bluuebunny/crossref_metadata_2025 huggingface dataset:
Time-resolved neural and experience dynamics of medium- and high-dose DMT
Authors: Lewis-Healey Evan , Pallavicini Carla , Cavanna Federico , D'Amelio Tomas , De La Fuente Laura Alethia , Copa Debora , Muller Stephanie , Bruno Nicolas , Tagliazucchi Enzo , Bekinschtein Tristan
Published: January 2025

N,N-Dimethyltryptamine (DMT) is a potent and fast-acting psychedelic drug that induces a radical reorganisation of the contents of consciousness, comprising the dissolution of time and space and perceptual immersion into an "alternate reality". While contemporary research has somewhat advanced our understanding of DMT, and psychedelics more broadly, there is little research that integrates time-resolved measures of subjective experience with temporally fine-grained brain imaging. We therefore present the current study, a repeated-measures dose-dependent study of the subjective and neural dynamics induced through DMT under naturalistic conditions. Nineteen participants received either a 20mg or 40mg dose of freebase DMT across two dosing sessions in a blinded, counterbalanced order, with blinding rates consistent across doses. Electroencephalography (EEG) data was collected, as well as time-resolved retrospective measures of subjective experience (Temporal Experience Tracing). Both doses of DMT induced rapid changes in experience dimensions. However, the 40mg dose induced significantly more extreme visual hallucinations and emotionally intense experiences. Further, we computed a variety of neural markers on the EEG data, and found that oscillatory alpha power and permutation entropy were most strongly associated with continuous subjective experience dimensions. Strikingly, lempel-ziv complexity, a previously hailed as a robust correlate of subjective experiences within the psychedelic-state, was the least strongly associated neural marker. These findings provide an important insight into how distinct neural dynamics may contribute to this radical and intense altered state of consciousness.
Polyglutamine expansion induced dynamic misfolding of Androgen Receptor
Authors: Heling Laurens W.H.J. , Sheikhhassani Vahid , Ng Julian , van Vliet Morris , Jiménez-Panizo Alba , Alegre-Martí Andrea , Woodard Jaie , van Roon-Mom Willeke , McEwan Iain J , Estébanez-Perpiñá Eva , Mashaghi Alireza
Published: January 2025

Spinal bulbar muscular atrophy (SBMA) is caused by a polyglutamine expansion (pQe) in the N-terminal transactivation domain of human androgen receptor (AR-NTD), resulting in a combination of toxic gain- and loss-of-function mechanisms. The structural basis of these processes has not been resolved due to the disordered nature of the NTD, which hinders experimental analyses of its detailed conformations. Here, using extensive computational modelling, we show that AR-NTD forms dynamic compact regions, which upon pQe re-organize dynamically, mediated partly by direct pQ interaction with the Androgen N-Terminal Signature (ANTS) motif. The altered dynamics of the NTD result in a perturbation of interdomain interactions, with potential implications for binding of the receptor protein to its response element. Oligomeric aggregation of the dynamic misfolded NTD exposes pQe, but blocks tau-5 and the FQNLF motif, which could lead to aberrant receptor transcriptional activity. These observations suggest a structural mechanism for AR dysfunction in SBMA.
T505A variant of ETV5 promotes proliferation of precursor B cells in a mouse model of acute lymphoblastic leukemia
Authors: Yi Joshua , Wu Michael , Dowling Michaela L. , MacKenzie Allanna C. E. , Iansavitchous James , DeKoter Rodney P.
Published: January 2025

Precursor B cell acute lymphoblastic leukemia (pre-B-ALL) arises as a result of precursor B cells acquiring driver mutations that lead to arrested differentiation and increased proliferation. Identification of driver mutations and understanding their biological function is critical to understanding pre-B-ALL development and advancing disease treatment. Using a mouse model of pre-B-ALL driven by deletion of genes encoding the related E26-transformation-specific (ETS) transcription factors PU.1 and Spi-B, we performed whole exome sequencing to identify secondary driver mutations. We identified recurrent variants in E26 transformation-specific transcription variant 5 (ETV5) resulting in R392P, V444I, and T505A amino acid changes. We found that the R392P and V444I variants altered the ability of ETV5 to bind to DNA using electrophoretic mobility shift assay. R392P and V444I variants did not activate a Dual-Specificity-Phosphatase 6 (DUSP6) reporter. In contrast, T505A ETV5 could interact with DNA and activate the DUSP6 promoter. To determine biological function, we forced expression of wild type, R392P, V444I, or T505A ETV5 in an interleukin-7-dependent pre-B cell line. Proliferation and apoptosis assays showed that T505A ETV5 conferred a proliferative advantage to pre-B cells. RNA sequencing showed that expression of ETV5 variants significantly altered gene expression in cultured cells. Through gene set enrichment analysis, T505A was suggested to downregulate the p53 pathway and the anti-proliferative protein, B cell translocation gene 2 (encoded byBtg2). In summary, these data suggest that ETV5 mutations play a role in pre-B-ALL by affecting proliferation and cell survival.
The relationship between auditory brainstem responses, cognitive ability, and speech-in-noise perception among young adults with normal hearing thresholds
Authors: DiNino Mishaela , Crowell Jenna , Kloiber Ilsa , Polonenko Melissa J.
Published: January 2025

Purpose

The goal of this research was to determine the contributions of auditory neural processing and cognitive abilities to predict performance on a competing talker task in young, normal hearing adults.

Methods

Two experiments were performed, each with separate cohorts of ∼30 young adults with normal hearing who performed a competing talker task which included a high-pass filtered condition that was designed to be more sensitive to auditory nerve functioning than are commonly used speech-in-noise perception tests. Predictors of performance on this speech-in-speech task included ABR waves I and V metrics and cognitive task performance. Experiment one included click ABRs at a moderate level commensurate with the level of the competing talker task, as well as the cognitive digit span working memory task. Experiment two included high-intensity click clinical ABRs and three cognitive tasks from the NIH Toolbox V3 that assessed working memory, cognitive flexibility and attention, and inhibitory control: List Sorting Working Memory, Dimensional Change Card Sort, and Flanker Inhibitory Control and Attention tests, respectively.

Results

Performance on the high-pass competing talker task varied across participants in both experiments. This variability was predicted by performance on the inhibitory control task, but not the tasks involving working memory or cognitive flexibility, nor by any of the auditory processing metrics from moderate or high-intensity click ABRs.

Conclusions

Among two groups of young adults with normal hearing, cognitive factors with very similar demands to the competing talker task seem to play the greatest role in speech-in-noise perception.
Dietary iron deficiency in the adult mouse increases brain endothelial uptake and blood-brain barrier transport of a high-affinity, anti-transferrin receptor antibody
Authors: Kostrikov Serhii , Johnsen Kasper Bendix , Burkhart Annette , Andresen Thomas Lars , Moos Torben
Published: January 2025

Background and objectives

Brain capillary endothelial cells (BCECs) express transferrin receptor 1 (TfR1) to ensure sufficient iron transport into the brain across the blood-brain barrier (BBB). Our main objective was to examine adult mice subjected to dietary iron deficiency (ID) for possible changes in the content of TfR1 in BCECs and the influence thereof on the uptake and transport of high-affinity anti-transferrin receptor IgG1 antibodies (clone Ri7217).

Material and methods

We subjected adult, female mice to dietary ID for 8 weeks. Iron and copper were measured using inductively coupled plasma mass spectrometry (ICP-MS) in various tissues, including total brain and isolated brain capillaries. Possible effects of ID on cerebral angioarchitecture were estimated using 3D confocal microscopy of optically cleared brain samples with endothelium labelled using intravenous injection of wheat germ agglutinin with subsequent machine learning-based segmentation and vascular tracing. TfR1 was quantified using ELISA. Ri7217 antibodies were conjugated with 1 nm nanogold and brain uptake quantified using ICP-MS.

Results

ID significantly reduced the iron content in isolated brain capillaries, liver, spleen, kidney, heart and skeletal muscles. ID increased the copper content in the brain. Analysis of cerebral cortex angioarchitecture revealed no changes following dietary ID except for a minor increase in tortuosity of small-caliber vessels. TfR1 protein was unchanged in the total brain and isolated brain capillaries. In contrast, uptake of nanogold-conjugated Ri7217 increased in the total brain, the supernatant fraction of isolated brain capillaries representing the post-vascular compartment, liver, spleen, and dissected retinae.

Conclusions

Targeting TfR1 in ID revealed increased uptake and transport across the BBB of Ri7217 antibodies. Possibly the elevated transport of transferrin receptors through BCECs is due to the increased trafficking of transferrin receptor-containing vesicles in ID, which appeared to have no major effects on the brain angioarchitecture.
Balancing Stability and Recovery: Impact of Spinal Fusion Length on Surgical Site Infections and Functional Outcomes in Traumatic Thoracic and Thoracolumbar Spinal Cord Injuries
Authors: Leister Iris , Katzensteiner Moritz , Wutte Christof , Mach Orpheus , Maier Doris , Vogel Matthias
Published: January 2025

Background

Spinal surgeries after traumatic thoracic or thoracolumbar spinal cord injuries (SCI) often involve extensive instrumentation, leading to an increased risk of surgical site infections (SSIs) and complications. This study investigates whether the number of spinal levels fused impacts functional recovery and the frequency of SSIs in individuals with vertebral fractures in the thoracic and/or lumbar spine and SCI.

Methods

In this retrospective analysis of 282 patients with traumatic thoracic or thoracolumbar SCI, data across two periods (2005–2009 vs. 2018–2022) were compared, including variables such as demographics, setting of the initial surgery (specialized SCI center or general trauma center), SCI severity, number of levels fused, fracture classification, the need for revision surgery, the presence of polytrauma and/or traumatic brain injury (TBI), and the occurrence of SSIs during hospitalization. Functional independence was assessed using the Spinal Cord Independence Measure (SCIM III). Unbiased recursive partitioning (URP-CTREE) was used to identify predictors of SSIs and functional outcomes.

Results

Patients undergoing longer fusions had a significantly higher rate of SSIs (median fusion length: 5 vs. 3 levels, p = 0.02). Revision surgery and age over 57 were identified as key predictors of SSIs. Shorter fusions (two spinal segments or less) were associated with better functional recovery, particularly in more severe SCI (AIS A, B, or C).

Conclusion

Longer fusion lengths increase the risk of SSIs and are linked to poorer functional outcomes in patients with thoracic and thoracolumbar SCI. Minimizing fusion length might optimize surgical outcomes and reduce complications. Future research should refine surgical strategies to balance stability with functional recovery.
Umbilical cord blood pTau217 and BD-tau are associated with markers of neonatal hypoxia: a prospective cohort study
Authors: Payne Emma , Gonzalez-Ortiz Fernando , Kramer Kaitlin , Payne Thomas , Marathe Shreeya , Mahajan Neha , Liu Ashly , Barry Jessica , Duckworth Andrew , Brookes Mitchell , de Vries Bradley , Moran Benjamin , Manning Helen , Blennow Kaj , Zetterberg Henrik , Zalcberg David , Sanders Robert D.
Published: January 2025

Objective

Current methods for early detection of hypoxic–ischemic encephalopathy (HIE) are limited by lack of specificity, cost, and time constraints. Blood tau protein concentrations reflect neuropathology in adults. This study examines tau as a potential HIE biomarker in neonates by relating cord blood levels to short-term fetomaternal outcomes.

Design

Prospective cohort study.

Setting

Royal Prince Alfred Hospital—a large Australian tertiary referral centre. Population: 107 maternal participants.

Methods

Simoa analysis of umbilical cord blood pTau217 and brain-derived (BD)-tau.

Main Outcome Measures

Primary: association of BD-tau with non-reassuring fetal status. Secondary: 1) correlations between cord blood tau and other biomarkers; 2) associations between tau levels and risk factors for fetomaternal morbidity; 3) associations between tau levels and short-term fetomaternal outcome.

Results

Of 509 deliveries, cord blood was analysed in 107/110 recruited maternal participants. BD-tau correlated with non-reassuring fetal status (OR=3.0;95%CI=1.6– 5.7;p=0.001), though not when adjusting for mode of delivery and gestational age. BD-tau was higher in vaginal deliveries, and positively associated with pTau217, NfL, and lactate (p<0.001), and negatively associated with pH and base excess. pTau217 was higher in preterm neonates and was associated with neurofilament light chain (Spearman’s rho=0.44,p<0.001). BD-tau and pTau217 were associated with maternal hypertension and placental abnormalities.

Conclusions

Cord blood BD-tau correlates with markers of fetal hypoxia, whilst pTau217 levels may indicate broader neurodevelopmental vulnerability. Further studies could explore whether these findings translate to clinical use of tau as an HIE biomarker.

Funding

US National Institutes of Health (grant:R01AG063849-01).
Type-2 diabetes biomarker discovery and risk assessment through saliva DNA methylome
Authors: Guo Wenbin , Morselli Marco , Paul Kimberly C. , Thompson Michael , Ritz Beate , Pellegrini Matteo
Published: January 2025

The rising prevalence of type 2 diabetes (T2D) motivates innovative strategies to deepen disease understanding and enhance diagnostic capabilities. This study measures diabetes-specific epigenetic signals in saliva, establishing saliva DNA methylome as a promising medium for T2D screening and study. By integrating comprehensive whole-genome bisulfite sequencing (WGBS) and high-depth targeted bisulfite sequencing (TBS), we developed a cost-efficient two-step approach to profiling DNA methylation at regions of interest. WGBS analysis confirmed T2D-specific methylation signatures in saliva, revealing their enrichment in immune and metabolic regulation pathways. TBS enabled accurate cell type deconvolution, revealing minimal differences in cellular composition between diabetic and non-diabetic samples, suggesting intrinsic molecular changes drive the observed methylation changes. Epigenome-wide association studies further identified significant CpG sites, notably in theABCG1region, with strong potential for T2D status prediction. These findings validate the saliva DNA methylome as a scalable, non-invasive resource for T2D biomarker discovery, advancing opportunities in T2D screening, risk assessment, and personalized medicine.
Whole-genome evaluation of genetic rescue: the case of a curiously isolated and endangered butterfly
Authors: MacDonald Zachary G. , Dupuis Julian R. , Glasier James R. N. , Sissons Robert , Moehrenschlager Axel , Bradley Shaffer H. , Sperling Felix A. H.
Published: January 2025

Genetic rescue, or the translocation of individuals among populations to augment gene flow, can help ameliorate inbreeding depression and loss of adaptive potential in small and isolated populations. Genetic rescue is currently under consideration for an endangered butterfly in Canada, the half-moon hairstreak (Satyrium semiluna). A small, unique population persists in Waterton Lakes National Park, Alberta, isolated from other populations by >350km. However, whether genetic rescue would actually be helpful has not been evaluated. Here, we generate the first chromosome-level genome assembly and whole-genome resequence data for the species. We find that the Alberta population’s genetic diversity is extremely low and very divergent from the nearest populations in British Columbia and Montana. Runs of homozygosity suggest this is due to a long history of inbreeding, and coalescent analyses show that the population has been small and isolated, yet stable for up to 40k years. When a population maintains its viability despite inbreeding and low genetic diversity, it has likely undergone purging of deleterious recessive alleles and could be threatened by their reintroduction via genetic rescue. Ecological niche modelling indicates that the Alberta population also exhibits environmental associations that are atypical of the species. Together, these results suggest that population crosses are likely to result in outbreeding depression. We infer that, in this case, genetic rescue has a relatively unique potential to be harmful rather than helpful at present. However, due to reduced adaptive potential, the Alberta may still benefit from future genetic rescue as climate conditions change. Proactive experimental population crosses should be completed to assess reproductive compatibility and offspring fitness.
Cerebellar organoids model cell type-specificFOXP2expression during human cerebellar development
Authors: Apsley Elizabeth J. , Riepsaame Joey , Cowley Sally A. , Becker Esther B. E.
Published: January 2025

In this study, we demonstrate the potential of cerebellar organoids for studying features of early human cerebellar development. Forkhead box protein P2 (FOXP2) is a transcription factor associated with speech and language development that is highly expressed in the developing brain. However, little attention has been directed to the study of FOXP2 in the early developing cerebellum. We used CRISPR gene editing in human iPSCs to generate a fluorescent FOXP2-reporter line. By combining transcriptomic analysis of iPSC-derived cerebellar organoids with published cerebellar datasets, we describe the expression and identify potential downstream targets of FOXP2 in the early developing human cerebellum. Our results highlight expression ofFOXP2in early human Purkinje cells and cerebellar nuclei neurons, and the vulnerability of these cell populations to neurodevelopmental disorders. Our study demonstrates the power of cerebellar organoids to model early human developmental processes and disorders.
A deep-learning tool for species-agnostic integration of cancer cell states
Authors: Rub Jonathan , Chan Jason E , Sussman Carleigh , Tap William D. , Singer Samuel , Tammela Tuomas , Betel Doron
Published: January 2025

Genetically engineered mouse models (GEMM) of cancer are a useful tool for exploring the development and biological composition of human tumors and, when combined with single-cell RNA-sequencing (scRNA-seq), provide a transcriptomic snapshot of cancer data to explore heterogeneity of cell states in an immunocompetent context. However, cross-species comparison often suffers from biological batch effect and inherent differences between mice and humans decreases the signal of biological insights that can be gleaned from these models. Here, we develop scVital, a computational tool that uses a variational autoencoder and discriminator to embed scRNA-seq data into a species-agnosticlatent spaceto overcome batch effect and identify cell states shared between species. We introduce the latent space similarity (LSS) score, a new metric designed to evaluate batch correction accuracy by leveraging pre-labeled clusters for scoring instead of the current method of creating new clusters. Using this new metric, we demonstrate scVital performs comparably well relative to other deep learning algorithms and rapidly integrates scRNA-seq data of normal tissues across species with high fidelity. When applying scVital to pancreatic ductal adenocarcinoma or lung adenocarcinoma data from GEMMs and primary patient samples, scVital accurately aligns biologically similar cell states. In undifferentiated pleomorphic sarcoma, a test case with noa prioriknowledge of cell state concordance between mouse and human, scVital identifies a previously unknown cell state that persists after chemotherapy and is shared by a GEMM and human patient-derived xenografts. These findings establish the utility of scVital in identifying conserved cell states across species to enhance the translational capabilities of mouse models.
Base-modified nucleotides mediate immune signaling in bacteria
Authors: Zeng Zhifeng , Hu Zeyu , Zhao Ruiliang , Rao Jikai , Mestre Mario Rodríguez , Liu Yanqiu , Liu Shunhang , Feng Hao , Chen Yu , He Huan , Chen Nuo , Zheng Jinshui , Peng Donghai , Luo Min , She Qunxin , Pinilla-Redondo Rafael , Han Wenyuan
Published: January 2025

Signaling from pathogen sensing to effector activation is a fundamental principle of cellular immunity. While cyclic (oligo)nucleotides have emerged as key signaling molecules, the existence of other messengers remains largely unexplored. Here, we reveal a bacterial anti-phage system that mediates immune signaling through nucleobase modification. Immunity is triggered by phage nucleotide kinases, which, combined with the system-encoded adenosine deaminase, produce deoxyinosine 5’-triphosphate (dITP) as immune messengers. The dITP signal activates downstream effector to mediate cellular NAD+depletion, resulting in population-level defense through the death of infected cells. To counteract immune signaling, phages deploy specialized enzymes that deplete cellular dAMP, the precursor of dITP messengers. Our findings uncover a nucleobase modification-based anti-phage signaling pathway, establishing noncanonical nucleotides as a new type of immune messengers in bacteria.
Horizontal gene transfers and terpene metabolism drive plant-fungal interaction inMarchantia polymorpha
Authors: El Mahboubi Karima , Beaulieu Chloé , Castel Baptiste , Libourel Cyril , Jariais Nathanaël , Amblard Emilie , van Beveren Fabian , Keller Jean , Martinez Yves , Nelson Jessica , Bonhomme Maxime , Jacquet Christophe , Delaux Pierre-Marc
Published: January 2025

The liverwortMarchantia polymorphahas emerged as a model for studying plant immunity in bryophytes, providing unique insights into conserved defense mechanisms across land plants. By contrast, Marchantia-specific immune mechanisms have not been explored. In this study, we investigated the genetic basis of quantitative resistance inM. polymorphaagainst the fungal pathogenColletotrichum nymphaeae, a naturally occurring compatible parasite. Through a combination of phenotypic, cytological and transcriptomic approaches, combined with genome-wide association studies (GWAS), we identified key defense-related genes and pathways. Transcriptomic analyses performed on two lines with contrasting suceptibilities to the pathogen revealed a strong overlap in immune responses betweenM. polymorphaand angiosperms, including the upregulation of PR proteins, transcription factors typically associated with biotic stresses, and enzymes involved in specialized metabolism. Leveraging the biological and genetic variability present in a collection of naturalM. polymorphaaccessions, highlight the role of horizontally transferred microbial-like terpene synthase (MTPSL) genes, which may contribute to the exceptional terpene diversity in liverworts and play a role in pathogen resistance. GWAS uncovered candidate loci associated with resistance traits, implicating both core immune components and specialized metabolic pathways. These results provide new insights into the specific molecular underpinnings of bryophyte immunity and underscore the evolutionary significance of horizontal gene transfer and specialized metabolites in shaping plant-pathogen interactions.
Glucocorticoids target postnatal oligodendrocyte precursor cells to modulate adult hippocampal network plasticity and stress-induced behavior
Authors: Mattioni Lorenzo , Poggi Giulia , Gallagher Celine , Becker Katrin , Papic Maja , Engbers Jasmin , Koskinen Maija-Kreetta , Abdollahzadeh Ali , Herzog David P , Nardi Leonardo , Conrad Andrea , Winterberg Sarah , Schwarzbach Hans , Engelmann Jan , Lutz Beat , Waisman Ari , Hovatta Iiris , Mittmann Thomas , Schmeisser Michael J. , Mueller Marianne B , Treccani Giulia
Published: January 2025

Aversive early experiences affect brain development and enhance the risk of psychiatric disorders. Recent evidence has implicated oligodendrocyte precursor cells (OPCs) in the pathophysiology of stress-related diseases. Beside their myelination-dependent functions, OPCs are involved in the fine-tuning of neuronal activity and responding to environmental challenges. OPCs express the glucocorticoid receptor (GR) binding glucocorticoids (GCs), and are sensitive to aversive experiences. To decipher the role of early postnatal GCs on OPC maturation, neuronal network activity and adult behavior we conditionally deleted GR in postnatal OPCs. Such deletion resulted in a reduction of oligodendrocytes in the hippocampus, alteration of hippocampal network activity and impairment in the formation of memories in adulthood. Our findings reveal a novel role for postnatal GRs in modulating OPC maturation, neuronal network excitability and adult memory formation. This provides the first evidence for a dual role of GR signaling in both the canonical and non-canonical functions of OPCs.
Direct observation of assembly and function of trigger responsive lipase biohybrids
Authors: Voutyritsa Errika , Sørensen Emily Winther , Oikonomou Athanasios , Lazou Thomai , Bushi Jonida , Christensen Sune M. , Velonia Kelly , Hatzakis Nikos S.
Published: January 2025

Protein-polymer biohybrids mark a cutting edge in the creation of advanced materials designed for high performance under diverse conditions by combining the intrinsic stability and adaptability of synthetic polymers with the remarkable functionality and specificity of proteins. Despite the existence of stimuli responsive polymers, their potential for achieving precise, trigger responsive control over both the function and the assembly of protein-polymer biohybrids has yet to be fully attained. Here, we report the synthesis and thorough characterization of pH and temperature responsive lipase-polymer conjugates at both the supramolecular and the single molecule level. In contrast to conventional ensemble measurements performed in solution, we extensively characterized the stimuli triggered reversibility of the self-assembly of these lipase-based biohybrids and recorded the enzymatic activity at the fundamental level of individual nanoparticles. Our findings unexpectedly demonstrated that the stimuli responsive biohybrids exhibited not only a twofold increased enzymatic activity as compared to native lipases in certain cases but also maintained the trigger responsive control over enzymatic activity by temperature. Direct single particle recordings of biohybrid activity showed a correlation of the biohybrid size to catalytic activity, revealing individual enzymes to display higher activity in smaller nanoparticles. The biohybrids exhibit impressive long-term stability, in some cases almost 95% of the enzymatic activity as compared to ∼40-60% for native lipases after 1 year of storage. The improved stability and activity as compared to native enzymes accompanied with their triggered responsiveness highlight their significant potential for tightly controlled biocatalysis and sustainable industrial applications.
STAT5B leukemic mutations, altering SH2 tyrosine 665, have opposing impacts on immune gene programs
Authors: Lee Hye Kyung , Chen Jichun , Philips Rachael L. , Lee Sung-Gwon , Feng Xingmin , Wu Zhijie , Liu Chengyu , Schultz Aaron B. , Dalzell Molly , Birnbaum Foster , Sexton Joel A. , Keating Amy E. , O’Shea John J. , Young Neal S. , Villarino Alejandro V. , Furth Priscilla A. , Hennighausen Lothar
Published: January 2025

STAT5B is a vital transcription factor for lymphocytes. Here, function of two STAT5B mutations from human T cell leukemias: one substituting tyrosine 665 with phenylalanine (STAT5BY665F), the other with histidine (STAT5BY665H) was interrogated.In silicomodeling predicted divergent energetic effects on homodimerization with a range of pathogenicity. In primary T cellsin vitroSTAT5BY665Fshowed gain-of-function while STAT5BY665Hdemonstrated loss-of-function. Introducing the mutation into the mouse genome illustrated that the gain-of-functionStat5bY665Fmutation resulted in accumulation of CD8+effector and memory and CD4+regulatory T-cells, altering CD8+/CD4+ratios. In contrast, STAT5BY665H‘knock-in’ mice showed diminished CD8+effector and memory and CD4+regulatory T cells. In contrast to wild-type STAT5, the STAT5BY665Fvariant displayed greater STAT5 phosphorylation, DNA binding and transcriptional activity following cytokine activation while the STAT5BY665Hvariant resembled a null. The work exemplifies how joiningin silicoandin vivostudies of single nucleotides deepens our understanding of disease-associated variants, revealing structural determinants of altered function, defining mechanistic roles, and, specifically here, identifying a gain-of function variant that does not directly induce hematopoietic malignancy.
The impact of musical expertise on disentangled and contextual neural encoding of music revealed by generative music models
Authors: Mischler Gavin , Li Yinghao Aaron , Bickel Stephan , Mehta Ashesh D. , Mesgarani Nima
Published: January 2025

Music perception involves the intricate processing of individual notes and their contextual relationships within a piece. However, how the brain encodes and organizes these features, particularly in relation to musical expertise, remains unclear. Using noninvasive and invasive electrophysiological recordings alongside generative music models, we reveal that musicians exhibit neural encoding that is more attuned to the separation and integration of complex musical structures, with a pronounced left-hemispheric bias compared to non-musicians. Invasive recordings further highlight a hierarchical and spatially organized representation of musical features and context across brain regions. These findings advance our understanding of how the brain processes music and the role of musical training in shaping auditory cognition.
Biofabrication of spatially organized temporo-mandibular fibrocartilage assembloids
Authors: Dufour Alexandre , Essayan Lucie , Kim Beomjoon , Salles Vincent , Marquette Christophe
Published: January 2025

The combination of mesenchymal stem cell (MSC) spheroids and polymeric scaffolds has been actively explored for engineering organized hyaline cartilage; however, its application to other types of cartilage remains under-explored. The temporo-mandibular joint (TMJ) fibrocartilage is a highly stratified tissue whose recapitulation remains challenging. In this study, the shape and growth orientation of assembloids were controlled by seeding early mature human adipose-derived MSC spheroids into polymeric scaffolds with a dual architecture of micron-scale fibers. This results in flattened asymmetric tissues with a single-sided articular surface. Structurally, the engineered fibrocartilage mimicked the histotypical organization observed in the native human condylar fibrocartilage, notably featuring a thick fibrous zone with flattened cells. Native-like distribution of general extracellular matrix (ECM) components, including glycosaminoglycans and total collagens, and ECM-specific components, such as type I and II collagens, aggrecan core protein, and fibronectin, were observed. Collagen organization, as demonstrated by polarized light microscopy and scanning electron microscopy at the fibril level, was also found to be similar to that of native human tissue. Zonal-dependent micromechanical properties were identified in both the engineered and native tissues, although lower mechanical properties were observed in the fibrous zone of the engineered tissue. This work provides further evidence that the combination of MSC spheroids and micron-sized fiber polymeric scaffolds is a versatile approach for engineering stratified cartilage and a promising strategy for engineering biomimetic fibrocartilage grafts for TMJ reconstruction.
The natural variability of a dexterous motor skill is stably encoded in the cortex of freely behaving mice
Authors: de Laittre Elizabeth A. , MacLean Jason N.
Published: January 2025

The nervous system enables precise, skilled movements across diverse contexts, consistently performed day after day. However, the extent to which the brain’s neural activity patterns are specific to each instance of a movement or behavior, and how similar these patterns are across days, remains unclear. To address this, we record calcium fluorescence activity in the motor cortex of freely moving mice performing a self-initiated, skilled reach-to-grasp task. The high trial counts and single-trial variability in this task allow for a rigorous statistical analysis of moment-to-moment movement encoding across matched behavioral sets over five days. We found that single neurons in motor cortex encode the single trial (reach-to-reach) details of paw, digit, and head movements, and this encoding is stable over days. This suggests that the stable contribution of individual cells in the motor circuit underlies the generation of skilled movements, even in complex sensory-driven tasks like reach-to-grasp.
A Prediction Method of Land Use Type Evolution Based on Long and Short-Term Memory Networks—Taking Gansu Province as an Example
Authors: Zhang Shiqi , Cao Chuhui
Published: January 2025

In the context of escalating global climate change and human activities, understanding the driving mechanisms behind land use change and predicting future trends is crucial. This study takes Gansu Province as a case, using land use type data from 1990 to 2020 to construct a Long Short-Term Memory (LSTM) model to predict land use changes over the next decade (2021–2030). The results indicate that land use types in Gansu Province exhibit significant dynamic changes, with forest area continuously increasing, built-up land rapidly expanding, and areas of unused land and grassland significantly decreasing. These changes reflect the combined effects of ecological protection policies, urbanization, and land development. The model’s predictions suggest that built-up land has absorbed substantial areas of unused land, grassland, and cultivated land, with accelerated urbanization. Forest area growth is attributed to the implementation of ecological restoration policies, while grassland and water areas show fluctuating changes, and the area of unused land continues to decrease. The findings not only provide data support for land resource management and ecological protection, but also offer scientific evidence for the formulation of sustainable land use policies, which can serve as an important reference for the sustainable use and management of land resources in Gansu Province and similar regions.
Parvovirus B19 genomic DNA concentrations in wastewater solids are associated with community infections
Authors: Zulli Alessandro , Linfield Rebecca Y. , Duong Dorothea , Shelden Bridgette , Boehm Alexandria B.
Published: January 2025

We assessed concentrations of parvovirus B19 DNA from two wastewater treatment plants in a county with a known outbreak in 2024. Wastewater viral concentrations correlated significantly with clinical cases, demonstrating wastewater’s potential for tracking parvovirus B19 infections. Peaks in wastewater concentrations were aligned with the peak in hydrops fetalis diagnoses.
Cryo-EM structures of engineered Shiga toxin-based immunogens capable of eliciting neutralizing antibodies with therapeutic potential against Hemolytic Uremic Syndrome
Authors: Cristófalo Alejandro Ezequiel , Sharma Arvind , Cerutti María Laura , Sharma Kedar , Melero Roberto , Pardo Romina , Goldbaum Fernando Alberto , Borgnia Mario , Zylberman Vanesa , Otero Lisandro Horacio
Published: January 2025

Shiga toxin-producingEscherichia coli-associated hemolytic uremic syndrome (STEC-HUS) is a serious disease that causes renal failure predominantly in children. Despite its significant impact, there are currently no licensed vaccines or effective therapies available. The B subunits of Shiga toxins 1 and 2 (Stx1B and Stx2B) are suitable targets for developing neutralizing antibodies, but their pentameric assembly is unstable when isolated from the whole toxin. Taking advantage of the oligomeric symmetry shared between Stx1B and Stx2B with the lumazine synthase fromBrucellaspp. (BLS), we have previously engineered the chimeric toxoids BLS-Stx1B and BLS-Stx2B as immunogens to generate therapeutic equine polyclonal antibodies. The resulting product (INM004) has successfully passed phases 1 and 2 clinical trials, and a phase 3 has been launched in Argentina and seven European countries. In this work, we present the cryo-EM structures of BLS-Stx1B and BLS-Stx2B, which confirm that these engineered immunogens effectively stabilize the StxB pentamers. Moreover, our results reveal that both chimeric constructs present high flexibility at their extremes, corresponding to motions of the StxBs with respect to the BLS core. Additionally, we present structural evidence of the interaction between the chimeras and polyclonal Fab (pFab) fragments derived from INM004, demonstrating that the elicited neutralizing antibodies block most of the interaction surface of the toxins with their cellular receptors. These findings further validate this promising antibody-based therapy for mitigating STEC-HUS and demonstrate that the BLS-Stx1B and BLS-Stx2B chimeras are potential candidates for developing a human vaccine.
The Mitotic Chromosome Periphery: A Fluid Coat That Mediates Chromosome Mechanics
Authors: Mendonca Tania , Urban Roman , Lucken Kellie , Coney George , Tassieri Manlio , Kad Neil M. , Wright Amanda J. , Booth Daniel G.
Published: January 2025

Mitotic chromosomes are specialised packets of condensed genetic material with dynamic mechanical properties. Each chromosome is coated by a sheath of proteins and RNA, called the mitotic chromosome periphery (MCP). The MCP is widely considered as an essential chromosome compartment where its multiple functions bestow material properties important for successful cell division. However, the details of the micromechanical properties of mitotic chromosomes, and specifically if and how the MCP contributes to these features, remain poorly understood. In this study, we present the most comprehensive characterisation of single-chromosome mechanics to date spanning a broadband frequency range, using optical tweezers and a novel microrheology technique. We extend this analysis to the first direct measurements of MCP micromechanics by manipulating levels of Ki-67, the chief organiser of this compartment, and apply a rheological model to isolate its contribution to chromosome dynamics. We report that the MCP governs high-frequency self-reorganisation dynamics and acts as a structural constraint, providing force-damping properties that mitigate mitotic stress. This work significantly advances our understanding of chromosome micromechanics and how the MCP contributes to the fundamental properties of chromosomes.
Evidence of flowering time advance in blue lupin (Lupinus angustifolius) in the last decades revealed by herbarium data and citizen science databases
Authors: Jiménez – López F.J. , Lara – Romero C. , Iriondo J.M. , Rubio Teso M.L. , García – Fernández A
Published: January 2025

Rapid adaptation to climate change in plants manifests through genetic modifications, epigenetic changes, or species-microbiome interactions, with short-living species having a greater potential for adaptation. The integration of historical collection data with modern databases improves our ability to study plant phenology and distribution shifts in response to global change. This study evaluates changes in the flowering phenology and vernalization requirements ofLupinus angustifoliuspopulations across the Iberian Peninsula, assessing the effectiveness of diverse data sources. Using herbarium specimens and field photographs, we compiled flowering data and estimated flowering peaks. Thermal time and vernalization requirements were estimated using recorded flowering stages and high-resolution climate data. Analyses revealed a progressive advancement inL. angustifoliusflowering in the last 60 years. Latitude and elevation emerged as significant influencing factors, with greater shifts observed at lower latitudes and elevations. Notably, plants now flower with fewer vernalization days, and higher thermal time, particularly at lower elevations. The adaptive responses of plants to global change are intricate and dynamic. Phenological advancement in flowering appears to be a key strategy for coping with environmental alterations, facilitating survival and reproduction through the interplay of genotype, phenotype, and environment, as well as existing genetic diversity. In this context, historical records and long-term monitoring prove invaluable for assessing the efficacy and pace of these adaptive processes. To improve our understanding of plant adaptation in the context of climate change, it is essential to synthesize diverse data sources and maintain ongoing collection efforts.
Age-related Increase in Locus Coeruleus Activity and Connectivity with Prefrontal Cortex during Ambiguity Processing
Authors: Dave Arjun , Ye Shuer , Bätz Leona Rahel , Lan Xiaqing , Jacobs Heidi I.L. , Ziaei Maryam
Published: January 2025

Interpreting ambiguous environmental cues, like facial expressions, becomes increasingly challenging with age, especially as cognitive resources decline. Managing these challenges requires adaptive neural mechanisms that are essential for maintaining mental well-being. The locus coeruleus (LC), the brain’s main norepinephrine source, regulates attention, arousal, and stress response. With extensive cortical connections, the LC supports adapting to cognitive demands and resolving conflicting cues from environment, particularly in later life. Previous research suggests that the LC interacts with the prefrontal cortex during high-conflict tasks. However, whether LC activity and its connectivity with the PFC support emotional ambiguity processing and contributes to emotional well-being in healthy aging remains unclear. To address this gap, we used 7T-MRI to examine LC function in 75 younger (25.8±4.02years, 35females) and 69 older adults (71.3±4.1 years, 35females) during facial emotion-recognition task morphed with varying ambiguity: anchor (unambiguous happy or fearful), intermediate- ambiguity (30% happy–70% fearful and 40%-happy–60% fearful expressions, in either direction), and absolute-ambiguity (50% happy-fearful). Behaviorally, participants had longer response times and lower confidence in the absolute-ambiguity condition, while older adults perceived ambiguous faces as happy more frequently than younger adults. Neuroimaging results revealed older adults exhibited greater LC activity and enhanced connectivity with dorsolateral PFC (dlPFC) during absolute-ambiguity compared to younger adults. This heightened connectivity in older adults was linked to better emotional resilience and mental well-being. These findings suggest greater LC activity supports managing cognitively demanding tasks, while enhanced LC-dlPFC connectivity helps maintain emotional well- being, underscoring the importance of this neural pathway for healthy aging.

Significance Statement

Understanding how the brain adapts to cognitive and emotional demands with age is key to promoting healthy aging. This study examined whether the locus coeruleus (LC), a brain region critical for regulating attention and arousal, undergoes adaptive changes with age, especially during emotional ambiguity task. Using ultra-high-field imaging, we explored younger and older adults recognize facial expressions with varying ambiguity levels. Our findings indicated that compared to young, older adults showed heightened LC activity and LC-dorsolateral prefrontal cortex (dlPFC) connectivity when processing absolute-ambiguous facial expressions, with enhanced connectivity linked to improved mental well-being. These results suggest higher LC activity supports cognitive demands of ambiguity processing with LC- dlPFC connectivity promoting emotional well-being and resilience, offering insights into mechanisms underlying healthy aging.
High-speed 10-plex DNA-PAINT with a larger sequence repertoire
Authors: Banerjee Abhinav , Srivastava Mansi , Vidwath Vedanth Shree , Ganji Mahipal
Published: January 2025

DNA-Points Accumulation for Imaging in Nanoscale Topography (DNA-PAINT) enables multiplexed super-resolution imaging of biological samples. We expand the repertoire of speed-optimized DNA sequences for DNA-PAINT imaging to facilitate the molecular-resolution imaging of up to ten targets in a sequential manner. These imager sequences showcase a range of binding kinetics, providing the flexibility to select optimal sequences for specific applications. We demonstrate the application of twelve speed-optimized imager sequences for multiplexed super-resolution imaging of the microtubular network and Nuclear Lamins in the cellular context. We anticipate that the ability to image as many as ten targets using the simple Exchange-PAINT strategy at accelerated speed will drive its further adoption for diverse cellular imaging applications.
Reduced signatures of gene duplication and non-random gene organization in shaping stage-specific patterns of gene expression across a relatively simple life cycle
Authors: DuBose James G. , Morran Levi T.
Published: January 2025

Complex eukaryotes generally experience some degree of ecological transition as they develop, which is usually accompanied by the expression of different traits across their ontogeny. Theory suggests the evolution of differentiation between life stages is facilitated by the expression of different genes at different points throughout ontogeny, which alleviates pleiotropic evolutionary constraints. Therefore, ascertaining what contributes to specialized patterns of gene expression across ontogeny is fundamental to understanding the evolution of ontogenetic complexity. Expression divergence between duplicate genes and gene organization on chromosomes have been identified as important features of relatively complex ontogenies. Therefore, one could predict that their link to transcriptional specialization across ontogeny may be weaker in relatively simpler life cycles. Here, we investigated the links between gene duplication, gene organization, and stage-specific patterns of expression across the relatively simpleCaenorhabditis eleganslife cycle. We found that signatures of stage-biased chromosomal regions were weaker inC. elegansthan what has been previously described in organisms with more complex ontogenies. Furthermore, we found the extent that duplicate genes varied in ontogenetic expression pattern was more constrained inC. elegans. Overall, our findings add to a body of evidence that suggests a link between gene duplication and gene organization and the evolution of complex ontogenies.