bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ungulate personality and the human shield contribute to long-distance migration loss
Authors: Cotterill Gavin G. , Cross Paul C. , Cole Eric K. , Dewey Sarah R. , Wise Benjamin L. , Graves Tabitha A. 
Published: December 2024

AbstractLong-distance ungulate migrations are declining and past research has focused on preserving migration paths where habitat fragmentation and loss disrupts movement corridors. However, changing residency-migration tradeoffs are the stronger driver of long-distance migration loss in some populations. The human shield effect relative to predation risk and anthropogenic food resources likely shapes these tradeoffs, but individual animals also vary in their propensity to tolerate proximity to humans and developed areas. We investigated how personality relative to human-habituation affects migration behavior. We categorized elk as bold or shy based on use of anthropogenic food resources identified through a clustering algorithm applied to GPS collar data. Bold elk were 4 times more likely to select wintering areas close to human activity and migrated 60% shorter distances compared to shy elk. As a result, elk wintering grounds were spatially structured such that conflict- and disease-prone individuals selected areas adjacent to human activity. Our results suggest that bold personality traits act as a precursor to human-habituation, which permits bold elk to reap the forage and predation rewards that occur in suburban landscapes. A multi-pronged approach beyond just maintaining habitat corridors may be necessary to conserve long-distance migrations for species that can become human-habituated.
ColBuilder: Flexible structure generation of crosslinked collagen fibrils
Authors: Monego Debora , Brosz Matthias , Buck Johanna , Viliuga Vsevolod , Jung Jaewoon , Stuehn Torsten , Schmies Matthias , Sugita Yuji , Gräter Frauke 
Published: December 2024

AbstractCollagen fibrils are fundamental building blocks of connective tissues, yet generating accurate molecular models of their structure remains challenging due to their hierarchical organization and complex crosslinking patterns. ColBuilder has been developed to automate the generation of atomistic models of crosslinked collagen fibrils and facilitate the setup of molecular simulations. The tool integrates homology modeling, higher-order structure generation and optimization to build complete fibril structures with precise control over sequence composition, crosslinking patterns, and dimensions. Users can explore different collagen sequences, manipulate crosslink chemistry through mixed ratios and densities, and generate fibrils of varying diameter and length. All-atom molecular dynamics simulations of 335 nm-long fibrils validate the generated structures, showing excellent agreement with experimental measurements of D-band periodicity and force-extension behavior. ColBuilder is available both as an open-source command-line application and through a web interface at colbuilder.mpip-mainz.mpg.de.
Quantification of morphological, functional, and biochemical features of H9c2 rat cardiomyoblast retinoic acid differentiation
Authors: York Nicole S. , Rivera Joel E. , Manesh Mohammadreza Rahmani , Lynes-Ford K’sana Wood , Smith Rory , Wicki-Stordeur Leigh E. , Arbour Laura T. , Swayne Leigh Anne 
Published: December 2024

AbstractCell culture models enable advancement in our understanding of heart development and heart disease. The H9c2 rat ventricular cardiomyoblast cell line can be differentiated, recapitulating certain components of cardiomyocyte development; however, morphological, functional, and biochemical changes are rarely investigated in parallel, thereby limiting fulsome understanding. We therefore characterized morphology, Ca2+handling, and gene expression after five days (5days-in-vitro, DIV5), and fourteen days (DIV14) of exposure to differentiation stimuli, consisting of retinoic acid and low serum. Subpopulations of cells showed evidence of differentiation to a cardiomyocyte-like phenotype that was enhanced over time. Differentiation was also associated with the formation of cytoplasmic actin clusters. Spontaneous Ca2+transients in differentiated H9c2 cells had decreased frequency and synchronicity compared to those observed in primary cardiomyocytes. Additionally, key cardiomyocyte cytoskeletal proteins and ion channel transcript and protein expression levels changed significantly with differentiation, in alignment with changes normally observed in cardiomyocyte development. Our findings suggest H9c2 cells may be used as a high throughput screening model to investigate cardiomyocyte biology in certain developmental contexts with relevance to heart health and disease.Significance statementRetinoic acid-differentiated rat ventricular H9c2 cardiomyoblast cells model aspects of cardiomyocyte development with quick turnover rates and potentially relatively high homogeneity compared to other common cell culture models. Characterizing morphology, Ca2+handling, and gene expression changes will help experimental design and contextualizing outcomes.Subsets of differentiated H9c2 cells exhibit morphology changes consistent with a cardiomyocyte-like phenotype, Ca2+signaling, and gene expression changes.These outcomes suggest H9c2 responses to differentiation increase over time and are somewhat heterogenous as only sub-populations appear to respond. These findings provide insight for designing cardiomyocyte development studies using H9c2 cells in healthy and disease state contexts.
Bicoid-nucleosome competition sets a concentration threshold for transcription constrained by genome replication
Authors: Degen Eleanor A. , Croslyn Corinne , Mangan Niall M. , Blythe Shelby A. 
Published: December 2024

SUMMARYTranscription factors (TFs) regulate gene expression despite constraints from chromatin structure and the cell cycle. Here we examine the concentration-dependent regulation ofhunchbackby the Bicoid morphogen through a combination of quantitative imaging, mathematical modeling and epigenomics inDrosophilaembryos. By live imaging of MS2 reporters, we find that, following mitosis, the timing of transcriptional activation driven by thehunchbackP2 (hbP2) enhancer directly reflects Bicoid concentration. We build a stochastic model that can explainin vivoonset time distributions by accounting for both the competition between Bicoid and nucleosomes athbP2 and a negative influence of DNA replication on transcriptional elongation. Experimental modulation of nucleosome stability alters onset time distributions and the posterior boundary ofhunchbackexpression. We conclude that TF-nucleosome competition is the molecular mechanism whereby the Bicoid morphogen gradient specifies the posterior boundary ofhunchbackexpression.
Monitoring in vivo transcription with synthetic serum markers
Authors: Watanabe Sho , Lee Sangsin , Harb Manwal , Nouraein Shirin , Raisley Emma , Li Honghao , Buitrago Nicolas , Pforr Beatrice , Szablowski Jerzy O. 
Published: December 2024

ABSTRACTUnderstanding transcription profiles of living tissues is critical for biology and medicine. However, measurement of the transcript levels is typically done in homogenized tissues post-mortem. Here, we present a new platform that enables non-invasive monitoring of specific mRNA levelsin vivo, without tissue destruction. We achieved this by combining two cutting-edge tools - synthetic serum markers, called Released Markers of Activity (RMAs), and RNA-based sensors of transcription. We call this platform IN-vivo Tracking of ACtive Transcription, orINTACT. In INTACT, when the target mRNA is expressed, the RNA sensor detects it and triggers the production and release of RMA reporters into the blood. Once in blood, the RMAs can be easily measured through a simple blood draw. Our data shows that INTACT can measure transcription of transgenes, as well as endogenous transcripts, such asc-FosorArc, bothin vivoin the brain and in tissue culture. INTACT enables simple measurement of transcript level histories in genetically-targetable cell populations of living animals.
All ribosomal RNAs and 45S spacers from humans to worms are packed with organism-specific motifs whose other copies are found predominantly in numerous nervous system genes including many associated with human disorders
Authors: Rigoutsos Isidore , Nersisyan Stepan , Londin Eric , Nazeraj Iliza , Dong Bonnie , Vourekas Anastasios , Loher Phillipe 
Published: December 2024

The nucleotide sequences of ribosomal RNAs (rRNAs) and the spacers of 45S are tuned to fulfill optimally their respective roles during ribosome biosynthesis and function. We report that these sequences satisfy additional genome-wide constraints in humans, mice, fruit flies, and worms. In all four organisms, the rRNAs and 45S spacers are densely packed with organism-specific nucleotide motifs with many additional identical copies throughout the genome. The human rRNAs and 45S spacers contain 1,723 motifs whose sequences are unique to the rRNAs/spacers of primates. These motifs have numerous additional exact intronic and exonic copies whose genomic placement is also unique to primates. Specific combinations of the motifs appear exclusively in 3,430 human nervous system and developmental genes, including 1,046 risk genes for autism, schizophrenia, and bipolar disorder. RNA/RNA crosslinking experiments show that the rRNA/spacer motifs are contact points for rRNA-mRNA and mRNA-mRNA heteroduplexes. RNA binding protein (RBP) assays show that these motifs are also in the binding sites of 113 RBPs. RNA sequencing reveals that rRNAs and spacers produce endogenous small non-coding RNAs (sncRNAs) that carry the same primate-specific motifs. Lastly, the motifs’ intergenic and intronic copies overlap 131 GWAS polymorphisms associated with neuropathologies (p-val<3.9e-12). The findings suggest that the motifs facilitate RNA/RNA and RBP/RNA interactions that are affected by polymorphisms and modulated by rRNA- and spacer-derived sncRNAs carrying the same motifs. Our study also genetically links for the first time rRNAs and 45S spacers to autism and other typically human neurological disorders. Mutation panels based on these motifs can lead to new molecular diagnostics for these disorders, whereas snRNAs carrying these motifs can serve as drugs or potential therapeutic targets.Graphical abstractThe human ribosomal RNAs and the 45S spacers share primate-specific motifs with thousands of nervous system genes, including risk genes for autism and other neurological disorders. Similar links between rRNAs/spacers and nervous system genes exist in mice, fruit flies, and worms but are achieved through motifs that are unique to each organism. In humans, the motifs are at the contact points of endogenous gene-gene and rRNA-gene heteroduplexes, as well as the binding sites of RNA binding proteins (RBPs) in genes and rRNAs/spacers. Endogenous small RNAs carrying these shared motifs modulate these endogenous interactions and are disrupted by mutations at the motifs’ genomic copies. Mutation panels based on these motifs can lead to new diagnostics for autism and other disorders, while the small RNAs carrying the motifs can serve as drugs or potential therapeutic targets.
Jan and mini-Jan, a model system for potato functional genomics
Authors: Xin Haoyang , Strickland Luke W. , Hamilton John P. , Trusky Jacob K. , Fang Chao , Butler Nathaniel M. , Douches David S. , Buell C. Robin , Jiang Jiming 
Published: December 2024

SummaryPotato (Solanum tuberosum) is the third most important food crop in the world. Although the potato genome has been fully sequenced, functional genomics research of potato lags relative to other major food crops due primarily to the lack of a model experimental potato line. Here, we present a diploid potato line, ‘Jan’, which possesses all essential characteristics for facile functional genomics studies. Jan has a high level of homozygosity after seven generations of self-pollination. Jan is vigorous and highly fertile with outstanding tuber traits, high regeneration rates, and excellent transformation efficiencies. We generated a chromosome-scale genome assembly for Jan, annotated genes, and identified syntelogs relative to the potato reference genome assembly DMv6.1 to facilitate functional genomics. To miniaturize plant architecture, we developed two “mini-Jan” lines with compact and dwarf plant stature using CRISPR/Cas9-mediated mutagenesis targeting theDwarfandErectagenes related to growth. Mini-Jan mutants are fully fertile and will permit higher-throughput studies in limited growth chamber and greenhouse space. Thus, Jan and mini-Jan provide an outstanding model system that can be leveraged for gene editing and functional genomics research in potato.
HDAC6-Mediated FoxO1 Acetylation And Phosphorylation Control Periodontal Inflammatory Responses
Authors: Lohner Hannah , Han Xiao , Ren Junling , Liang Shuang , Liang Ruqiang , Wang Huizhi 
Published: December 2024

AbstractPost-translational modifications (PTMs) are critical regulators of protein function and cellular signaling. While histone deacetylation by histone deacetylases (HDACs) is well established, the role of specific HDACs in modulating non-histone protein PTMs, particularly in an infectious context, is poorly understood. Here, we reveal a pivotal role for HDAC6 in orchestrating periodontal inflammation through its dual regulatory effects on FoxO1 acetylation and phosphorylation. UsingPorphyromonas gingivalis, a key periodontal pathogen, as a model pathogen, we observed that infection induces HDAC6 activation, driving inflammatory responses via modulating FoxO1 activity. HDAC6 depletion increased FoxO1 acetylation and phosphorylation, leading to its cytoplasmic sequestration and subsequent suppression of FoxO1- mediated pro-inflammatory cytokine production in macrophages. Mechanistically, HDAC6 deficiency not only directly enhances the acetylation of FoxO1 but also upregulates the expression of Rictor, a critical component of the mTORC2 complex, thereby promoting Akt phosphorylation and subsequently FoxO1 phosphorylation. This results in its cytoplasmic retention and attenuated inflammatory transcriptional activity. Functional studies demonstrated that HDAC6 depletion suppressed the production of key inflammatory mediators, including TNFα, IL-6, IL-12p40, and MIP-2, while promoting macrophage polarization toward anti-inflammatory M2 phenotypes.In vivo, using oral gavage infection and ligature-induced mouse periodontitis models, HDAC6 deficiency significantly reduced inflammatory cell infiltration in gingival tissues and protected against alveolar bone loss. These findings establish HDAC6 as a central regulator of periodontal inflammation, acting through the coordinated modulation of FoxO1 acetylation and phosphorylation. Beyond its role in oral pathology, HDAC6 may serve as a promising therapeutic target for managing inflammatory diseases linked to immune dysregulation.
MuSkeMo: Open-source software to construct, analyze, and visualize human and animal musculoskeletal models and movements in Blender
Authors: van Bijlert Pasha A. 
Published: December 2024

AbstractMusculoskeletal models for multibody dynamic analysis provide unique insights into human and animal movement. Although some biomechanical simulators provide model-building tools, these presuppose substantial preprocessing by the user, and resulting models are generally not cross-platform compatible. Thus, the workflow from anatomical 3D scans to musculoskeletal model is time-consuming, requiring numerous processing and conversions steps between software packages, and the process differs between simulators. Despite the popularity of musculoskeletal modelling within biomechanics, no cross-platform, open source software package exists for constructing musculoskeletal models.Here, I introduce MuSkeMo: A software suite for defining 3D musculoskeletal models entirely within Blender (open-source 3D computer graphics software). MuSkeMo provides a visual interface, enabling users to interactively define all aspects of a musculoskeletal model (including rigid bodies, skeletal geometry, joint centres, muscles, landmarks, and body-fixed reference frames). MuSkeMo can calculate 3D inertial tensors from arbitrary meshes (e.g., from CT scans), and also implements automated convex-hull based mass-estimation approaches from the literature. Joints can be defined using shape-fitting of bony surfaces, and muscles can wrap around primitive shapes.Models can be analyzed within MuSkeMo using popular pose-sampling procedures, or exported to multiple text-based formats for use in biomechanical simulators. A conversion script to OpenSim is included.MuSkeMo is compatible with models created for popular biomechanical simulators (OpenSim and Gaitsym). MuSkeMo can import these models and simulation trajectories, enabling users to create publication-ready stills and animations with Blender’s ray tracing. These visualisations include volumetric muscles based on the contractile parameters, which can be more visually intuitive than traditional constant-diameter tube segments.Whether the end goal is a highly-detailed subject-specific human model, or a simplified animal model, MuSkeMo includes features that can aid this process. By consolidating many elements of common model construction workflows into a cohesive package, MuSkeMo substantially simplifies musculoskeletal modelling.
Downstream branches of receptor tyrosine kinase signaling act interdependently to shape the face
Authors: Hanne Nicholas , Hu Diane , Vidal-García Marta , Allen Charlie , Shakir M. Bilal , Liu Wei , Hallgrímsson Benedikt , Marcucio Ralph 
Published: December 2024

AbstractBackgroundPreviously we found that increasing fibroblast growth factor (FGF) signaling in the neural crest cells within the frontonasal process (FNP) of the chicken embryo caused dysmorphology that was correlated with reduced proliferation, disrupted cellular orientation, and lower MAPK activation but no change in PLCy and PI3K activation. This suggests RTK signaling may drive craniofacial morphogenesis through specific downstream effectors that affect cellular activities. In this study we inhibited three downstream branches of RTK signaling to determine their role in regulating cellular activities and how these changes affect morphogenesis of the FNP.ResultsSmall molecule inhibitors of MEK1/2, PI3K, and PLCy were delivered individually and in tandem to the right FNP of chicken embryos. All treatments caused asymmetric proximodistal truncation on the treated side and a mild expansion on the untreated side compared to DMSO control treated FNPs. Inhibiting each pathway caused similar decreased proliferation and disrupted cellular orientation, but did not affect apoptosis.ConclusionsSince RTK signaling is a ubiquitous and tightly regulated biochemical system we conclude that the downstream pathways are robust to developmental perturbation through redundant signaling systems.Bullet pointsInhibiting three downstream effectors of receptor tyrosine kinase (RTK) signaling (MEK1/2, PLCy, and PI3K) in the frontonasal process of chicken embryos caused similar mild truncation of growth. Combining all three inhibitors had a slightly stronger effect on truncation.Individual inhibitors did not have specific effects on cellular proliferation, apoptosis, or cellular orientation.The downstream branches of RTK signaling likely have shared interdependent effects on cellular activities that contribute to morphogenesis.
A spreading, multi-tissue wound signal initiates whole-body regeneration
Authors: Breen Catriona , Srivastava Mansi 
Published: December 2024

ABSTRACTAnimal bodies are equipped to sense injuries and respond, and rapid activation of ERK signaling at wound sites has emerged as a recurring mechanism across metazoans. During whole-body regeneration, distant species including cnidarians, planarians and echinoderms activate ERK at wounds to drive early transcriptional changes. However, it is unclear to what extent these are distinct phenomena, utilizing a common effector pathway but with different upstream inputs and downstream functions, or are more deeply alike, sharing upstream inputs, activating cell type(s), or spatiotemporal dynamics. To facilitate thorough comparisons across animals, we examined wound-induced ERK during whole-body regeneration in the acoelHofstenia miamia. ERK signaling is induced at wound sites within 10 minutes post-amputation and peaks in activity within one hour. ERK is required for head and tail regeneration and inhibiting ERK suppresses the expression of wound-induced genes, which are themselves required for regeneration. Quantification of spatial dynamics revealed that active ERK spreads rapidly away from the wound site during the first 30 minutes post-amputation and continues to expand in space through 3-6 hours, albeit at lower levels. Multiple cell types activate ERK including neoblasts (stem cells) and muscle, and ERK is spatially dynamic within both cell types, however, ERK activation in muscle does not require neoblasts. Finally,neuregulin-1, a putative ligand produced exclusively by muscle cells, is required for ERK activation at wounds. Altogether, our data identify a key signaling role of muscle cells in driving ERK activation in multiple cell types after injury, and describe a spatial spreading phenomenon with parallels to dynamic ERK patterns in other systems.
Solution structure of the Z0 domain from transcription repressor BCL11A sheds light on the sequence properties of protein-binding zinc-fingers
Authors: Harris Rilee E. , Whitehead Richard D. , Alexandrescu Andrei T. 
Published: December 2024

AbstractThe transcription repressor BCL11A, which governs the switch from fetal to adult hemoglobin during development, is the target of the first FDA-approved CRISPR/Cas9 gene-editing therapy in humans. By targeting BCL11A, fetal hemoglobin expression is de-repressed to substitute for defective adult hemoglobin in inherited diseases including beta-thalassemia and sickle-cell anemia. BCL11A has six CCHH-type zinc-fingers of which domains 4-6 are necessary and sufficient for dsDNA binding. Here, we focus on the CCHC-type ZNF at the N-terminus of BCL11A (residues 46-72), Z0, thought to modulate oligomerization of the transcription repressor. Using NMR and CD spectroscopy, Z0 is shown to be a thermostable CCHC zinc-finger with a pM dissociation constant for zinc. The NMR structure of Z0 has a prototypical beta-beta-alpha fold, with a hydrophobic knob comprising about half the structure. The unusual proportion of hydrophobic residues in Z0 led us to investigate if this is more general in zinc-fingers that do not bind dsDNA. We used the ZF and WebLogo servers to examine sequences of zinc fingers with demonstrated DNA-binding function, non-binders, and the CCHC-type family of protein-binders. DNA-binders are distinguished by contiguous stretches of high-scoring zinc-fingers. Non-DNA-binders show a depletion of polar residues at the positions expected to contact nucleotides and increased divergence from sequence consensus making these domains more likely to be annotated as atypical, degenerate, or to be missed as zinc-fingers. We anticipate these sequence patterns will help distinguish DNA-binders from non-binders, an open problem in the functional understanding of zinc-finger motifs.