bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative analysis of Endoxifen, Tamoxifen and Fulvestrant: A Bioinformatics Approach to Uncover Mechanisms of Action in Breast Cancer
Authors: Remmel H. Lawrence , Hammer Sandra S. , Singh Harjinder , Shneyderman Anastasia , Veviorskiy Alexander , Alawi Khadija M. , Korzinkin Mikhail , Zhavoronkov Alex , Quay Steven C. 
Published: October 2024

AbstractBreast cancer remains a significant health challenge, with estrogen receptor positive (ER+) subtypes being particularly prevalent forms of breast cancer. Current anti-estrogen therapies, such as tamoxifen and fulvestrant, have limitations, including partial agonist activity and resistance development, which evidence the need for more potent alternatives. Endoxifen, a metabolite of tamoxifen, has emerged as a promising breast cancer therapeutic candidate due to its superior anti-estrogenic effects and side effect profile. The omics signatures for endoxifen, tamoxifen and fulvestrant, obtained from publicly available datasets, were aggregated and harmonized by means of the PandaOmics platform, a commercially available target-discovery platform using multiple AI engines including generative pretrained transformers. Pathway enrichment analyses provided insight into these agents’ mechanisms of action (MOA) in breast cancer. The analyses revealed unexpected variances in several key pathways from expected interactions via estrogen-dependent and independent effects. All three drugs downregulated estrogen signaling and cell cycle-related pathways, such as E2F targets, G2-M checkpoints, Myc targets, and mitotic spindle, and stimulated apoptosis. Fulvestrant and tamoxifen activated pro-inflammatory and immune pathways and perturbed epithelial-mesenchymal transition (EMT). Endoxifen perturbed the PI3K/Akt/mTORC1 pathway, pursuant to distinct molecular mechanisms compared to its parent compound, tamoxifen, and fulvestrant. In summary, advanced AI-driven methodologies demonstrate the capacity to analyze multi-omics data in a comparative way to advance the understanding of endocrine therapy mechanisms in breast cancer. This insight into the distinct effects of endoxifen, tamoxifen, and fulvestrant may aid in selecting the most effective therapies for specific indications and in identifying drug-specific biomarkers.
Does sex matter in neurons’ response to hypoxic stress?
Authors: Voogd Eva J.H.F. , Levers Marloes R. , Hofmeijer Jeannette , Frega Monica , van Putten Michel J.A.M. 
Published: October 2024

AbstractBackgroundStroke exhibits significant sex differences in incidence, response to treatment and outcome. Preclinical studies suggest that hormones, particularly estrogens, are key to differential sensitivity, as female neurons demonstrate enhanced resilience compared to males in both in vivo and in vitro models. This study investigates whether these sex-specific differences in neuronal vulnerability extend to the ischemic penumbra and explores the effects of estrogens under such conditions.MethodsPrimary cortical neuronal networks were generated from male and female new-born Wistar rats and cultured on micro-electrode arrays or glass coverslips. Male and female networks were subjected to hypoxic conditions, followed by a recovery phase, with or without exogenous estrogen treatment. Electrophysiological activity, including spikes and bursts, was monitored and analyzed. Apoptosis was assessed through immunocytochemistry, focusing on caspase-dependent and apoptosis inducing factor (AIF)-dependent pathways.ResultsUnder hypoxic conditions, male and female neuronal networks exhibited a similar decrease in firing and network burst rates, with an associated increase in network burst durations. Estrogen treatment altered these dynamics, leading to increased network burst rates and decreased network burst duration for both sexes. During recovery, no significant differences were observed between estrogen-treated and untreated networks. Immunocyto-chemistry revealed that estrogen significantly influenced caspase-dependent apoptosis, and to a lesser extent AIF-dependent apoptosis.ConclusionsIn our model of the ischemic penumbra, sex-dependent differences in neuronal responses to hypoxic injury are primarily driven by estrogen, rather than intrinsic neuronal characteristics. Although our electrophysiological data demonstrated that estrogen influenced network activity, it did not offer long-term neuroprotection after hypoxia.
Interspecies systems biology links bacterial metabolic pathways to nematode gene expression, behavior, and survival
Authors: Athanasouli Marina , Loschko Tobias , Rödelsperger Christian 
Published: October 2024

AbstractAll animals live in tight association with complex microbial communities, yet studying the effects of individual bacteria remains challenging. Here, we exploit the system of the bacterial feeding nematodePristionchus pacificus, where specific interactions can be studied in isolation. We sequenced the genomes of 84Pristionchus-associated bacteria to investigate how differences in bacterial metabolic potential affect nematode traits. Specifically, we identified the Paerucumarin biosynthesis pathway as a strong candidate for nematode survival. Hypothesizing that bacterial production of coumarin derivatives contributed to increased lethality, we demonstrated nematicidal effects of two related compounds using supplementation assays. To explore metabolic interactions at a broader scale, we generated nematode transcriptomes for 38 bacterial diets and constructed a coexpression network that revealed distinct developmental and environmental signatures. Interspecies association studies resulted in a bipartite network with more than 2,800 interactions which may assist future studies to identify metabolites affecting various biological processes.
The Composition of the Bacterial Community in Raw Milk from Holstein Dairy Cattle Correlated with the Occurrence ofKlebsiella pneumoniaeClinical Mastitis Infections
Authors: O’Brien Bridget , Jung Dongyun , Park Soyoun , Kurban Daryna , Cai Zhangbin , Nguyen Ngoc Sang , Li Zhiwei , Dufour Simon , Ronholm Jennifer 
Published: October 2024

AbstractKlebsiella pneumoniaeis a common, opportunistic bacterial pathogen that can cause severe clinical mastitis in dairy cattle. Optimizing the bovine udder microbiome to resist mastitis pathogens is a growing area of research; however, previous work has not examined which members of the mammary microbiome may have antagonistic interactions withK. pneumoniae. In this study, we collected quarter-level milk samples from Holstein dairy cows in Québec, Canada every two weeks for 14 months and analyzed differences in the milk microbiome between samples that were collected from healthy quarters, quarters that developed subclinical mastitis, and quarters that experiencedK. pneumoniaeclinical mastitis (KP-CM) (n= 512 milk samples). The occurrence of subclinical mastitis did not cause significant differences in the alpha-diversity of the milk microbiome, nor did subclinical mastitis alter the interactions between taxa in the microbiome. However, the occurrence of KP-CM caused reductions in Shannon diversity in raw milk relative to healthy milk and altered the interactions between taxa. Specifically,K. pneumoniaeshowed negative interactions with the genusAerococcus.The negative interactions betweenAerococcusspp. andK. pneumoniaein the context of the bovine milk microbiome should be analyzed further.
ChIPbinner: An R package for analyzing broad histone marks binned in uniform windows from ChIP-Seq or CUT&RUN/TAG data
Authors: Padilla R. , Bareke E. , Hu B. , Majewski J. 
Published: October 2024

AbstractBackgroundThe decreasing costs of sequencing, along with the growing understanding of epigenetic mechanisms driving diseases, have led to the increased application of chromatin immunoprecipitation (ChIP-Seq), Cleavage Under Targets & Release Using Nuclease (CUT&RUN) and Cleavage Under Targets and Tagmentation (CUT&TAG) sequencing – which are designed to map DNA or chromatin-binding proteins to their genome targets – in biomedical research. Existing software tools, namely peak-callers, are available for analyzing data from these technologies, although they often struggle with diffuse and broad signals, such as those associated with broad histone post-translational modifications (PTMs).ResultsTo address this limitation, we present ChIPbinner, an open-source R package tailored for reference-agnostic analysis of broad PTMs. Instead of relying on pre-identified enriched regions from peak-callers, ChIPbinner divides (bins) the genome into uniform windows. Thus, users are provided with an unbiased method to explore genome-wide differences between two samples using scatterplots, principal component analysis (PCA), and correlation plots. It also facilitates the identification and characterization of differential clusters of bins, allowing users to focus on specific genomic regions significantly affected by treatments or mutations. We demonstrated the effectiveness of this tool through a case study assessing H3K36me2 depletion following NSD1 knockout in head and neck squamous cell carcinoma, highlighting the advantages of ChIPbinner in detecting broad histone mark changes over existing software.ConclusionsBinned analysis provides a more holistic view of the genomic landscape, allowing researchers to uncover broader patterns and correlations that may be missed when solely focusing on individual peaks. ChIPbinner offers researchers a convenient tool to perform binned analysis. It improves on previously published software by providing a clustering approach that is independent of each bin’s differential enrichment status, while also offering additional features for downstream analysis of these differentially enriched bins.
Understanding genetic diversity and phylogeography of Common Teal and its phylogenetic relationship with other water bird species in the wetlands of Kashmir Himalayas
Authors: Ahmad Khursheed , Bisht Divyanshi , Joshi Bheem Dutt , Goyal Surender P. , Nigam Parag , Khan Khurshid Alam , Haq Iqram ul , Javid Mohsin 
Published: October 2024

AbstractUnderstanding the genetic diversity and phylogeography of migratory species is critical for biodiversity conservation and the effective management of wetland ecosystems. The Kashmir Himalayas, an integral part of the Central Asian Flyway, host several key wetlands that provide critical wintering grounds for a variety of migratory birds.This study focuses on assessing the genetic characteristics and phylogenetic relationships of the Common Teal (Anas crecca) in comparison to other species within the families Anatidae and Rallidae. We analysed 149 blood samples, including 71 fromA. creccaand 78 from other species in the two families, collected from wetlands in the Kashmir region. Using four mitochondrial markers—cytochrome oxidase subunit I (COI), cytochrome b (Cyt b), 16S rRNA, and the control region—we evaluated the genetic diversity and lineage connectivity of these species.Our findings reveal that the mitochondrial DNA haplotypes ofA. creccain the Kashmir Himalayas are shared with European populations, indicating strong maternal gene flow and connectivity between distant populations. A minimum spanning haplotype network analysis showed minimal nucleotide differences among haplotypes, particularly in the Cyt b and control regions, suggesting low genetic differentiation and a high degree of similarity among individuals. Notably, we identified at least four distinct maternal lineages ofA. creccain the Kashmir wetlands, reflecting diverse migratory sources.Our results also highlight that DNA barcoding using COI exhibited both high and low species resolution, with significant intraspecific variation, making it a valuable tool for further phylogeographic studies. The observed genetic diversity and haplotype sharing with distant populations underscore the ecological importance of Kashmir’s wetlands as crucial habitats for migratory species. Our study emphasizes the need for targeted conservation and management strategies to preserve these vital ecosystems and the biodiversity they support.
A membrane-targeted photoswitch restores physiological ON/OFF responses to light in the degenerate retina
Authors: Ziraldo Gaia , Cupini Sara , Sesti Valentina , Delfino Emanuela , Lanzani Guglielmo , Bertarelli Chiara , Benfenati Fabio , Di Marco Stefano 
Published: October 2024

ABSTRACTThe lack of effective therapies for visual restoration inRetinitis pigmentosaand macular degeneration has led to the development of new strategies such as optogenetics and retinal prostheses. However, visual restoration is poor due to the massive light-evoked activation of retinal neurons, regardless of the segregation of visual information in ON and OFF channels, essential for contrast sensitivity and spatial resolution. Here, we show that Ziapin2, a membrane photoswitch which modulates neuronal capacitance and excitability in a light-dependent manner, is capable of reinstating, in two distinct genetic models of photoreceptor degeneration, brisk and sluggish ON, OFF, and ON-OFF responses in retinal ganglion cells evoked by full-field stimuli, with reactivation of their excitatory and inhibitory conductances. Intravitreally injected Ziapin2 in fully blind rd10 mice restored light-driven behavior and optomotor reflexes. The results indicate that Ziapin2 is a promising molecule for reinstating physiological visual responses in the late stages of retinal degeneration.
Nanotextured steel surface exhibits antifungal activity
Authors: Tripathi Anuja , Champion Julie A. 
Published: October 2024

AbstractFungal adhesion to stainless steel, an alloy commonly used in food and beverage sectors, public and healthcare settings, and numerous medical devices, can give rise to serious infections, ultimately leading to morbidity, mortality, and significant healthcare expenses. In this study, we demonstrate that nanotextured stainless steel (nSS) fabricated using an electrochemical technique is an antibiotic-free biocidal surface againstCandida AlbicansandFusarium Oxysporumwith 98% and 97% reduction, respectively. The nanoprotrusion features on nSS can have both physical contact with cell membranes and chemical impact on cells through production of reactive species, this material should not contribute to drug resistant fungus as antibiotics can. As nSS is also antibacterial and compatible with mammalian cells, demonstration of antifungal activity gives nSS the potential to be used to create effective, scalable, and sustainable solutions to broadly and responsibly prevent fungal and other microbial infections caused by surface contamination.Abstract Figure
De-novoGenome Assembly of the Edwardsiid AnthozoanEdwardsia elegans
Authors: Rutlekowski Auston , Modepalli Vengamanaidu , Ketchum Remi , Moran Yehu , Reitzel Adam 
Published: October 2024

AbstractCnidarians (sea anemones, corals, hydroids, and jellyfish) are a key outgroup for comparisons with bilaterial animals to trace the evolution of genomic complexity and diversity within the animal kingdom, as they separated from most other animals 100s of millions of years ago. Cnidarians have extensive diversity, yet the paucity of genomic resources limits our ability to compare genomic variation between cnidarian clades and species. Here we report the genome forEdwardsia elegans, a sea anemone in the most specious genus of the family Edwardsiidae, a phylogenetically important family of sea anemones that contains the model anemoneNematostella vectensis. TheE. elegansgenome is 396 Mb and predicted to encode approximately 49,000 proteins. We annotated large conservation of macrosynteny betweenE. elegansand other Edwardsiidae anemones as well as conservation of both microRNAs and ultra conserved noncoding elements previously reported in other cnidarians species. We also highlight microsyntenic variation of clustered developmental genes and ancient gene clusters that vary between species of sea anemones, despite previous research showing conservation between cnidarians and bilaterians. Overall, our analysis of theE. elegansgenome highlights the importance of using multiple species to represent a taxonomic group for genomic comparisons, where genomic variation can be missed for large and diverse clades.
High Throughput Morphological Screening Identifies Chemically Defined Media for Mesenchymal Stromal Cells that Enhances Proliferation and Supports Maintenance of Immunomodulatory Function
Authors: Spoerer Thomas M. , Larey Andrew M. , Asigri Winifred , Daga Kanupriya R. , Marklein Ross A. 
Published: October 2024

AbstractWhile mesenchymal stromal cell (MSC) therapies show promise for treating several indications due to their regenerative and immunomodulatory capacity, clinical translation has yet to be achieved due to a lack of robust, scalable manufacturing practices. Expansion using undefined fetal bovine serum (FBS) or human platelet lysate contributes to MSC functional heterogeneity and limits control of product quality. The need for tunable and consistent media has thus encouraged development of chemically defined media (CDM). However, CDM development strategies are rarely comprehensive nor considerate of a medium’s impact on MSC therapeutic function. Standard practice often neglects high-level interactions of media components, such as growth factors, that are critical to MSC growth and function. Given that MSC morphology has been shown to predict their immunomodulatory function, we employed a high throughput screening (HTS) approach to elucidate effects of growth factor compositions on MSC phenotype and proliferation in a custom CDM. This approach led to the discovery and refinement of several formulations that enhanced MSC proliferation and demonstrated wide ranging impacts on MSC immunomodulation. Overall, this work reflects how our novel HTS approach serves as a generalizable tool for the comprehensive improvement of MSC manufacturing processes.
Optimal Control of Spiking Neural Networks
Authors: Costa Tiago , Castiñeiras de Saa Juan R. , Renart Alfonso 
Published: October 2024

AbstractControl theory provides a natural language to describe multi-areal interactions and flexible cognitive tasks such as covert attention or brain-machine interface (BMI) experiments, which require finding adequate inputs to a local circuit in order to steer its dynamics in a context-dependent manner. In optimal control, the target dynamics should maximize a notion of long-term value along trajectories, possibly subject to control costs. Because this problem is, in general, not tractable, current approaches to the control of networks mostly consider simplified settings (e.g., variations of the Linear-Quadratic Regulator). Here, we present a mathematical framework for optimal control of recurrent networks of stochastic spiking neurons with low-rank connectivity. An essential ingredient is a control-cost that penalizes deviations from the default dynamics of the network (specified by its recurrent connections), which motivates the controller to use the default dynamics as much as possible. We derive a Bellman Equation that specifies a Value function over the low-dimensional network state (LDS), and a corresponding optimal control input. The optimal control law takes the form of a feedback controller that provides external excitatory (inhibitory) synaptic input to neurons in the recurrent network if their spiking activity tends to move the LDS towards regions of higher (lower) Value. We use our theory to study the problem of steering the state of the network towards particular terminal regions which can lie either in or out of regions in the LDS with slow dynamics, in analogy to standard BMI experiments. Our results provide the foundation of a novel approach with broad applicability that unifies bottom-up and top-down perspectives on neural computation.
A 3D Image Segmentation Study of U-Net on CT Images of the Human Aorta with Morphologically Diverse Anatomy
Authors: Chen Jiasong , Qian Linchen , Wang Pengce , Sun Christina , Qin Tongran , Kalyanasundaram Asanish , Zafar Mohammad , Elefteriades John , Sun Wei , Liang Liang 
Published: October 2024

AbstractFor the machine learning -assisted diagnosis of cardiac diseases, such as thoracic aortic aneurysm, the geometries of the heart and blood vessels need to be reconstructed from medical images, which is usually done by image segmentation followed by meshing. In this study, we applied U-Net (2D and 3D versions), a deep neural network with a U-shaped architecture, to segment human aorta from CT images. From our experiments, we have the following observations: (1) 2D U-Net, which segments each of the 2D slices of a 3D CT image independently, produced erroneous fragments (e.g., missing part of the aorta) and boundaries (i.e., aortic walls) in 3D; (2) 3D U-Net, which does segmentation in 3D regions of a 3D CT image, performed much better than 2D U-Net. We also observe the major weakness of the 3D U-Net: the reconstructed geometries of the aortic wall had large errors (measured by HD95) for some cases. The 3D U-Net in this study serves as a baseline for developing more advanced architectures of deep neural networks for more accurate geometry reconstruction of human aorta.
Gas1-Mediated Suppression of Hepatoblastoma Tumorigenesis
Authors: Chen Keyao , Wang Huabo , Ma Bingwei , Knapp Jessica , Henchy Colin , Lu Jie , Stevens Taylor , Ranganathan Sarangarajan , Prochownik Edward V. 
Published: October 2024

AbstractBackground and AimsHepatoblastoma (HB), the most common pediatric liver cancer, often dysregulates the Wnt/β-catenin, Hippo and NFE2L2/NRF2 pathways. Pairwise combinations of oncogenically active forms of the terminal transcription factor effectors of these pathways, namely β-catenin (B), YAP (Y) and NRF2 (N) generate HBs in mice, with the triple combination (B+Y+N) being particularly potent. Each tumor group alters the expression of thousands of B-,Y- and N-driven unique and common target genes. Identifying those most responsible for transformation is thus an important question as it might reveal new mechanistic insights and therapeutic opportunities.Approach and ResultsTranscriptional profiling of >60 murine HBs driven by the above oncogenic combinations and different B mutants and in genetic backgrounds that impair tumor growth rates but not initiation has revealed a common set of 22 “BYN genes” that are similarly deregulated in all cases. Many are associated with multiple “Cancer Hallmarks” and their expression levels often correlate with survival in human HBs, hepatocellular carcinomas and other cancers. Among the most down-regulated of these isGas1, which encodes a Glycosylphosphatidylinositol (GPI)-linked outer membrane protein. We show here that restoring Gas1 expression impairs B+Y+N-driven HB tumor growthin vivoand in HB-derived immortalized cell linesin vitroin a manner than requires membrane anchoring of the protein via its GPI moiety.ConclusionsOur findings implicate Gas1 as a proximal mediator of HB pathogenesis and validate the BYN gene set as one deserving of closer additional scrutiny in future studies.