bluuebunny/crossref_metadata_2025 huggingface dataset:
Large-scale investigation for antimicrobial activity reveals novel defensive species across the healthy skin microbiome
Authors: Nguyen Uyen Thy , Salamzade Rauf , Sandstrom Shelby , Swaney Mary Hannah , Townsend Elizabeth C. , Wu Sherrie , Cheong J.Z Alex , Sardina Joseph A , Ludwikoski Isabelle , Rybolt Mackinnley , Wan Hanxiao , Carlson Caitlin M. , Zaronowaki Robert , Andes David R , Currie Cameron , Kalan Lindsay
Published: November 2024

The human skin microbiome constitutes a dynamic barrier that can impede pathogen invasion by producing antimicrobial natural products. Gene clusters encoding for production of secondary metabolites, biosynthetic gene clusters (BGCs), that are enriched in the human skin microbiome relative to other ecological settings, position this niche as a promising source for new natural product mining. Here, we introduce a new human microbiome isolate collection, the EPithelial Isolate Collection (EPIC). It includes a large phylogenetically diverse set of human skin-derived bacterial strains from eight body sites. This skin collection, consisting of 980 strains is larger and more diverse than existing resources, includes hundreds of rare and low-abundance species, and hundreds of unique BGCs. Using a large-scale co-culture screen to assess 8,756 pairwise interactions between skin-associated bacteria and potential pathogens, we reveal broad antifungal activity by skin microbiome members. Integrating 287 whole isolate genomes and 268 metagenomes from sampling sites demonstrates that while the distribution of BGC types is stable across body sites, specific gene cluster families (GCFs), each predicted to encode for a distinct secondary metabolite, can substantially vary. Sites that are dry or rarely moist harbor the greatest potential for discovery of novel bioactive metabolites. Among our discoveries are four novel bacterial species, three of which exert significant and broad-spectrum antifungal activity. This comprehensive isolate collection advances our understanding of the skin microbiomes biosynthetic capabilities and pathogen-fighting mechanisms, opening new avenues towards antimicrobial drug discovery and microbiome engineering.
Open-source Tools for CryoET Particle Picking Machine Learning Competitions
Authors: Harrington Kyle I. , Zhao Zhuowen , Schwartz Jonathan , Kandel Saugat , Ermel Utz , Paraan Mohammadreza , Potter Clinton , Carragher Bridget
Published: November 2024

We are launching a machine learning (ML) competition focused on particle picking in cryo-electron tomography (cryoET) data, a crucial task in structural biology. To support this, we have created a comprehensive suite of open-source tools to develop resources for our competition, including copick for dataset management, napari plugins for interactive visualization, utilities for converting particle picks to segmentation masks, and PyTorch tools for custom dataset sampling. These resources streamline the processes of data handling, labeling, and visualization, allowing participants to focus on model development. By leveraging these tools, competitors will be better equipped to tackle the unique challenges of cryoET data and push forward advancements in particle picking techniques.
Chimeric music reveals an interaction of pitch and time in electrophysiological signatures of music encoding
Authors: Shan Tong , Lalor Edmund C. , Maddox Ross K.
Published: November 2024

Pitch and time are the essential dimensions defining musical melody. Recent electrophysiological studies have explored the neural encoding of musical pitch and time by leveraging probabilistic models of their sequences, but few have studied how the features might interact. This study examines these interactions by introducing “chimeric music,” which pairs two distinct melodies, and exchanges their pitch contours and note onset-times to create two new melodies, thereby distorting musical pattern while maintaining the marginal statistics of the original pieces’ pitch and temporal sequences. Through this manipulation, we aimed to dissect the music processing and the interaction between pitch and time. Employing the temporal response function (TRF) framework, we analyzed the neural encoding of melodic expectation and musical downbeats in participants with varying levels of musical training. Our findings revealed differences in the encoding of melodic expectation between original and chimeric stimuli in both dimensions, with a significant impact of musical experience. This suggests that the structural violation due to decoupling the pitch and temporal structure affect expectation processing. In our analysis of downbeat encoding, we found an enhanced neural response when participants heard a note that aligned with the downbeat during music listening. In chimeric music, responses to downbeats were larger when the note was also a downbeat in the original music that provided the pitch sequence, indicating an effect of pitch structure on beat perception. This study advances our understanding of the neural underpinnings of music, emphasizing the significance of pitch-time interaction in the neural encoding of music.

Significance Statement

Listening to music is a complex and multidimensional auditory experience. Recent studies have investigated the neural encoding of pitch and timing sequences in musical structure, but they have been studied independently. This study addresses the gap in understanding of how the interaction between pitch and time affects their encoding. By introducing “chimeric music,” which decouples these dimensions in melodies, we investigate how this interaction influences the neural activities using EEG. Leveraging and the temporal response function (TRF) framework, we found that structural violations in pitch-time interactions impact musical expectation processing and beat perception. These results advance our knowledge of how the brain processes complex auditory stimuli like music, underscoring the critical role of pitch and time interactions in music perception.
H3K4me3 methyltransferase KMT2F promotes pre-initiation complex formation by RNA Polymerase I to regulate ribosomal RNA transcription
Authors: Lone Kaisar Ahmad , Karole Amit Mahendra , Ravindran Geethanjali , Tyagi Shweta
Published: November 2024

Trimethylation of histone 3 lysine 4 (H3K4me3) is mark of active transcription and its regulatory role in RNA polymerase II-mediated transcription has been well-studied. However, if and how this mark regulates RNA polymerase I (RNA Pol I) is not known. Here we used customized genome assemblies for rDNA to demonstrate that KMT2A and KMT2F bind to entire rDNA loci. The binding of these enzymes were mirrored by the binding of H3K4me2 and H3K4me3 marks. Using biochemical assays, we demonstrate the interaction of KMT2-specific subunits with RNA Pol I transcriptional machinery. Our findings reveal KMT2F as the primary KMT depositing the H3K4me3 on rDNA. Loss of H3K4me3 adversely affects the epigenetic landscape and promotes heterochromatization of rDNA locus. Mechanistically, we show that KMT2F promotes pre-initiation complex formation of RNA Pol I. Our findings highlights the thus far undiscovered role of H3K4me3 in the transcriptional initiation of rDNA genes.
Antagonism as a foraging strategy in microbial communities
Authors: Stubbusch Astrid K.M. , Peaudecerf François J. , Soo Lee Kang , Paoli Lucas , Schwartzman Julia , Stocker Roman , Basler Marek , Schubert Olga T. , Ackermann Martin , Magnabosco Cara , D’Souza Glen G.
Published: November 2024

In natural habitats, nutrient availability limits bacterial growth. We discovered that bacteria can overcome this limitation by acquiring nutrients through lysing neighboring cells via contact-dependent antagonism. Using single-cell live imaging and isotopic markers, we found that during starvation the type VI secretion system, which transfers toxins into neighboring cells, increases growth by enabling the uptake of nutrients from lysing cells. In a spatially structured environment, the gradual lysis of just a few target cells allows for the growth of a new antagonist cell. Genomic adaptations in antagonists, characterized by a reduced metabolic gene repertoire, and the prevalence of the type VI secretion system in natural environments, such as global oceans and soils, suggest that bacterial antagonism has the potential to substantially contribute to nutrient transfer within microbial communities across various ecosystems.
Mechanical load conditions the spectrin network to ‘runon’ proteolysis and promotes early onset neurodegeneration
Authors: Malaiwong Nawaphat , Dahse Anne-Kristin , Lin Li-Chun , Das Ravi , Porta-de-la-Riva Montserrat , Scholz Nicole , Krieg Michael
Published: November 2024

The correct homeostasis of the neuronal cytoskeleton and its dynamics is important for health and disease. Forces constantly act on the neurons in our body, leading to subtle axonal deformations and length changes. The spectrin cytoskeleton is known as a key player that protects neurons against mechanical damage. How the spectrin cytoskeleton changes with age and how it influences mechanoprotection in aging animals is not well understood. Using an interdisciplinary approach, we show that age causes a loss of proprioception during the first few days of adulthood inC. elegansvia spectrin unfolding, loss of mechanical tension and degradation of the spectrin cytoskeleton. Guided by a proteomic screen to identify potential spectrin binding partners, we found that this early-onset neurodegeneration can be suppressed inclp-1mutants and by targeted expression of an engineered chaperone derived from humanαB-crystallin. Our data suggest that the spectrin cytoskeleton is sensitized to proteolytic damage by calcium-sensitive proteases when mechanical stresses conspires with high-calcium concentrations as in proprioceptive signaling. These results may have implications for the etiology of diseases in which high calcium dynamics and mechanical stress co-incide.
Targeting the energy metabolism of melanoma cells: FX-11 acts as a mitochondrial uncoupler
Authors: Preis Jasmin Renate , Rolvering Catherine , Kirchmeyer Mélanie , Behrmann Iris , Haan Claude
Published: November 2024

In a compound screen on melanoma cells, which included different microenvironmental contexts aiming at better representing the environmental and growth characteristics of tumours, we identified several drugs efficiently suppressing cell viability. Here we focus on results obtained with FX-11, reported to be an inhibitor of lactate dehydrogenase (LDH). FX-11 dose-dependently inhibited growth of 624Mel and Wm3248 melanoma cells grown in a modular physiologic medium (MPM). Importantly, FX-11 was able to reduce the growth of the corresponding drug-resistant melanoma sublines equipotently.

When testing the on-target activity of FX-11, the results were unexpected: in contrast to other LDH inhibitors (used as positive controls), FX-11 did not decrease the NAD+/NADH ratio, the glucose uptake, or the lactate secretion of melanoma cells. However, in seahorse assays, FX-11 increased the oxygen consumption rate as well as the extracellular acidification rate of cells, behaving like the mitochondrial uncouplers FCCP and Bam15. Treatment with FX-11, FCCP, or Bam15 induced an increase in acetyl-CoA carboxylase phosphorylation and a decrease in serine 65 phosphorylation of the eukaryotic initiation factor 4E-binding protein 1, indicative of AMPK activation by a decreased ATP/ADP ratio. Importantly, FX-11 and Bam15 drastically decreased the mitochondrial membrane potential in contrast to the LDH inhibitors LDH-IN-I and GNE-140.

Taken together, we provide evidence that FX-11 effectively inhibits the growth of melanoma cells, including drug-resistant ones. FX-11 profoundly affects their energy metabolism, although it does not seem to act as other LDH inhibitors, but as a mitochondrial uncoupler.
Spatiotemporal transcriptomic niches of complement pathway and serine protease inhibitor activation in aging and infection
Authors: Kern Fabian , Wagner Viktoria , Wahl Vanessa , Ludwig Nicole , Graf Simon , Amand Jeremy , Foltz Aulden , Atkins Micaiah , Kedir Blen , Hadjilaou Alexandros , Flotho Matthias , Grandke Friederike , Wartenberg Philipp , Hollenhorst Monika I. , Lotter Hanna , Müller Rolf , Boehm Ulrich , Hahn Oliver , Jacobs Thomas , Krasteva-Christ Gabriela , Wyss-Coray Tony , Keller Andreas
Published: November 2024

Aging is a multifactorial and complex physiological process, affecting every organ with characteristic manifestations. Understanding the molecular mechanisms that drive aging processes is crucial to targeting age-related disorders. Recent reports suggest that severe post-infection syndromes can partially accelerate aging. However, the underlying gene-encoded regulatory interplay, whether being shared or distinct between aging and infection biology are poorly understood. Here, we employed spatial transcriptomics to establish a multi-organ atlas (brain, heart, kidney, liver, lung, and spleen) across the mouse lifespan (4, 17, and 26 months). Dissecting high-quality fresh-frozen tissue samples at unbiased molecular resolution, we found both organ-specific and cross-organ gene dysregulation upon aging. We identified age-related trajectories in gene expression and cell state, some only detectable within their spatial context, and provide validation at subcellular resolution. The most prominent effect was organ-wide immune system activation with spatially variable severity. We therefore evaluated how aging mimics the expression signatures observed in systemic infection, using spatial transcriptomics slices from young mice infected with Plasmodium berghei ANKA. While on the gene level the effect sizes caused by the infection outweighed those of aging, we reveal a shared activation of the early complement pathway (C4b) and serine protease inhibitors (Serpin gene family) within by phenotype distinct spatial niches. We show that this common RNA signature is driven by tissue-specific cell types and eventually affects protein levels in the aged brain, rendering them a target for future mechanistic and drug discovery studies. Taken together, our study provides a coherent in-depth and cross-organ transcriptomics atlas to systematically study aging and infection in the mouse at spatiotemporal resolution.

Key highlights

Large-scale and high-resolution atlas of spatial transcriptomics from six organs to study aging and systemic infection across two mouse cohorts.

Strong transcriptional alterations found in distinct organ-specific niches for aging and acute malaria, with organ- and cell type-associated immune responses.

Dysregulation of early complement proteases (C4b) and serine protease inhibitors (Serpina3n) as common theme across central nervous system and peripheral organs.
Systematic effects of retinotopic biases and category selectivity across human occipitotemporal cortex
Authors: Silson Edward H , Groen Iris I A , Baker Chris I
Published: November 2024

The organization of human visual cortex has traditionally been studied using two different methods: retinotopic mapping and category-selectivity mapping. Retinotopic mapping has identified a large number of systematic maps of the visual field, while category-selectivity mapping has identified clusters of neural populations that reliably respond more strongly to specific image categories such as objects, faces, scenes and body parts compared to other categories. While early investigations seemed to suggest that these two organizing principles were largely separated in the brain, with retinotopic maps in posterior visual cortex and category-selective regions in anterior visual cortex, recent work shows that category-selective regions overlap with retinotopic maps, giving rise to spatial visual field biases within these regions.

Here, we collected fMRI responses whilst performing both retinotopic and category mapping within the same participants, allowing detailed comparison of neural tuning for space and category at the single voxel level. We use these data to evaluate two previous proposals of how retinotopic biases relate to category-selectivity: 1) complementary quadrant biases (upper vs. lower contralateral visual field) inherited from early visual cortex explain the presence of paired regions selective for thesame categoryacross lateral and ventral occipitotemporal cortex (lOTC, vOTC); and 2) eccentricity biases (center vs. periphery of the visual field) explain the presence of selectivity fordifferent categories, specifically differentiating face-versus scene-selectivity within the ventral surface.

Confirming and extending previous findings for a comprehensive set of face-, scene-, object, and place-selective regions of interest, we provide robust evidence that category-selective regions do not sample visual space uniformly, exhibiting systematic biases towards either the upper or lower field (all category regions) and center vs. periphery (face vs. place regions). Consistent with 1), we find that quadrant biases differ systematically between lateral and ventral OTC, with lateral regions showing systematic lower field biases and ventral regions showing upper field biases, differentiating regions selective for the same category in terms of their spatial bias. However, contrary to 2), we find that eccentricity tuning does not strongly predict the strength of face-or scene category-selectivity in a given voxel. Specifically, highly face-selective voxels are not solely confined to the fovea, and while most scene-selective voxels show peripheral tuning, highly scene-selective voxels actually show strong foveal tuning, particularly in anterior medial-ventral cortex.

Collectively, these results demonstrate that spatial biases in category-selective cortex are widespread and robust, whilst also suggesting there is no simple relation between spatial tuning and category-selectivity.
Using phage display for rational engineering of a higher affinity humanized 3’phosphohistidine-specific antibody
Authors: Martyn Gregory D. , Kalagiri Rajasree , Veggiani Gianluca , Stanfield Robyn L. , Choudhuri Indrani , Sala Margaux , Meisenhelder Jill , Chen Chao , Biswas Avik , Levy Ronald M. , Lyumkis Dmitry , Wilson Ian A. , Hunter Tony , Sidhu Sachdev S.
Published: November 2024

Histidine phosphorylation (pHis) is a non-canonical post-translational modification (PTM) that is historically understudied due to a lack of robust reagents that are required for its investigation, such as high affinity pHis-specific antibodies. Engineering pHis-specific antibodies is very challenging due to the labile nature of the phosphoramidate (P-N) bond and the stringent requirements for selective recognition of the two isoforms, 1-phosphohistidine (1-pHis) and 3-phosphohistidine (3-pHis). Here, we present a strategy forin vitroengineering of antibodies for detection of native 3-pHis targets. Specifically, we humanized the rabbit SC44-8 anti-3-pTza (a stable 3-pHis mimetic) mAb into a scaffold (herein referred to as hSC44) that was suitable for phage display. We then constructed six unique Fab phage-displayed libraries using the hSC44 scaffold and selected high affinity 3-pHis binders. Our selection strategy was carefully designed to enrich antibodies that bound 3-pHis with high affinity and had specificity for 3-pHis versus 3-pTza. hSC44.20N32FL, the best engineered antibody, has an ∼10-fold higher affinity for 3-pHis than the parental hSC44. Eleven new Fab structures, including the first reported antibody-pHis peptide structures were solved by X-ray crystallography. Structural and quantum mechanical calculations provided molecular insights into 3-pHis and 3-pTza discrimination by different hSC44 variants and their affinity increase obtained throughin vitroengineering. Furthermore, we demonstrate the utility of these newly developed high-affinity 3-pHis-specific antibodies for recognition of pHis proteins in mammalian cells by immunoblotting and immunofluorescence staining. Overall, our work describes a general method for engineering PTM-specific antibodies and provides a set of novel antibodies for further investigations of the role of 3-pHis in cell biology.

Significance Statement

Histidine phosphorylation is an elusive PTM whose role in mammalian cell biology is largely unknown due to the lack of robust tools and methods for its analysis. Here we report the development of antibodies with unprecedented affinity and specificity towards 3-pHis and present the first crystal structures of a pHis peptide in complex with an antibody. Finally, we show how these antibodies can be used in standard molecular biology workflows to investigate pHis-dependent biology.
Predicted meta-omics: a potential solution to multi-omics data scarcity in microbiome studies
Authors: Cosma Bianca-Maria , Pillay Stephanie , Calderón-Franco David , Abeel Thomas
Published: November 2024

Imbalances in the gut microbiome have been linked to conditions such as inflammatory bowel disease, diabetes, and cancer. While metagenomics and amplicon sequencing are commonly used to study the microbiome, they do not capture all layers of microbial functions. Other meta-omics data can provide more insights, but these are more costly and laborious to procure. The growing availability of paired meta-omics data offers an opportunity to develop machine learning models that can infer connections between metagenomics data and other forms of meta-omics data, enabling the prediction of these other forms of meta-omics data from metagenomics. We evaluated several machine learning models for predicting meta-omics features from various meta-omics inputs. Simpler architectures such as elastic net regression and random forests generated reliable predictions of transcript and metabolite abundances, with correlations of up to 0.77 and 0.74, respectively, but predicting protein profiles was more challenging. We also identified a core set of well-predicted features for each meta-omics output type, and showed that multi-output regression neural networks performed similarly when trained using fewer output features. Lastly, our experiments demonstrated that predicted features can be used for the downstream task of inflammatory bowel disease classification, with performance comparable to that of experimental data.
Flow parsing as causal source separation: A computational model for concurrent retrieval of object and self-motion information from optic flow
Authors: Scherff Malte , Lappe Markus
Published: November 2024

Optic flow, the retinal pattern of motion that is experience during self-motion contains information about one’s direction of heading. If the visual scene contains other moving objects optic flow becomes a combination of self-motion and independent object motion. The global pattern due to self-motion is locally confounded, and the locally restricted object flow is the sum of components due to these different causal sources of motion. Nonetheless, humans are able to retrieve information from such flow accurately, including the direction of heading and the scene-relative motion of an object.

One way to handle such complex flow is flow parsing, a process speculated to allow the brain’s sensitivity to optic flow to separate the causal sources of retinal motion in information due to self-motion and information due to object motion. In a computational model that retrieves object and self-motion information from optic flow, we implemented such a process of causal separation based on heading likelihood maps, whose distributions indicate the consistency of parts of the flow with self-motion alone. The flow parsing allows for concurrent estimation of heading, the detection and localization of and independently moving object, and the estimation of scene-relative motion of that object.

We developed a paradigm that allows the model to perform all the different estimations while system-atically varying how the object contributes to the flow field. Simulations of that paradigm showed that the model replicates many aspects of human performance, including the dependence of heading estimation on object speed and how different object movements bias that estimation. Regarding object detection and motion estimation, the model’s results fit human behavioral data, the latter even for flow of reduced quality.
Genome-wide mapping of RPA1 and RAD9 reveals the management of polycistronic transcription, replication initiation, and responses to replication stress inLeishmania
Authors: Black J.A. , Virgilio S. , Bastos M.S. , Silva G.L.A. , Damasceno J.D. , Lapsley C. , McCulloch R. , Tosi L.R.O.
Published: November 2024

When exposed single-stranded DNA accumulates at stalled or collapsed replication forks, the replication stress response is triggered to prevent genome instability.Leishmaniaare parasitic eukaryotes where gene expression is universally polycistronic and whose plastic genomes facilitate rapid adaptations in response to stress, with evidence implicating intrinsic replication stress as a source. Little is known about theLeishmaniareplication stress response. In this study, we reveal the global dynamics of the replication stress response inL. majorpromastigotes by performing ChIP-seq on three key replication stress response proteins, γH2A, RPA1 and RAD9, in the absence and presence of replication stress. We show that common ‘hotspots’ of replication stress correlate with DNA replication initiation and transcription termination inLeishmania. When DNA replication is stalled, replication stress response factors accumulate at early S-phase origins, with a signal pattern reminiscent of bidirectional replication fork progression. Under conditions of chronic replication stress, increased accumulation of replication stress response factors emerges at wider sites of transcription initiation, suggestingLeishmaniamay possess compensatory strategies to limit the effects of replication stress and ensure DNA replication can complete under these conditions. In contrast, chronic replication stress enhances RSR factor accumulation at transcription termination sites, highlighting these regions as key replication stress ‘hotspots’ inLeishmania. Lastly, variations in RPA dynamics in ATR-deficient cells uncover crucial roles of this protein kinase in managing polycistronic transcription and DNA replication, particularly under replication stress, inLeishmania.

Strict controls operate to precisely copy an organism’s DNA. However, cells need ways to rapidly adapt and respond to stimuli. In some cases, these beneficial adaptations come from problems during replication.Leishmaniaparasites cause serious neglected infections in humans and animals across the world’s tropics and sub-tropics. Remarkably, recent evidence suggests thatLeishmaniaDNA experiences enhanced stress during replication that can drive its ability to rapidly adapt in response to stress. How Leishmaniarespond to DNA replication stress is still poorly understood. Here, using a genome-wide approach to map the locations of key proteins that manage DNA replication stress and maintain genome integrity, we show ‘hotspots’ of DNA replication stress coincide with start sites of DNA replication and regions of transcription termination.
Brain-wide population activity during reaching integrates action-mediated goal expectation
Authors: Peng Yangfan , Lindersson Carl , Tinelli Sasha , Stedehouder Jeffrey , Shah Rahul S , Lak Armin , Stagg Charlotte J , Sharott Andrew
Published: November 2024

Large scale recordings have revealed that neurons encoding motor and non-motor variables are highly distributed across the brain. While these neurons generate population level dynamics during spontaneous behavior, it remains unclear how these latent subspaces relate to the simultaneous motor and cognitive demands during ongoing goal-directed behavior. Here, we show that continuously anticipated action outcome, in addition to movement, drives ubiquitous latent dynamics during goal-directed movements. We used multiple Neuropixels probes to simultaneously record spiking activity from cortical and subcortical regions during a reaching task in head-fixed mice. Task-related population dynamics covaried within a common latent subspace across regions and was conserved across recording days and animals. These latent dynamics preceded movement onset and were modulated by reach distance and reward availability. Furthermore, their temporal progression continuously scaled with the timing of reward consumption and their activity decreased afterwards, despite ongoing stereotypical re-reaches. Our findings thus provide evidence for a brain-wide latent subspace for continuous representation of action-mediated proximity to goal, which could provide the basis for ubiquitous temporal difference learning based on predicted action outcome.
SeedMatExplorer: The transcriptome atlas of Arabidopsis seed maturation
Authors: Artur Mariana A. S. , Koetsier Robert A. , Willems Leo A. J. , Bakermans Lars L. , van Driel Annabel D. , Dongus Joram A. , Dekkers Bas J. W. , Marques Alexandre C. S. S. , Sami Asif Ahmed , Nijveen Harm , Bentsink Leónie , Hilhorst Henk , Teixeira Renake Nogueira
Published: November 2024

Seed maturation is a critical developmental phase during which seeds acquire essential traits for nutritional value and desiccation survival. Abscisic acid (ABA) signalling has long been recognized as a key positive regulator of this process, coordinating the expression of genes that drive the acquisition of vital seed quality traits (SQTs) crucial for survival, resilience, and storage. However, the precise molecular regulation of many SQTs remains elusive. To address this gap, we conducted an extensive transcriptome analysis of seed maturation inArabidopsis thaliana, focusing on Col-0 wild-type and ten mutant lines affecting ABA biosynthesis, signaling, and catabolism from 12 days after pollination up to the dry seed stage. Our study employed Weighted Gene Co-Expression Network Analysis (WGCNA) and module-trait correlation to uncover specific gene groups linked to the regulation of multiple SQTs. We identifiedLate Embryogenesis Abundant(LEA) genes uniquely associated with desiccation tolerance and threeDREB AND EAR MOTIF PROTEIN(DEAR) transcription factors involved in seed longevity regulation. The value of our dataset lies not only in its depth and detail, but also in its integration into SeedMatExplorer, a web tool specifically designed to advance seed maturation research. SeedMatExplorer serves as a unique resource, enabling researchers to explore, visualize, and generate new hypotheses about gene expression regulation during seed maturation and the intricate control of SQTs. This physiological and transcriptomic atlas offers unprecedented insights into the complex, coordinated gene expression that drives SQT acquisition in Arabidopsis seeds, making it an invaluable asset for the scientific community.
Repetitive magnetic stimulation induces plasticity of excitatory synapses through cooperative pre- and postsynaptic activity
Authors: Galanis Christos , Lenz Maximilian , Farahani Mohammadreza Vasheghani , Vlachos Andreas
Published: November 2024

Transcranial magnetic stimulation (TMS) is a widely used non-invasive technique in research and clinical settings. Despite its success, the cellular and molecular mechanisms underlying TMS-induced changes in the brain remain incompletely understood. Current protocols are largely heuristic, based on system-level observations. This study employed in vitro repetitive magnetic stimulation (rMS) in mouse brain tissue cultures, combined with computational modeling to develop an experimentally validated approach for predicting TMS effects. Unlike electrical or optogenetic stimulation, rTMS uniquely enhances plasticity by activating both pre- and postsynaptic neurons, with brain-derived neurotrophic factor (BDNF) playing a crucial role. Our simulations accurately predicted the frequency-dependent effects of rTMS, providing a critical step towards developing robust, validated tools that will enhance the precision and effectiveness of TMS applications across both research and clinical settings.

Significance Statement

This study elucidates the mechanisms by which TMS promotes neural plasticity, specifically long-term potentiation (LTP) of excitatory neurotransmission. By demonstrating that rMS engages both pre- and postsynaptic neurons with BDNF as a key mediator, it provides a mechanistic basis for the therapeutic effects of rTMS. These insights advance our understanding of rTMS-induced brain plasticity and support the development of predictive computer models, paving the way for more effective and standardized TMS protocols in research and clinical applications.
An alpine plant shows no decrease in genetic diversity associated with rapid post-glacial range expansion
Authors: Urquhart-Cronish Mackenzie , Berg Colette S. , Moxley Dylan , Rahn Olivia J. , Fishman Lila , Angert Amy L.
Published: November 2024

While range expansion is hypothesized to be a mechanism for species persistence under climate change, many eco-evolutionary models describe demographic and genetic processes during range expansion that may decrease genetic variation and increase genetic load at the leading edge (i.e., expansion load). These predictions are related to dispersal limitation at the leading edge driving colonization dynamics, a scenario common in post-glacial range expansion at the continental scale (∼20,000 years ago). However, post-glacial range expansion can also occur on contemporary time scales, such as alpine glacier recession following the end of The Little Ice Age (∼150 years ago) and our understanding of dispersal limitation structuring these instances of rapid range expansion are relatively understudied. Here, we test whether there is evidence supporting the role of dispersal limitation during range expansion following alpine glacier retreat using the native alpine plantErythranthe (Mimulus) lewisiiby examining patterns of neutral genetic diversity (single nucleotide polymorphisms) across the history of glacier recession (i.e., glacier chronosequence) across two glacier forelands in Garibaldi Provincial Park, BC. We find weak support for the prediction of increasing clines in genetic differentiation towards the range edge, and no support for decreasing clines in genetic diversity, suggesting dispersal limitation is not characterizing colonization during range expansion, with the implication that the accumulation of expansion load at the range edge is likely not applicable on these spatiotemporal scales. Together, our results suggest that loss of genetic diversity for range-shifting species in the alpine is likely not a key contributing factor to any decreased fitness over time.
ASD-AssociatedCNTNAP2Variants Disrupt Neuronal Arborization Through Impaired Regulation by Ectodomain Shedding
Authors: Lobete Miguel , Dionisio Leonardo E. , McCoig Emmarose , Piguel Nicolas H. , Spielman Benjamin P. , Socas Silvia , dos Santos Marc , Boers-Escuder Cristina , Penzes Peter , Martin-de-Saavedra M. Dolores
Published: November 2024

Ectodomain shedding (ES) is a process by which a protease cleaves the extracellular portion of membrane-bound proteins, releasing soluble fragments that influence diverse cellular functions. ES is critical in neurodevelopment, plasticity, and neurodegenerative disorders, such as Alzheimer’s disease, and has recently been implicated in neurodevelopmental conditions, including autism spectrum disorders (ASD). Contactin-associated protein-like 2 (CNTNAP2) is an adhesion molecule regulated by ES, releasing a soluble ectodomain (sCNTNAP2) that enhances neuronal synchrony. CNTNAP2 is implicated in ASD, schizophrenia, and cortical dysplasia focal epilepsy syndrome (CDFE) and it is known to regulate neuronal arborization, as well as dendritic spine maturation and maintenance. However, little is known about how neuroplasticity impacts ES or the role of CNTNAP2 ES in dendritic arborization. Here, we show that the brain sheddome is enriched in shed ectodomains that regulate neuronal projections, and that its molecular and functional composition is modulated by sensory deprivation in a sex dependent manner, with a decrease in sCNTNAP2 levels observed only in male mice. Furthermore, we demonstrate that sCNTNAP2 promotes dendritic arborization, while ASD-associated CNTNAP2 variants present reduced sCNTNAP2 levels in culture and decreased neuronal branching. Together, these findings underscore the role of ES in neuroplasticity and ASD and reveal how CNTNAP2 genetic variations disrupt its regulation by ES, leading to altered dendritic branching.
Volume conductor models for magnetospinography
Authors: O’Neill George C. , Spedden Meaghan E. , Schmidt Maike , Mellor Stephanie , Stenroos Matti , Barnes Gareth R.
Published: November 2024

The recent development of small, wearable, magnetic field sensors allow for the investigation of biomagnetic fields with a flexibility previously unavailable. We test models to describe how current flow in the spinal cord and thorax gives rise to measurable magnetic fields outside the torso. We compare various open-access volume conductor models, in order to select the most parsimonious and accurate descriptor of the magnetic fields due to source current in the spinal cord.

We find that fields produced due to current flow along the superior-inferior axis of the cord are relatively insensitive to the choice of volume conductor model. However, fields produced by current flow in predominantly left-right or anterior-posterior direction are significantly attenuated by the presence of bone in the forward model. Furthermore, volume conductors with bone demonstrate larger differences in field topographies for nearby sources compared to bone-free models. These findings suggest that precise modelling of spinal cord location and surrounding vertebrae will be important a-priori knowledge going forward.
Aerobic carbon metabolism modulates nitrite ammonifiers for inhibiting nitrogen loss as revealed by microcosm experiment of agricultural upland soil
Authors: Wu Xiaogang , Yu Siyu , Sui Weikang , Zhang Xinyu , Li Ji , Wu Qiaoyu , Zhang Xiaojun
Published: November 2024

Denitrification and dissimilatory nitrate reduction to ammonium (DNRA), two divergent nitrogen metabolism pathways, share nitrite as a common intermediate during anaerobic reduction. However, these pathways influence the environment and soil nutrients differently. Unlike denitrification, which involves nitrogen loss through gaseous nitrogen emission and nitrate leaching, DNRA is beneficial for the conservation of nitrogen. Nevertheless, the key mechanism underlying the joint regulation of aerobic carbon metabolism to nitrite ammonifiers in soil is still unclear, although previous studies have reported factors such as carbon and oxygen can independently affect DNRA. Here, microcosm experiments with agricultural upland soil were conducted under different aeration conditions supplemented with labile carbon to analyze the process of anaerobic nitrogen metabolism. The results indicated that denitrification exclusively dominated nitrite reduction when the soil was directly placed in an anaerobic environment. Nonetheless, a significant increase in DNRA activity and the attenuation of denitrification were detected when the soil was incubated aerobically with the addition of glucose prior to anaerobic incubation. Specifically, up to 55.8% of nitrite reduction switched to nitrogen conservation mainly via DNRA under high-carbon conditions. Quantitative assays of thenrfAgene and metagenomic data revealed a significant increase in DNRA-related genes after aerobic carbon metabolism. Furthermore,nrfAgene sequence analysis revealed a significant shift in the composition of nitrite ammonifiers community. These results indicate that nitrate/nitrite metabolic flux in the soil could be regulated to enhance DNRA by stimulating facultative anaerobic nitrite ammonifiers such asSedimentibacterunder alternating aerobic and anaerobic environments with carbon metabolism.

IMPORTANCE

This study revealed that aerobic conditions with a carbon supply strongly influence the community assembly of nitrite ammonifiers. Nitrite ammonifiers such asSedimentibacterenriched under sufficient carbon and aeration conditions promoted the subsequent DNRA process under anaerobic conditions. Therefore, regulating the competition between DNRA and denitrification by altering functional microbiota would be a promising approach for improving the efficiency of fertilizer application and for reducing greenhouse gas emissions from denitrification. These findings are essential for understanding the biological mechanism of nitrogen cycling in dryland agricultural soil. Based on these findings, we may design a strategy to increase the abundance of nitrite ammonifiers in agricultural soil, which might promote DNRA metabolism to improve nitrogen retention. This strategy would ultimately enhance fertilizer use efficiency and mitigate the detrimental environmental effects of nitrogen fertilizer abuse.
Opportunistic pathogens are prevalent across the culturable exogenous and endogenous microbiota of stable flies captured at a dairy facility
Authors: Sommer Andrew J. , Deblois Courtney L. , Tu Andrew D. J. , Suen Garret , Coon Kerri L.
Published: November 2024

Stable flies in the genusStomoxysare highly abundant, blood-feeding pests on dairy farms; however, their role in the carriage and potential transmission of pathogens is largely understudied. Here, we report on the frequency and distribution of culturable bacteria collected fromStomoxysflies captured in free stall barns and nearby calf hutches over a three-month period on a focal research farm in Wisconsin, USA. Mastitis-associated bacterial taxa, includingStaphylococcus,Escherichia,Enterobacter, andKlebsiellaspp., were frequently isolated from pooled samples of the internal or external portions of the flies. Conversely, selective enrichment protocols from these samples yielded only a single isolate ofSalmonellaand no enterohemorrhagicEscherichia coliO157. Neither trap location nor time of capture had a significant impact on the observed frequency of most bacterial genera isolated from the flies. Our results confirm thatStomoxysflies harbor both mastitis-associated bacterial taxa and bacterial taxa associated with opportunistic infections in humans. Further research into the transmission of fly-associated microbes could be important in the control of mastitis or other bacterial diseases on dairy farms.
A global dopaminergic learning rate enables adaptive foraging across many options
Authors: Grima Laura L. , Guo Yipei , Narayan Lakshmi , Hermundstad Ann M. , Dudman Joshua T.
Published: November 2024

In natural environments, animals must efficiently allocate their choices across multiple concurrently available resources when foraging, a complex decision-making process not fully captured by existing models. To understand how rodents learn to navigate this challenge we developed a novel paradigm in which untrained, water-restricted mice were free to sample from six options rewarded at a range of deterministic intervals and positioned around the walls of a large (∼2m) arena. Mice exhibited rapid learning, matching their choices to integrated reward ratios across six options within the first session. A reinforcement learning model with separate states for staying or leaving an option and a dynamic, global learning rate was able to accurately reproduce mouse learning and decision-making. Fiber photometry recordings revealed that dopamine in the nucleus accumbens core (NAcC), but not dorsomedial striatum (DMS), more closely reflected the global learning rate than local error-based updating. Altogether, our results provide insight into the neural substrate of a learning algorithm that allows mice to rapidly exploit multiple options when foraging in large spatial environments.
A consensus definition for deep layer 6 excitatory neurons in mouse neocortex
Authors: Kim Su-Jeong , Babola Travis A. , Lee Kihwan , Matney Chanel J. , Spiegel Alina C. , Liew Michael H. , Schulteis Eva M. , Coye Austin E. , Proskurin Mikhail , Kang Hyunwook , Kim Julia A. , Chevée Maxime , Lee Kiwoong , Kanold Patrick O. , Goff Loyal A. , Kim Juhyun , Brown Solange P.
Published: November 2024

To understand neocortical function, we must first define its cell types. Recent studies indicate that neurons in the deepest cortical layer play roles in mediating thalamocortical interactions and modulating brain state and are implicated in neuropsychiatric disease. However, understanding the functions of deep layer 6 (L6b) neurons has been hampered by the lack of agreed upon definitions for these cell types. We compared commonly used methods for defining L6b neurons, including molecular, transcriptional and morphological approaches as well as transgenic mouse lines, and identified a core population of L6b neurons. This population does not innervate sensory thalamus, unlike layer 6 corticothalamic neurons (L6CThNs) in more superficial layer 6. Rather, single L6b neurons project ipsilaterally between cortical areas. Although L6b neurons undergo early developmental changes, we found that their intrinsic electrophysiological properties were stable after the first postnatal week. Our results provide a consensus definition for L6b neurons, enabling comparisons across studies.
Aging drives a program of DNA methylation decay in plant organs
Authors: Dai Dawei , Chen Ken , Tao Jingwen , Williams Ben P.
Published: November 2024

How organisms age is a question with broad implications for human health. In mammals, DNA methylation is a biomarker for biological age, which may predict age more accurately than date of birth. However, limitations in mammalian models make it difficult to identify mechanisms underpinning age-related DNA methylation changes. Here, we show that the short-lived model plantArabidopsis thalianaexhibits a loss of epigenetic integrity during aging, causing heterochromatin DNA methylation decay and the expression of transposable elements. We show that the rate of epigenetic aging can be manipulated by extending or curtailing lifespan, and that shoot apical meristems are protected from this aging process. We demonstrate that a program of transcriptional repression suppresses DNA methylation maintenance pathways during aging, and that mutants of this mechanism display a complete absence of epigenetic decay. This presents a new paradigm in which a gene regulatory program sets the rate of epigenomic information loss during aging.
PII interactions with BADC and BCCP proteins co-regulate lipid and nitrogen metabolism in Arabidopsis
Authors: Garneau Matthew G. , Jorge Gabriel Lemes , Shockey Jay , Thelen Jay J. , Bates Philip D.
Published: November 2024

In plants the initiation of fatty acid synthesis is catalyzed by acetyl-CoA carboxylase (ACCase) which produces malonyl-CoA. The heteromeric form of ACCase (htACCase) is a holoenzyme consisting of biotin carboxylase and carboxyltransferase sub-complexes, both of which are subject to extensive regulation. Biotin carboxylase activity is controlled in part by the presence of the catalytic biotin carboxyl carrier proteins (BCCP1/2) and/or the non-catalytic, non-biotinylated, biotin/lipoyl attachment domain-containing proteins (BADC1/2/3) that associate with backbone biotin carboxylase (BC) protein. However, the mechanisms regulating BADC and BCCP interaction with BC and thus ACCase activityin plantaare not clear. Here we demonstrate theArabidopsis thalianaregulatory protein PII modulates htACCase activity through independent interactions with BADC and BCCP proteins in a selective manner. Analysis ofbadc1/2andbadc1/3mutant lines and the respectivepiitriple mutants reveal that changes in seed oil and protein accumulation ofbadcdouble mutants are PII/nitrogen dependent. Absolute quantification of htACCase subunits and PII in developing seeds suggests that Arabidopsis exerts tight regulation over individual protein stoichiometry to balance oil and protein accumulation. The effects on vegetative and seed development indicate PII and BADC proteins have distinct but overlapping roles in the regulation of plant metabolism.