human phosphoproteome has an annotated functional role. A common method of predicting functionally relevant phosphosites is conservation analysis. However, extensive evolutionary studies involving large numbers of species are scarce. In this study, we explore the conservation of 20,751 confident human phosphosites across 100 eukaryotic species. We link the observed conservation patterns to the functional relevance of phosphosites and investigate the evolution of associated protein domains and kinases. We identify several protein functions that are likely regulated by phosphorylation, including ancient functions conserved across all life and relatively new functions only conserved in species closely related to humans. We demonstrate the importance of conservation analysis in identifying organisms suitable as biological models for studying conserved signalling pathways relevant to human biology and disease. Finally, we use human protein sequences as a reference to apply conservation analysis and predict over 1,000,000 potential phosphosites in analysed eukaryotes. Our results can ultimately be used to improve proteome annotations of several species and direct downstream research surrounding the evolution and functional relevance of eukaryotic phosphosites.
AI-Driven Toolset for IPF and Aging Research Associates Lung Fibrosis with Accelerated Aging
Authors: Galkin Fedor , Chen Shan , Aliper Alex , Zhavoronkov Alex , Ren Feng
Published: January 2025

Idiopathic pulmonary fibrosis (IPF) is a condition predominantly affecting the elderly and leading to a decline in lung function. Our study investigates the aging-related mechanisms in IPF using artificial intelligence (AI) approaches. We developed a pathway-aware proteomic aging clock using UK Biobank data and applied it alongside a specialized version of Precious3GPT (ipf-P3GPT) to demonstrate an AI-driven mode of IPF research. The aging clock shows great performance in cross-validation (R2=0.84) and its utility is validated in an independent dataset to show that severe cases of COVID-19 are associated with an increased aging rate. Computational analysis using ipf-P3GPT revealed distinct but overlapping molecular signatures between aging and IPF, suggesting that IPF represents a dysregulation rather than mere acceleration of normal aging processes. Our findings establish novel connections between aging biology and IPF pathogenesis while demonstrating the potential of AI-guided approaches in therapeutic development for age-related diseases.
Genomic exaptation and regulatory landscape shifts as key mechanisms enabling flatworm terrestrialization
Authors: Benitez-Alvarez Lisandra , Garcia-Vernet Raquel , Eleftheriadi Klara , Vargas-Chavez Carlos , Escudero Nuria , Salces-Ortiz Judit , Rojo Inaki , Fernandez-Alvarez Fernando Angel , Chiva Cristina , Sabido Eduard , Mateos Eduardo , Carbayo Fernando , Fernandez Rosa
Published: January 2025

Understanding the genomic toolkit that facilitated animal terrestrialization - the transition from aquatic to terrestrial environments - is crucial for unravelling the evolutionary processes behind the origin and diversification of terrestrial biodiversity. Despite its significance, the genomic foundations driving the physiological and metabolic adaptations required for life on land remain largely unexplored across most terrestrial animal phyla. Planarians (phylum Platyhelminthes) represent an ideal model for studying terrestrialization, as only one terrestrial lineage, the family Geoplanidae (order Tricladida) is known to exist. Here, we used an integrative approach combining genomics, transcriptomics, and proteomics to investigate the genetic underpinnings potentially facilitating adaptation to terrestrial environments. Our analysis revealed a significant burst of gene gain preceding the diversification of terrestrial planarians and their split from freshwater relatives, in the branch leading to Tricladida. Upon exposure to abiotic stress, terrestrial and freshwater planarians exhibited distinct genetic toolkits: most differentially expressed genes emerged in orthologous groups gained specifically in the branch leading to Tricladida, over half of which showed signs of strong directional selection in terrestrial flatworms, indicating their adaptive importance for land colonization. Transcriptomic analyses further revealed contrasting stress responses: terrestrial planarians upregulated ancient genes whose origin predates the Geoplanidae lineage to cope with abiotic stress, while freshwater planarians downregulated a separate set of ancestral genes. Our genomic, transcriptomic, and proteomic data consistently show that the genetic toolkit for abiotic stress response in terrestrial planarians is highly differentiated from that of their freshwater counterparts, with significant regulatory shifts as well. Overall, our findings suggest a burst of gene gain in the Tricladida lineage, with co-option of these genes, rather than clade-specific innovations, playing a critical role in the origin and diversification of terrestrial flatworms. This underscores genomic exaptation and regulatory landscape shifts as key mechanisms enabling terrestrialization within Platyhelminthes. This study offers the first genome-wide insight into the genetic toolkit underlying flatworm terrestrialization and contributes broadly to understanding the genomic basis of animal terrestrialization.
Cadmium tolerance is associated with tissue-specific plasticity of metallothionein gene expression inGammarus fossarumfield populations
Authors: Lalouette Auréline , Chaumot Arnaud , Lepeule Louveline , Gaget Karen , Delorme Nicolas , Garnero Laura , Calevro Federica , Degli Esposti Davide
Published: January 2025

The metallothionein gene family codes for proteins involved in metal homeostasis and acute detoxification of non-essential toxic metal ions across the tree of life. We have previously documented increased cadmium (Cd) tolerance in field populations of the crustaceanGammarus fossarumexposed to chronic metallic contamination of geochemical origin. This tolerance is lost during maintenance of organisms in the laboratory, and is transmitted to offspring via parental effects. This study investigated whether the expression of the Cd-responsive metallothionein genemt1could be related to Cd-tolerance plasticity inG. fossarum. In eleven populations with different chronic Cd exposure history, we simultaneously assessed Cd-tolerance (mortality tests) andG. fossarum mt1expression levels by RT-qPCR in the gills and caeca of adult males and in neonates.mt1expression levels in the two organs were correlated to Cd-tolerance in field organisms and a loss of tolerance was observed in parallel with a decreased expression ofmt1in the caeca after maintenance in uncontaminated water. We also recorded a greater inducibility ofmt1expression in offspring of tolerant populations in the laboratory when re-exposed to Cd along with the bi-parental transmission of Cd-tolerance. These results suggest that the control ofmt1expression is involved in the plasticity of Cd-tolerance in gammarid populations with different histories of Cd exposure.

Highlights

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mt1gene expression in the gills and in the hepatopancreatic caeca is associated with Cd tolerance inGammarus fossarumpopulations.

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Plasticity ofG. fossarum mt1gene expression is associated to loss of Cd tolerance.

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Parental effect in Cd tolerance is supported by transgenerational control ofmt1expression, underlid by an increased induction ofmt1during Cd exposure.
Interfacial tension and growth both contribute to mechanical cell competition
Authors: Valon Léo , Matamoro-Vidal Alexis , Villars Alexis , Levayer Romain
Published: January 2025

Tissue plasticity and homeostasis rely on the mutual interplay between cell behaviour and mechanical inputs. Yet, mechanical stress can also contribute to the evolution of some pathologies, notably by accelerating pretumoural cell expansion through the process of mechanical cell competition. Mechanical cell competition is a conserved process in which one cell population is preferentially eliminated when mixed with another cell population due to its higher sensitivity to mechanical stress. Most of the recent theoretical and experimental explorations of mechanical cell competition focused so far on the contribution of growth and pressure to cell elimination and were limited to few genetic contexts, including the activation of Ras in vivo, and the mutation of the polarity gene scribble in mammalian cell culture. However, it remains unclear whether other oncogenes can trigger similar mechanisms and whether growth is generally the only central regulator of cell compaction and cell elimination. Using the Drosophila pupal notum (a single layer epithelium), quantitative live imaging and vertex modelling, we revisited the mechanisms contributing to cell compaction and cell elimination during mechanical cell competition. Doing so, we outlined the co-existence of two modes of wild type (WT) cell compaction near oncogenic cells, namely the compaction driven by growth versus local compaction driven by increased tension at tumoural/WT cell interfaces in zones of high curvature (similar to Laplace pressure). We highlighted distinctive signatures in cell deformation and cell elimination distribution that can delineate these two modes of compaction, and we recapitulated them in silico and in vivo using genetic backgrounds affecting growth and/or interfacial tension independently. Altogether, this study reveals for the first time the contribution of interfacial tension-driven compaction to mechanical cell competition and outlines the co-existence of various modes of compaction during cell elimination and pretumoural clone expansion.
Altered RNA-processing provides a mechanistic framework delineating human sex-reversal associated with pathogenic variants in the RNA-helicase DHX37
Authors: Elzaiat Maëva , Talouarn Estelle , Wankanit Somboon , Schlick Laurène , Eozenou Caroline , Bignon-Topalovic Joëlle , Kornobis Etienne , Commere Pierre-Henri , Baum Chloé , Seffer Valérie , McElreavey Ken , Bashamboo Anu
Published: January 2025

Recurrent heterozygous missense variants in the highly conserved RNA-helicaseDHX37,which is required for ribosome biogenesis, are a frequent cause of 46,XY sex-reversal or testis regression syndrome. How these missense variants specifically disrupt testis formation is unknown. Here, we demonstrate that mutant DHX37 proteins retain their ATPase activity and are not associated with stabilization of cellular β-catenin. Transfection of DHX37 p.R674Q mutant protein in anin-vitrocellular model recapitulating human Sertoli cell formation, showed a reduced activation of pro-testis genes compared to the WT protein. The expression of a DHX37 mutant protein inin-vitroderived human Sertoli-like cells (iSLCs) was also associated with global changes in gene expression, predicted to impact basic cellular functions. To define RNA transcripts interacting with either the WT or a mutant (p.R674Q) protein, we combined HyperTRIBE and single-cell full-length RNA-sequencing approaches using iSLCs. Gene ontology analysis indicated that transcripts targeted by WT DHX37 were primarily associated with cytoskeleton organization, including cell motility and cell adhesion. However, in contrast transcripts targeted by the mutated DHX37 protein, were not only associated with cytoskeleton organization but also with protein degradation and cell death. These data provide mechanistic framework that may explain how variants in the DHX37 protein can result in 46,XY sex-reversal through altered RNA networks that are required for the formation and maintenance of the supporting cell lineages of the human testis.
The PST repeat region of MDC1 is a tunable multivalent chromatin tethering domain
Authors: Heyza Joshua R. , Mikhova Maria , Perez Gloria I. , Broadbent David G. , Schmidt Jens C.
Published: January 2025

DNA double strand breaks (DSBs) are widely considered the most cytotoxic DNA lesions occurring in cells because they physically disrupt the connectivity of the DNA double helix. Homologous recombination (HR) is a high-fidelity DSB repair pathway that copies the sequence spanning the DNA break from a homologous template, most commonly the sister chromatid. How both DNA ends, and the sister chromatid are held in close proximity during HR is unknown. Here we demonstrate that the PST repeat region of MDC1 is a mutlivalent nucleosome binding domain, sufficient to tether chromatin in multiple contexts. In mitotic cells the affinity of the PST repeats for chromatin is downregulated by phosphorylation to prevent chromosome missegregation, while still contributing to DNA break tethering by the MDC1-TOPBP1-CIP2A complex. In interphase, the PST repeat region is critical for RAD51 focus formation but not the recruitment of 53BP1 to DNA breaks, consistent with a chromatin tethering function. In total, this work demonstrates that the PST repeat region of MDC1 is a multivalent chromatin binding domain with tunable affinity that contributes to DNA break tethering during HR and in mitosis.
Euprymna berryias a comparative model host forVibrio fischerilight organ symbiosis
Authors: Imes Avery M. , Pavelsky Morgan N. , Badal Klodia , Kamp Derrick L. , Briseño John L. , Sakmar Taylor , Vogt Miranda A. , Nyholm Spencer V. , Heath-Heckman Elizabeth A. C. , Grasse Bret , Septer Alecia N. , Mandel Mark J.
Published: January 2025

Functional studies of host-microbe interactions benefit from natural model systems that enable exploration of molecular mechanisms at the host-microbe interface. BioluminescentVibrio fischericolonize the light organ of the Hawaiian bobtail squid,Euprymna scolopes, and this binary model has enabled advances in understanding host-microbe communication, colonization specificity,in vivobiofilms, intraspecific competition, and quorum sensing. The hummingbird bobtail squid,Euprymna berryi,can be generationally bred and maintained in lab settings and has had multiple genes deleted by CRISPR approaches. The prospect of expanding the utility of the light organ model system by producing multigenerational host lines led us to determine the extent to which theE. berryilight organ symbiosis parallels known processes inE. scolopes. However, the nature of theE. berryilight organ, including its microbial constituency and specificity for microbial partners, have not been examined. In this report, we isolate bacteria fromE. berryianimals and tank water. Assays of bacterial behaviors required in the host, as well as host responses to bacterial colonization, illustrate largely parallel phenotypes inE. berryiandE. scolopeshatchlings. This study revealsE. berryito be a valuable comparative model to complement studies inE. scolopes.

IMPORTANCE

Microbiome studies have been substantially advanced by model systems that enable functional interrogation of the roles of the partners and the molecular communication between those partners. TheEuprymna scolopes-Vibrio fischerisystem has contributed foundational knowledge, revealing key roles for bacterial quorum sensing broadly and in animal hosts, for bacteria in stimulating animal development, for bacterial motility in accessing host sites, and forin vivobiofilm formation in development and specificity of an animal’s microbiome.Euprymna berryiis a second bobtail squid host, and one that has recently been shown to be robust to laboratory husbandry and amenable to gene knockout. This study identifiesE. berryias a strong symbiosis model host due to features that are conserved with those isE. scolopes, which will enable extension of functional studies in bobtail squid symbioses.
An extended and apical supracellular actin network interconnects squamous carcinoma cells
Authors: Marpeaux Léa , Baudouin Claire , Delsin Lara Elis Alberici , Plutoni Cédric , Keil Sarah , Emery Gregory
Published: January 2025

Epithelial tissues form protective barriers while supporting critical functions such as absorption and secretion. Their structural and functional integrity relies on adherens junctions, which coordinate migration and transmit forces between adjacent cells by connecting their actin cytoskeleton. In this study, we report the presence of an apical supracellular actin network in squamous epithelial cells. Using squamous carcinoma A431 cells as a model, we characterized this network composed of star-shaped actin structures interconnected by linear actin bundles that span multiple cells. We demonstrate that the network’s formation and maintenance require actomyosin contractility and intact adherens junctions, while tight junctions seem dispensable. Furthermore, this network dynamically reorganizes as cells migrate and preferentially aligns with the direction of movement. This contractile structure generates mechanical tension that extends across the apical surface of multiple cells. Our findings suggest that this supracellular actin network functions as a long-range force transmission device in squamous cells, advancing our understanding of the biomechanical properties of epithelia.
Interindividual differences (bold and shy strategies) in neophobia may explain the invasive success of the wormEisenia fetida
Authors: Pedraza Alexandra Rodriguez
Published: January 2025

When they are confronted to novel environments individuals may express different kinds of behaviors. They can move a little or even stay immobile with few exploration of the new environment or they can increase their activity, move a lot and explore actively the new place. Several studies on neophobia have been conducted on vertebrate species and they distinguish bold and shy patterns in animals’ reactions. Less studies have been conducted on invertebrates in this area. Here I present the case of the worm Eisenia fetida that I tested in open field tests in order to detect if they present different response profiles when confronted to a novel environment and how these profiles can vary depending on size factor. I was able to distinguish two profiles, a shy/philopatric reaction present in young and adults and a bold/explorer reaction that can be observed in mature worms. From the 311 worms tested one half was bold/explorer and the other half was shy/philopatric. The existence of these two profiles may explain the invasiveness of the species: some indivivuals stay and occupy the known environments and some individuals enhance their activity in order to colonize other environments.
Assessing Inflammatory Protein Biomarkers in COPD Subjects with and without Alpha-1 Antitrypsin Deficiency
Authors: Moll Matthew , Hobbs Brian D. , Pratte Katherine A. , Zhang Chengyue , Ghosh Auyon J. , Bowler Russell P. , Lomas David A , Silverman Edwin K. , DeMeo Dawn L.
Published: January 2025

Rationale

Individuals homozygous for the Alpha-1 Antitrypsin (AAT) Z allele (Pi*ZZ) exhibit heterogeneity in COPD risk. COPD occurrence in non-smokers with AAT deficiency (AATD) suggests inflammatory processes may contribute to COPD risk independently of smoking. We hypothesized that inflammatory protein biomarkers in non-AATD COPD are associated with moderate-to-severe COPD in AATD individuals, after accounting for clinical factors.

Methods

Participants from the COPDGene (Pi*MM) and AAT Genetic Modifier Study (Pi*ZZ) were included. Proteins associated with FEV1/FVC were identified, adjusting for confounders and familial relatedness. Lung-specific protein-protein interaction (PPI) networks were constructed. Proteins associated with AAT augmentation therapy were identified, and drug repurposing analyses performed. A protein risk score (protRS) was developed in COPDGene and validated in AAT GMS using AUC analysis. Machine learning ranked proteomic predictors, adjusting for age, sex, and smoking history.

Results

Among 4,446 Pi*MM and 352 Pi*ZZ individuals, sixteen blood proteins were associated with airflow obstruction, fourteen of which were highly expressed in lung. PPI networks implicated regulation of immune system function, cytokine and interleukin signaling, and matrix metalloproteinases. Eleven proteins, including IL4R, were linked to augmentation therapy. Drug repurposing identified antibiotics, thyroid medications, hormone therapies, and antihistamines as potential AATD treatments. Adding protRS improved COPD prediction in AAT GMS (AUC 0.86 vs. 0.80, p = 0.0001). AGER was the top-ranked protein predictor of COPD.

Conclusions

Sixteen proteins are associated with COPD and inflammatory processes that predict airflow obstruction in AATD after accounting for age and smoking. Immune activation and inflammation are modulators of COPD risk in AATD.
High Cognitive Violation of Expectations is Compromised in Cerebellar Ataxia
Authors: Daniel A Leonardo , Vakil Eli , Saban William
Published: January 2025

While traditionally considered a motor structure, the cerebellum is also involved in cognition. However, the underlying cognitive mechanisms through which the cerebellum contributes to evolutionarily novel cognitive abilities remain poorly understood. Another open question is how this structure contributes to a core unifying mechanism across domains. Motivated by the evolutionary principle of neural reuse, we suggest that a successful account of cerebellar contributions to higher cognitive domains will build on the structure’s established role in motor behaviors. We conducted a series of neuropsychological experiments, assessing selective impairments in participants with cerebellar ataxia (CA) compared to neurotypicals in solving sequential discrete problems. In three experiments, participants were asked to solve symbolic subtraction, alphabet letter transformation, and novel artificial grammar problems, which were expected or unexpected. The CA group exhibited a disproportionate cost when comparing expected problems to unexpected problems, suggesting that the cerebellum is critical for violation of expectations (VE) across tasks. The CA group impairment was not found either when the complexity of the problem increased or in conditions of uncertainty. Together, these results demonstrate a possible causal role for the human cerebellum in higher cognitive abilities. VE might be a unifying cerebellar-dependent mechanism across motor and cognitive domains.

Significance Statement

While the cerebellum, a phylogenetically ancient brain region, is traditionally viewed as a motor structure, evidence suggests its involvement in cognition. However, the mechanisms by which the cerebellum supports evolutionarily novel cognitive abilities remain poorly understood. In addition, despite theoretical proposals, direct evidence for the cerebellum’s contribution to a core unifying mechanism across non-motor domains is lacking. Drawing on the principle of neural reuse, we present neuropsychological evidence highlighting the cerebellum’s causal role in symbolic arithmetic reasoning, alphabet transformation, and grammar problems via violation of expectations processes. The results offer a new perspective on how, rather than merely if, the cerebellum contributes to higher cognition, suggesting a constraint on its role in cognitive domains.
Barriers and facilitators to alcohol support for South Asian communities: a qualitative framework analysis of UK service provider perspectives
Authors: Jennings Stacey , Dein Simon , Foster Graham R
Published: January 2025

Background

Despite displaying pronounced alcohol-related physical and psychological harms, South Asian groups are critically underrepresented in alcohol treatment and research. Aggregate categorisation of diverse ethnic groups into ‘BAME’ collectives has perpetuated substantial knowledge gaps about the alcohol support needs of individual ethnic groups. Whilst there has been a recent growth in studies exploring the specific alcohol behaviours and support needs of South Asian groups, there is limited knowledge of professional experiences. This study aimed to address this gap by exploring service provider perspectives on barriers and facilitators to alcohol support for South Asian communities in the UK.

Methods

We carried out individual semi structured interviews with multidisciplinary staff spanning statutory and specialist services within East London in the UK. Interviews explored staff experiences and attitudes towards topics such as alcohol use triggers, maintenance factors, suitability of support options, and professional training needs. We adopted an intersectional lens during analysis to explore the influence and interplay of other relevant characteristics with ethnicity. We used qualitative framework analysis to identify relevant themes and map them onto a pre-existing risk environment framework across different levels (micro, meso, macro) of influence.

Results

10 participants took part. 5 themes were developed that reflect barriers and facilitators to alcohol support across macro (‘service structure’), meso (‘cultural competence’, ‘gendered experience’ ‘religio-cultural norms’) and micro (‘lifestyle choice’) levels of influence. An intersectional lens indicated gendered, ethnic, and religious nuances in drinking and treatment seeking experiences. Whilst the overlapping nature of the micro-meso-macro levels was evident in the study findings, meso level factors were most established.

Conclusions

This study highlighted key areas of focus and unique barriers for diverse South Asian groups seeking support for alcohol misuse, with clear implications for culturally competent policy and practice in the UK context. Barriers such as short funding cycles, historical discrimination, ‘one size fits all’ approaches and training gaps on sensitive communication strategies pose challenges. Conversely, facilitators like targeted family education strategies and improving collaborative efforts between alcohol service types enhance support. Tailored specialist alcohol support for South Asian women is crucial.
Short-term variability of chronic musculoskeletal pain
Authors: Zheng Xuanci , Rajwal Swati , Ashworth Carl , Ho Sharon Yuen Shan , Seymour Ben , Shenker Nicholas , Mancini Flavia
Published: January 2025

BACKGROUND

Chronic musculoskeletal (MSK) pain can be characterized by its temporal variability and evolution, affecting both pain management and treatment outcomes. While pain variability is traditionally studied over long timescales (e.g. days or weeks), few studies have explored short-term fluctuations (e.g. minutes to seconds) and their clinical relevance. This study investigated the short-term variability of chronic musculoskeletal pain across consecutive days, examining whether these fluctuations are stable, exhibit consistent temporal patterns, and relate to clinical severity. We also explored whether individuals with chronic MSK pain could predict their pain intensity on the following day, suggesting an ability to learn about their pain’s levels.

METHODS

Eighty-one participants with chronic MSK pain to the back, neck, leg or arm rated their pain continuously over two days, using a smartphone-based app.

FINDINGS

Results indicated that pain ratings were stable and exhibited consistent temporal patterns across days, with a temporally correlated structure. High mean pain levels were associated with lower variability, possibly reflecting a stabilized pain state. Short-term pain variability negatively correlated with clinical severity, indicating that greater variability is linked to milder pain.

IMPLICATIONS

These findings highlight the importance of short-term variability as a distinct and clinically relevant feature of chronic MSK pain, with implications for personalized pain management strategies.
Can Rights-Based Conditional Cash Transfers Improve Children’s Nutrition at scale? Evidence from India’s Maternity Benefit Program
Authors: Ray Soumyajit , Chakrabarti Suman , Pal Sumantra , Nguyen Phuong Hong , Scott Samuel , Menon Purnima
Published: January 2025

This study evaluates the impact of India’s Pradhan Mantri Matru Vandana Yojana (PMMVY), a large-scale conditional cash transfer (CCT) program targeting women during their first birth, on child nutrition. Using National Family Health Survey (NFHS) data from 2005 to 2021, we assess changes in growth for 296,782 children under five years old before and after PMMVY implementation. To address potential biases, we employ a quasi-experimental approach with a Triple Difference analysis, comparing first- to second-born children of CCT and non-CCT mothers. We find that potential exposure to PMMVY is associated with improvements in weight-for-age and height-for-age z-scores. These effects likely operate through increased pregnancy registration, antenatal care, and immunizations. PMMVY is cost-effective, with a short-run benefit-cost ratio of 1.35. This study underscores the importance of CCT programs targeting mothers in enhancing child nutrition in low- and middle-income countries.
Microscopic Control of Cortical Flows in PolarizedC. elegansZygotes
Authors: White Elizabeth D. , Li Younan , Kadzik Rachel , Qiu Yuqing , Dinner Aaron R. , Munro Edwin M.
Published: January 2025

Cell polarization, migration, and cytokinesis rely on flows of the cell cortex, a network of actin filaments, cross-linkers, and motors beneath the plasma membrane of animal cells. While actin network architecture, assembly dynamics, and motor activity are known to be important for cortical flows, how their modulation tunes macroscopic flow dynamics remains poorly quantifiedin vivo. Here, we use quantitative microscopy to constrain agent-based simulations that account for filament assembly, crosslinking, and motor activity. We calibrate the model to reproduce steady-state flows in polarizedC. eleganszygotes and then challenge it to predict the results of RNA interference (RNAi) experiments. Our model predicts, and experiments largely confirm, a biphasic dependence of flow speed on microscopic rates of actin filament assembly and crosslinking. This biphasic dependence reflects a competition between the tendencies of perturbations to disrupt both transmission of and resistance to cortical forces. Our results provide new insights into how variations in microscopic features shape the emergent dynamics of the cell cortex. By establishing a well-calibrated model of cortical flow in a highly tractable model cell, we also provide a foundation for future studies of microscopic origins and biological control of cortical contractility and flowin vivo.
Squid primary cell culture as a model system and experimental tool
Authors: Kim Yoonji , Tanner Hailey M. , Rosenthal Joshua J. C. , Brangwynne Clifford P.
Published: January 2025

Squid primary cells from various tissues and ages are isolated, maintained in culture, and express exogenous genes. This protocol opens up numerous opportunities in molecular biology, neuroscience, and marine biology, enabling molecular and cellular-level investigations into processes specific to squids, including their complex behaviors, rapid color change mechanisms, RNA editing capabilities, with broader implications in basic cell physiology. We also describe procedures that harness life-stage tractability inEuprymna berryisquids towards future studies of aging in this model marine organism.

Highlights

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Squid primary cells are isolated from optic lobes, gills, eyes, and the skin

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Cells from these tissues can be dissociated from any life stage of the squid

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Isolated cells can express exogenous genes through mRNA transfections and are subject to live and/or fixed cell imaging

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Specific details for optimized media conditions, trypsinization, plating, and passaging are included