bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defined cellular reprogramming of androgen receptor-active prostate cancer to neuroendocrine prostate cancer
Authors: Li Shan , Song Kai , Sun Huiyun , Tao Yong , Huang Arthur , Bhatia Vipul , Hanratty Brian , Patel Radhika A. , Long Henry W. , Morrissey Colm , Haffner Michael C. , Nelson Peter S. , Graeber Thomas G. , Lee John K. 
Published: February 2025

SUMMARYNeuroendocrine prostate cancer (NEPC) arises primarily through neuroendocrine transdifferentiation (NEtD) as an adaptive mechanism of therapeutic resistance. Models to define the functional effects of putative drivers of this process on androgen receptor (AR) signaling and NE cancer lineage programs are lacking. We adapted a genetically defined strategy from the field of cellular reprogramming to directly convert AR-active prostate cancer (ARPC) to AR-independent NEPC using candidate factors. We delineated critical roles of the pioneer factors ASCL1 and NeuroD1 in NEtD and uncovered their abilities to silence AR expression and signaling by remodeling chromatin at the somatically acquired AR enhancer and global AR binding sites with enhancer activity. We also elucidated the dynamic temporal changes in the transcriptomic and epigenomic landscapes of cells undergoing acute lineage conversion from ARPC to NEPC which should inform future therapeutic development. Further, we distinguished the activities of ASCL1 and NeuroD1 from the inactivation of RE-1 silencing transcription factor (REST), a master suppressor of a major neuronal gene program, in establishing a NEPC lineage state and in modulating the expression of genes associated with major histocompatibility complex class I (MHC I) antigen processing and presentation. These findings provide important, clinically relevant insights into the biological processes driving NEtD of prostate cancer.
Tuning of Task-Relevant Stiffness in Multiple Directions
Authors: Zhang Chenguang , Tessari Federico , Hermus James , Akolkar Himanshu , Hogan Neville , Schwartz Andrew B. 
Published: February 2025

AbstractThe dynamics of any mechanical system can be described in terms of forces and motions. The interaction of these terms is often captured in the metric of mechanical impedance – a generalization of stiffness – used to describe how a mechanical system resists the application of force. The ability to adaptively change impedance is advantageous when encountering variable environmental conditions. Changing impedance in robotic systems is limited, whereas humans can rapidly and elegantly adapt the impedance of their limbs, especially during initial contact with objects. This is especially true for movements of our arms and hands. Multiple studies have examined the arm’s response to perturbation with the idea of impedance as areactivecomponent. In this study, we investigate the ability of humans topredictivelyset their arm impedance in a contact breaking task to perform fast movements to target positions in different directions. Our findings show that subjects (n=20) predictively co-activate antagonist muscles to primarily adjust one component of the arm’s impedance – stiffness – to match different task constraints before the movement begins irrespective of movement direction. Interestingly, the subjects’ performance was limited by the task-dependent stiffness rather than the required force and they tended to generate minimal stiffness to perform the task. With this robust strategy, task success is optimized at the expense of energy efficiency. This type of control is essential for the uniquely human ability to interact with objects.
Predicting animal movement with deepSSF: a deep learning step selection framework
Authors: Forrest Scott W. , Pagendam Dan , Hassan Conor , Drovandi Christopher , Potts Jonathan R. , Bode Michael , Hoskins Andrew J. 
Published: February 2025

AbstractPredictions of animal movement are vital for understanding and managing wild populations. However, the fine-scale, complex decision-making of animals can pose challenges for the accurate prediction of trajectories. Step selection functions (SSFs), a common tool for inferring relationships between animal movement and the environment, are also increasingly used to simulate animal trajectories for prediction. Although admitting a lot of flexibility, the SSF framework is limited to its reliance on pre-defined functional forms for fitting to data, and SSFs that involve complex functional forms to model detailed processes can be prohibitively difficult to fit and interpret.Here, we presentdeepSSF, an approach to fit and predict animal movement data using deep learning. Whilst not specific to any particular model, we denote thedeepSSFapproach as building and training a neural network architecture that receives multiple environmental layers and scalar values as inputs, and outputs a single layer representing the next-step probability. To demonstrate adeepSSFmodel, we build a model inPyTorchthat has distinct but interacting habitat selection and movement subnetworks, which allows for explicit representation of both processes and interpretable intermediate outputs. We apply our model to GPS data of introduced water buffalo (Bubalus bubalis) in the tropical savannas of Northern Australia.OurdeepSSFmodel was able to learn features that are present in the habitat covariate layers, such as linear features (rivers, forest edges), and the composition of certain habitat areas, without having to specify them pre-emptively within the SSF framework. It was also able to capture the complex interactions between the habitat covariates as well as temporal dynamics across time of day and year.We expect that thedeepSSFapproach will generate accurate and informative animal movement trajectories, which can be used for deepening our understanding of animal-environment systems and for the practical management of species. Considering the wide range of deep learning tools, thedeepSSFapproach could be extended to represent memory and social dynamic processes, with the potential for integrating non-spatial data sources such as accelerometers and physiological sensors.
Single Cell RNA-sequencing of BCG naïve and recurrent non-muscle invasive bladder cancer reveals a CD6/ALCAM-mediated immune-suppressive pathway
Authors: Juric Ivan , Fink Emily E. , Qiu Hong , Desprez Pierre-Emmanuel , Ravi Arvind , Holton Mark , Makarov Vladimir , Almassi Nima , Min Booki , Getz Gad , Chan Timothy A. , Alban Tyler , Ting Angela H. , Lee Byron H. 
Published: February 2025

ABSTRACTNon-muscle invasive bladder cancer (NMIBC) represents 70–80% patients with newly diagnosed bladder cancer, and Bacillus Calmette-Guérin (BCG) remains a cornerstone treatment for intermediate-and high-risk NMIBC to prevent disease recurrence and progression. However, many patients experience recurrence after induction BCG, posing significant challenges in the management of the disease. We conducted single cell RNA sequencing on freshly collected NMIBC samples, distinguishing between those naïve to BCG treatment and those that recurred post-BCG treatment. We observed a clear activation of inflammatory pathways across cell types during recurrence, but these were not associated with canonical immune checkpoint or T cell exhaustion phenotypes. Analysis of cell-to-cell communication revealed enhanced interactions between T cells and urothelial cells in BCG-recurrence, predominantly modulated by CD6 and ALCAM. Furthermore, we found CD6hiT cells to be immunosuppressed and enriched in recurrent samples, suggesting a potential role for CD6 as an immune evasion signal in NMIBC.SIGNIFICANCEThese findings uncover a novel mechanism responsible for bladder cancer recurrence after BCG treatment. Enhanced T cell-urothelial cell communication in recurrent tumors mediated by CD6 and ALCAM leads to an immunosuppressed state. Thus, CD6 may have potential as a therapeutic target to augment BCG response in non-muscle invasive bladder cancer.
TET3 protects the Dlk1-Dio3 Imprinted Locus from DNA hypomethylation during adult NSC Reprogramming
Authors: Lázaro-Carot Laura , Jiménez-Villalba Esteban , Planells Jordi , Lozano-Ureña Anna , Díaz-Moncho Jennifer , Montalbán-Loro Raquel , Lleches-Padilla Adela , Kirstein Martina , Ito Mitsuteru , Radford Elizabeth J. , Ferrón Sacri R. 
Published: February 2025

AbstractGenomic imprinting is an epigenetic mechanism that drives monoallelic gene expression depending on parental origin. Loss of imprinting (LOI) is associated with human imprinting disorders, fetal development, and cancer progression. Imprinted genes, organized in clusters, are regulated by methylation at imprint control regions (ICRs), differentially methylated regions (DMRs) between parental chromosomes. Somatic cell reprogramming into induced pluripotent stem cells (iPSCs) is a valuable tool for studying pluripotency and holds promise for patient-specific therapies. Discerning whether genomic imprinting changes during reprogramming represent epigenetic abnormalities or essential adaptations linked to pluripotency is crucial. Here, we perform RNA-seq and MeDIP-seq analysis on mouse iPSCs derived from neural stem cells (NSCs). Our findings reveal that ICRs undergo DNA hypomethylation, confirming widespread LOI in pluripotent cells. However, the IG-DMR within the Dlk1-Dio3 imprinted cluster resists hypomethylation, a hallmark of successful pluripotency acquisition. We also identify a non-canonical role of TET3 in IG-DMR methylation protection through transcriptional regulation ofOct4andTrim28. These findings highlight genomic imprinting as a key mechanism of gene dosage control in pluripotency acquisition and maintenance.
Changes in Spo0A~P pulsing frequency control biofilm matrix deactivation
Authors: Palma C.S.D. , Haller D.J. , Tabor J.J. , Igoshin O.A. 
Published: February 2025

AbstractUnder starvation conditions,B. subtilissurvives by differentiating into one of two cell types: biofilm matrix-producing cells or sporulating cells. These two cell-differentiation pathways are activated by the same phosphorylated transcription factor - Spo0A~P. Despite sharing the activation mechanism, these cell fates are mutually exclusive at the single-cell level. This decision has been shown to be controlled by the effects of growth rate on gene dosage and protein dilution in the biofilm matrix production network. In this work, we explore an alternative mechanism of growth rate-mediated control of this cell fate decision. Namely, using deterministic and stochastic modeling, we investigate how the growth-rate-dependent pulsing dynamics of Spo0A~P affect biofilm matrix deactivation and activation. Specifically, we show that the Spo0A~P pulsing frequency tunes the biofilm matrix deactivation probability without affecting the probability of biofilm matrix activation. Interestingly, we found that DNA replication is the cell cycle stage that most substantially contributes to the deactivation of biofilm matrix production. Finally, we report that the deactivation of biofilm matrix production is not primarily regulated by the effects of growth rate on gene dosage and protein dilution. Instead, it is driven by changes in the pulsing period of Spo0A~P. In summary, our findings elucidate the mechanism governing biofilm deactivation during the late stages of starvation, thereby advancing our understanding of how bacterial networks interpret dynamic transcriptional regulatory signals to control stress-response pathways.Author SummaryBacteria have evolved various adaptation mechanisms to survive under challenging environmental conditions. For instance, under mild starvation,B. subtilisbacteria form biofilms — communities of cells encapsulated in a protective extracellular matrix. On the other hand, these bacteria differentiate into highly resistant spores under severe starvation. Interestingly, sporulating cells are often found within biofilm communities, but they do not contribute to biofilm matrix production. This is thought to be an energy-conservation strategy, as biofilm formation is an energy-intensive process and is therefore halted before sporulation begins. Though previous work has focused on the mechanisms driving biofilm disassembly, few studies have explored the regulatory processes thatB. subtilisemploys to halt matrix production prior to starting sporulation. In this study, we use mathematical models to demonstrate that the temporal dynamics of the biofilm master regulator Spo0A~P control the deactivation of matrix production. Understanding the regulation of biofilm, a common lifestyle in bacteria, can lead to the development of synthetic strategies to either enhance or disrupt biofilm formation, with potential applications in medicine and industry.
Combined Transplantation of Mesenchymal Progenitor and Neural Stem Cells to repair cervical spinal cord injury
Authors: White Seok Voon , Ma Yee Hang Ethan , Plant Christine D , Harvey Alan R , Plant Giles W 
Published: February 2025

AbstractMesenchymal progenitor cells (MPC) are effective in reducing tissue loss, preserving white matter and improving forelimb function after spinal cord injury (SCI) (White et al., 2016). We proposed that by preconditioning the mouse by intravenous delivery (IV) of MPCs for 24 hours following SCI that this would provide a more favorable tissue milieu for NSC intraspinal bridging transplantation at day 3 and day 7. In com-bination these transplants will provide better anatomical and functional outcomes. The intravenous MSCs would provide cell protection and reduce inflammation. NSCs would provide a tissue bridge for axonal regeneration and myelination and reconnect long tract spinal pathways. Results showed that initial protection of the injury site by IV MPCs transplantation resulted in no increased survival of the NSCs transplanted at Day 7. However, integration of transplanted NSCs was increased at the Day 3 time point indicating MPCs influence very early immune signaling. We show in this study that MPC transplantation resulted in a co-operative NSC cell survival improvement at Day 3 post SCI. In addition to increased NSC survival at day 3 there was an increase in NSC derived mature oligodendrocytes at this early time point. In vitro analysis confirmed MPC driven oligodendrocyte differentiation which was statistically increased when compared to control NSC only cultures. These observations provide important information about the combination, delivery, and timing of two cellular therapies in treating SCI. This study provides important new data on understanding the MPC inflammatory signaling within the host tissue and time points for cellular transplantation survival and oligodendroglia differentiation. These results demonstrate that MPC transplantation can alter the therapeutic window for intraspinal transplantation by controlling both the circulating inflammatory response and local tissue milieu.
The 5-HT1F Receptor Agonist Lasmiditan improves Cognition and Ameliorates Associated Cortico-Hippocampal Pathology in Aging Parkinsonian Mice
Authors: Ishii Atsushi , Meredith Jasmine R , Corenblum Mandi J , Bernard Kelsey , Wene Paige V , Menakuru Nainika , Santiago Paul V , Schnellmann Rick G , Madhavan Lalitha 
Published: February 2025

ABSTRACTWhile the etiopathology of Parkinson’s disease (PD) is complex, mitochondrial dysfunction is established to have a central role. Thus, mitochondria have emerged as targets of therapeutic interventions aiming to slow or modify PD progression. We have previously identified serotonergic 5-HT1F receptors as novel mediators of mitochondrial biogenesis (MB) - the process of producing new mitochondria. Given this, here, we assessed the therapeutic potential of the FDA-approved 5-HT1F receptor agonist, lasmiditan, in a chronic progressive PD model (Thy1-aSyn ‘line 61’ mice). It was observed that systemic lasmiditan exhibited robust brain penetration and reversed cognitive deficits in young (4-5.5 months old) Thy1-aSyn mice (1mg/kg, every other day). Anxiety-like behavior was also improved while motor function remained unaffected. These behavioral changes were associated with enhanced MB and mitochondrial function, paired with reduced alpha-synuclein aggregation particularly in cortico-hippocampal regions. Furthermore, in older (10-11.5 months old) mice, although the effects were milder, daily lasmiditan administration increased MB and bettered cognitive abilities. In essence, these findings indicate that repurposing lasmiditan could be a potent strategy to address PD-related cognitive decline.
Effects of Lamina-Chromatin Attachment on Super Long-Range Chromatin Interactions
Authors: Delafrouz Pourya , Farooq Hammad , Du Lin , Ma Ao , Liang Jie 
Published: February 2025

AbstractThe interactions between chromatin and lamin proteins localized on the nuclear envelope play a crucial role in the three-dimensional (3D) organization of the genome. This study investigates the influence of lamin associated domains (LADs) on genome organization at the chromosome level using 3D polymer models of mouse embryonic fibroblasts (MEFs) and embryonic stem cells (mESCs). By integrating genome-wide LAD maps from DamID assays, we simulated chromatin conformations with and without LAD attachment to the nuclear envelope. Our results show that incorporating LAD-lamin interactions yields a radial chromatin distribution consistent with experimental observations. Moreover, LAD-lamin interactions induce significant super long-range chromatin contacts across distant genomic regions. These findings suggest two distinct mechanisms driving induction of chromatin interactions by LAD-lamin attachment.
Phenethylaminylation: PreliminaryIn VitroEvidence for the Covalent Transamidation of Psychedelic Phenethylamines to Glial Proteins using 3,5-Dimethoxy-4-(2-Propynyloxy)-Phenethylamine as a Model Compound
Authors: Rangan Rajiv S. , Petty R. Max , Acharya Suchismita , Emmitte Kyle A. , do Valle Rafael S. , Lam Chandra , Essajee Salman I. , Mayhew William , Young Olivia , Brooks Calvin D. , Forster Michael J. , Tovar-Vidales Tara , Clark Abbot F. 
Published: February 2025

AbstractPsychedelics are well known for their ability to produce profoundly altered states of consciousness. But, more importantly, the effects of psychedelics can influence neurobehavioral changes that last well after these acute subjective effects end. This phenomenon is currently being leveraged in the development of psychedelic-assisted psychotherapies for the treatment of multiple neuropsychiatric disorders. The cellular and molecular mechanisms by which single doses of psychedelics are able to mediate long-term cognitive changes are an active area of research. We hypothesize that psychedelics contribute to long term changes in cellular state by covalently modifying proteins. This post-translational modification by psychedelics is possible through the transglutaminase-mediated transamidation of their amine termini to glutamine carboxamide residues. Here, we synthesize and utilize a propargylated analogue of mescaline – the classic serotonergic psychedelic phenethylamine found in cacti species – to identify putative protein targets of psychedelic modifications through the use of click-chemistry in a primary human astrocyte cell culture model. Our preliminary findings indicate that a diverse array of glial proteins may be substrates for transglutaminase 2-mediated monoaminylation by our model phenethylamine (“phenethylaminylation”). Based on these points, we speculatively highlight new directions for the study of this putative noncanonical psychedelic activity.
Kingdom-Wide CRISPR Guide Design with ALLEGRO
Authors: Mohseni Amirsadra , Nia Reyhane Ghorbani , Tafrishi Aida , Liu Xin-Zhan , Stajich Jason E. , Wheeldon Ian , Lonardi Stefano 
Published: February 2025

AbstractDesigning CRISPR single guide RNA (sgRNA) libraries targeting entire kingdoms of life will significantly advance genetic research in diverse and underexplored taxa. Current sgRNA design tools are often species-specific and fail to scale to large, phylogenetically diverse datasets, limiting their applicability to comparative genomics, evolutionary studies, and biotechnology. Here, we present ALLEGRO, a combinatorial optimization algorithm able to design minimal, yet highly effective sgRNA libraries targeting thousands of species. Leveraging integer linear programming, ALLEGRO identified compact sgRNA sets simultaneously targeting several genes of interest for over 2,000 species across the fungal kingdom. We experimentally validated the sgRNAs designed by ALLEGRO inKluyveromyces marxianus, Komagataella phaffii, andYarrowia lipolytica. In addition, we adopted a generalized Cas9-Ribonucleoprotein delivery system coupled with protoplast transformation to extend ALLEGRO’s sgRNA libraries to other untested fungal genomes, such asRhodotorula araucariae. Our experimental results, along with cross-validation, show that ALLEGRO enables efficient CRISPR genome editing, supporting the development of universal sgRNA libraries applicable to entire taxonomic groups.
Bioinformatics analysis of next generation sequencing data reveals novel biomarkers and signaling pathways associated with recurrent implantation failure
Authors: Vastrad Basavaraj , Vastrad Chanabasayya 
Published: February 2025

AbstractRecurrent implantation failure (RIF) is a cases in which women have had three fruitless in vitro fertilization (IVF) bid with positive quality embryos. The RIF originates from uterine endometrium microbiota has been implicated in reproductive failure, and poor prognosis and lacks effective treatment. Efforts have been made to elucidate the molecular pathogenesis of RIF. To identify key genes and signaling pathways in RIF, the next genetation sequencing data GSE243550 was downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between RIF and normal controls samples were identified using t-tests in the limma R bioconductor package. Using the DEGs, we further performed a series of gene ontology (GO) and REACTOME pathway enrichment analyses. Protein-protein interaction network was derived using the IMex interactome database and visualized using Cytoscape software. The most significant modules from the PPI network were selected for GO and pathway enrichment analysis. A miRNA-hub gene regulatory network and TF-hub gene regulatory network were constructed depending on key hub genes and visualized using Cytoscape software. A receiver operating characteristic curve (ROC) analysis was plotted to diagnose RIF. In total, 958 DEGs were identified, of which 479 were up regulated genes and 479 were down regulated genes. GO and REACTOME pathway enrichment analysis results revealed that the upregulated genes were mainly enriched in multicellular organismal process, membrane, small molecule binding and extracellular matrix organization, whereas downregulated genes were mainly enriched in organonitrogen compound metabolic process, intracellular anatomical structure, catalytic activity and translation. Through analyzing the PPI network, we screened hub genes APP, HSP90AA1, CAND1, CUL1, HSP90AB1, SIRT7, SRC, CDKN1A, ISG15 and RPS16 by the Cytoscape software. The regulatory network analysis revealed that microRNAs (miRNAs) include hsa-miR-574-3p and hsa-mir-208a-3p, and transcription factors (TFs) include SREBF1 and RELA might be involved in the development of RIF. Receiver operating characteristic curve analysis demonstrated that the hub genes screened for RIF were of good diagnostic significance. Overall, these results thus highlight a range of novel signaling pathways and genes that are linked to the incidence and progression of RIF, providing a list of important diagnostic and prognostic molecular markers that have the potential to aid in the clinical diagnosis and treatment of RIF.