bluuebunny/crossref_metadata_2025_split huggingface dataset:
Isolation and characterization of microbiota from human pancreatic tumors and small intestine
Authors: Awad Dominik , Attebury Holly , Hong Ryan , Kim Kwi , Zhang Li , Bischoff Allison , deDekker Aaron , Hoostal Matthew , Nieto Carrion Joseph A. , Nelson Noah S. , Strayhorn Chris , Frankel Timothy , di Magliano Marina Pasca , Lyssiotis Costas A. , Schmidt Thomas M. , Daley Donnele 
Published: December 2024

AbstractPancreatic ductal adenocarcinoma has a unique tumor microbiome and the systemic depletion of bacteria or fungi using antibiotic/antifungal cocktails leads to a decrease in pancreatic tumor burden in mice. However, functional studies remain rare due to the limited availability of clinically relevant microbiota. Here, we describe in detail the isolation of bacteria and fungi from the small intestine and tumor of pancreatic cancer patients at the Rogel Cancer Center. We then further characterized the impact of a newly isolatedKlebsiella oxytocastrain (UMKO1) on the pancreatic tumor microenvironment using bacterial genome sequencing, untargeted and targeted metabolomics, as well as anex vivotumor transplant system. We found thatUMKO1possesses a gene for the long form of cytidine deaminase, which can inactivate the standard PDAC chemotherapeutic agent gemcitabine. In addition, we found thatUMKO1can produce several indoles when grown in tumor-like conditions, metabolites that can lead to an immune suppressive environment and interfere with therapy outcome. To test this in detail, we assessed changes in immune populations in pancreatic tumor explants upon exposure to the supernatant ofUMKO1and other isolated bacteria grown in tumor Interstitial fluid media (TIFM). We found that while none of the bacterial supernatants changed the abundance of CD8 T cells, granzyme B positive CD8 T cells were the lowest in tumor explants exposed toUMKO1, and not other isolatedKlebsiellaspecies or the non-pathogenic laboratory strainE. coli K12. In summary, the isolated collection of bacteria and fungi from this study are a valuable toolbox to study the impact of microbiota on pancreatic cancer.
Development of the Tool for Advancing Practice Performance, a practice-level survey to assess primary care structures and processes
Authors: Kwok Lorraine , Paul Margaret M. , Albert Stephanie L. , Harel Daphna , Blecker Saul B. , Weiner Bryan J. , Damschroder Laura J. , Cohen Deborah J. , Nguyen Ann M. , Shelley Donna R. , Berry Carolyn A. 
Published: December 2024

AbstractDespite progress to define primary care practice transformation models, there remains gaps in translating evidence-based guidelines into routine clinical care. Primary care providers (MD, DO, NP, PA) and researchers need tools to assess modifiable factors that improve practice performance to inform practice transformation efforts. We aimed to develop a pragmatic tool for assessing practice-level primary care structures and processes that are associated with better care quality and clinical outcomes. We generated 314 candidate items for the Tool for Advancing Practice Performance (TAPP) using data from a comprehensive literature review, Delphi study, and qualitative interviews with high-performing practices. We used empirical criteria and expert review to eliminate redundancy and improve clarity via removing and retaining items. The retained items were formatted into a survey tool, and we further revised the tool based on feedback elicited from cognitive interviews and pilot testing with primary care providers and staff. The final candidate pool comprised 126 items after refinement and expert review. For the survey tool, we adapted and developed survey questions for each of the 126 items. Eight cognitive interview participants reviewed the tool and provided feedback on its content and language. Based on this feedback, we eliminated 13 items because they were poorly or incorrectly understood by participants, resulting in a 113-item tool. Fifteen participants pilot tested the tool and no additional items were eliminated. The TAPP is a novel, low-burden tool that researchers and primary care providers can use to identify areas for improvement at the practice-level. Practices and health systems could use the TAPP to assess their own performance and identify gaps in their structures and processes, and practice networks and health systems can use the tool to assess structures and processes at individual clinics, track this information over time, and evaluate its relationship to care quality and clinical outcomes.
Functional composition of subsoil microbial communities changes with oak mortality
Authors: Goodman Anna C. , Walker Ernest N. , Bogar Glade D. , Bogar Laura M. 
Published: December 2024

AbstractTree mortality in oak savannas is increasing under climate change, but its impact on microbial communities and soil carbon below the top 20 centimeters is relatively unknown. Deep tree roots, their ectomycorrhizal fungi, and associated bacteria may have a particularly important effect on landscape carbon storage, as they mediate the transfer of recently fixed plant carbon into deep soil and subsoil layers. To investigate how tree mortality impacts microbes and soil carbon, we sampled under living and recently deadQuercus douglasiitrees in a California oak savanna, gathering depth-resolved soil cores to 45 cm below the surface. We captured finely resolved biological detail on these soil samples, comparing living (RNA-based) to potential and historical (DNA-based) microbial communities and assessing microbial biomass with phospholipid fatty acid analysis. Tree mortality greatly reduced the abundance of ectomycorrhizal fungi, particularly in subsoils. Fungal niches were more variable at depth under dead trees than under living ones, and RNA-based profiling captured substantially different communities than DNA, especially under living trees. However, tree mortality three years prior to our study did not impact the overall quantity of carbon stored in the soil. Tree mortality can have profound effects on the interactions between tree roots, mycorrhizal fungi, and soil bacteria, which may shift soil carbon dynamics over long time scales. Understanding the mechanisms of these interactions, and their time scales, will improve our ability to predict and manage soil carbon in savanna landscapes as drought and heat events kill more oaks in arid climates.HighlightsRibosomal RNA, from living cells, revealed different communities than from DNA.Microbial functions changed more with depth and tree health than taxonomy.Differences were most extreme below 20 cm depth.Microbial population distributions changed under living and dead trees.Total microbial biomass and carbon were similar beneath living and dead trees.
Tackling the Complexity of Spatial Transcriptomics Data Interpretation with Large Language Models
Authors: Khan Taushif , Farley Colleen M. , Wilson John J. , Chang Chih-Hao , Chaussabel Damien 
Published: December 2024

ABSTRACTSpatial transcriptomics offers unprecedented insights into the complex cellular landscapes of tissues, particularly in cancer research where understanding the tumor microenvironment is crucial. However, interpreting the vast and intricate data generated by this technology remains a significant challenge. This study explores the potential of Large Language Models (LLMs) to assist in the analysis and interpretation of spatial transcriptomic data from a murine melanoma tumor model. We first evaluated the performance of multiple LLM models in describing and quantifying spatial gene expression patterns. Our benchmarking revealed that spatial transcriptomics data interpretation proved challenging for most models, with only a few demonstrating sufficient capability for this complex task. Using Claude 3.5 Sonnet, which showed the highest accuracy in spot quantification and pattern recognition, we developed a systematic workflow for analyzing the tumor immune landscape. The model first assisted in identifying and prioritizing panels of M1 and M2 macrophage-associated markers through knowledge-driven scoring. It then demonstrated remarkable ability to integrate spatial expression data with extensive immunological knowledge, providing sophisticated interpretation of local immune organization. When analyzing individual tumor regions, the model identified coordinated immunosuppressive mechanisms including metabolic barriers and disrupted pro-inflammatory signaling cascades, findings that both aligned with and extended current understanding of tumor immunology. This study highlights the potential of LLMs as powerful assistive tools in spatial transcriptomics analysis, capable of combining advanced pattern recognition with extensive knowledge integration to enhance data interpretation. While significant development work remains to make such workflows scalable, our proof of concept demonstrates that LLMs can help accelerate the translation of spatial transcriptomics data into biological insights.
RCVT: a novel diagnostic to quantify compositional biases among taxa for phylogenomics
Authors: Steenwyk Jacob L , Buida Thomas J. 
Published: December 2024

AbstractPhylogenomics aims to reconstruct the history of genes and genomes. However, noise or error during inference can stem from diverse sources, such as compositional biases. Here, we introduce RCVT (RelativeCompositionVariability amongTaxa), a novel metric to quantify compositional biases among taxa. We demonstrate the utility of RCVT using example data and quantify compositional biases in 16 empirical phylogenomic datasets, revealing variation in biases across datasets and taxa therein. RCVT may help researchers diagnose and potentially ameliorate phylogenomic noise associated with compositional biases.
P4ward: an automated modelling platform for Protac ternary complexes
Authors: Jofily Paula , Kalyaanamoorthy Subha 
Published: December 2024

AbstractProteolysis Targeting Chimeras (Protacs) are a new class of drugs which promote degradation of a protein of interest (POI) by hijacking the Ubiquitin-Proteasome system. Struc tural knowledge of an E3 ligase: Protac:POI ternary complex is required for Protac rational design, and computational modelling of such heteromeric complex structures is nontrivial. To date, few programs have been developed to address this challenge, however, there remains a need for readily accessible tools that can significantly improve ternary complex modelling accuracy. Particularly, programs that can also support the screening phase of Protac discovery, where speed and the ability to test multiple Protacs is essential to advance the field of Protac therapeutics. To bridge these gaps, we present P4ward, a free and fully automated Protac ternary complex modelling pipeline. P4ward achieves a hit-rate of 76.5% with an average rank of 7.26, and substantially reduces the rank of the near-native pose by 73-98% compared to earlier programs. We believe that P4ward could be a user-friendly, fast, and effective tool for gaining atomistic insights necessary for Protac modelling and optimization.
Viral mimicry redirects immunosuppressed colorectal tumour landscapes towards a proinflammatory and CMS1-like regenerative state
Authors: Corry Shania M , Sakhnevych Svetlana , Mohamed Noha Ehssan , Malla Sudhir B , Byrne Ryan , Young Andrew , Amirkhah Raheleh , Bull Courtney , Lees Andrea , Redmond Keara , Lannagan Tamsin , Ridgway Rachel , Taggart Fiona R , Fisher Natalie C , Maughan Tim , Lawler Mark , Campbell Andrew , Leedham Simon J , Ryan Aideen E , Longley Dan B , Small Donna , Sansom Owen J , Dunne Philip D 
Published: December 2024

AbstractIn colorectal cancer (CRC), tumours classifier as consensus molecular subtype 4 (CMS4) have the worst prognosis and derive negligible benefit from chemotherapy. We previously described how repressed interferon-related signalling is associated with increased relapse in CMS4 tumours. Although the viral mimetic poly(I:C) can reduce liver metastasisin vivo, the initial phenotypic changes that underpin its anti-metastatic response remain poorly described, particularly in the immunosuppressed CMS4 tumour microenvironment.Here we characterise lineage-specific anti-metastatic responses induced by poly(I:C), including acute macrophage polarisation and a novel CMS1-like regenerative stem cell state, which drive pro-inflammatory microenvironmental changes in CRC. These insights enabled the development of tractable biomarkers that identify an “immune-warm” patient subset most likely to respond to poly(I:C), enriched for mismatch-repair proficient (pMMR), anti-inflammatory macrophages and CMS4-like features. The viral mimetic poly(I:C) offers a tailored treatment option for CMS4 tumours, by reprogramming stem cell states and activation of an innate-adaptive anti-metastatic response.
ST6GAL1-mediated sialyl linkage switching in tumor-associated macrophages drives cancer-promoting nanotubes carrying α2,6-sialylation in anti-inflammatory cells
Authors: Dipta Priya , Bansal Naaz , Sumer-Bayraktar Zeynep , Chien Arthur , Ugonotti Julian , Chau The Huong , Anugraham Merrina , Kolarich Daniel , Tirosh Boaz , Kawahara Rebeca , Thaysen-Andersen Morten 
Published: December 2024

AbstractTumor-associated macrophages (TAMs) form functionally diverse populations of innate immune cells in the tumor microenvironment (TME). Pro- and anti-inflammatory TAMs are central to cancer progression by shaping inflammation and immune (im)balance, but it remains unknown if polarization-induced remodeling of the TAM glycocalyx critical for cellular communication occurs within the TME. Taking a systems glycobiology approach, we here firstly used cell surface-focused glycomics and lectin flow cytometry ofex vivopolarized monocyte-derived macrophages to demonstrate profound sialyl linkage switching of the surfaceN-glycome in pro-inflammatory (α2,3-sialo-favored) and anti-inflammatory (α2,6-sialo-dominant) macrophages. In contrast, no polarization-induced alterations in sialylation were observed in the surfaceO-glycome. ST6GAL1 that modifiesN-glycans with α2,6-sialylation was elevated in anti-inflammatory compared to levels in pro-inflammatory macrophages providing a mechanistic basis for the sialyl linkage switching, which was supported byST6GAL1silencing. Interestingly, SNA-focused lectin cytochemistry of anti-inflammatory macrophages revealed dense networks of dynamic α2,6-sialylated protein-based nanotubules forming inter-connecting cellular structures that were absent in pro-inflammatory macrophages. TemporalST6GAL1silencing in anti-inflammatory macrophages caused nanotubule disintegration as evidenced by SNA and biotin fluorescence microscopy. Moreover, live cell recordings of anti-inflammatory macrophages cultured with and without colorectal cancer (CRC) cells showed reduced macrophage motility, attenuated inter-macrophage and macrophage-CRC cell interactions and diminished CRC cell proliferation upon ST6GAL1 disruption indicating functional roles of the α2,6-sialylated nanotubules. Finally, sialyl linkage switching was recapitulated in pro- and anti-inflammatory TAMs from tumor tissues of patients with advanced CRC. We report on the mechanistic basis for and functional consequences of glycocalyx remodeling accompanying TAM polarization.
microRNA-544a as a new modulator of the Wnt-signalling network in the articular cartilage and osteoarthritis
Authors: Heluany Cintia Scucuglia , Day Nicholas J , Santos Keemo Delos , De Palma Anna , Swingler Tracey E , Sochart David , Clark Ian M , Kapoor Mohit , Nalesso Giovanna 
Published: December 2024

AbstractObjectiveDetermining the effect of microRNA-544a (miR-544a) in articular chondrocytes isolated from patients affected by osteoarthritis (OA) and its role in the modulation of the Wnt signalling.MethodsArticular chondrocytes were isolated from patients undergoing joint replacement because of OA. Expression levels of miR-544a were measured by PCR and by in situ hybridization. Putative targets of miR-544a were confirmed by reporter assay and by qPCR in cells stimulated with a miR-544a mimic. The effect of miR-544a on chondrocyte metabolism was monitored by qPCR for phenotypic markers, protein expression levels of aggrecan neoepitopes/MMP-13 and modulation of alcian blue content in micromass cultures, upon stimulation with a miR-544a mimic. The expression levels of MMP-13 and Aggrecan neoepitopes in response to miR-544a stimulation was also measured in co-stimulation with Xav-939 and KN93, which are respectively β-catenin and CaMKII inhibitors.ResultsOur results suggest that miR-544a enhances the activation of the Wnt-signalling in the articular chondrocytes, by downregulating the expression of components of the Wnt/β-catenin destruction complex. The expression of miR-544a is higher in chondrocytes isolated from damaged areas of the articular cartilage removed from OA patients, and can be upregulated by pro-inflammatory and pro-fibrotic cytokines. miR-544a exerts a pro-catabolic effect of articular chondrocytes, which is rescued both by the inhibition of the Wnt/β-catenin and Wnt/CaMKII signalling pathways.Conclusionour results point to miR-544a as a new, important modulator of the Wnt signalling network within the articular cartilage suggesting a key role for microRNAs in regulating how the multiple branches of the network and their interaction modulate cartilage homeostasis.
Dynamic remodeling of mechano-sensing complexes in suspended fibroblast cell-sheets under external mechanical stimulus
Authors: Suzuki Madoka , Kawauchi Keiko , Machiyama Hiroaki , Hirata Hiroaki , Ishiwata Shin’ichi , Fujita Hideaki 
Published: December 2024

AbstractFreestanding cell-sheets are valuable bio-materials for use in regenerative medicine and tissue engineering. Because cell-sheets experience various mechanical stimulations during handling, it is important to understand the responses of cells to these stimulations. Here, we demonstrate changes in the localization of various proteins during the stretching of fibroblast cell-sheets. These proteins are known to be involved in mechano-sensing. Upon stretching, actin filaments appear parallel to the stretching direction. At cell-cell junctions, β-catenin forms clusters that co-localize with accumulated vinculin and zyxin as well as the actin filaments. The p130 Crk-associated substrate, known to be present in focal adhesions, is also recruited to these clusters and phosphorylated. Our results suggest that mechano-sensing machinery is formed at cell-cell junctions when the cell-sheets are stretched.
The MultiMusic multidomain intervention including choral practice in community-dwelling older people: A study protocol for Brain-Derived Neurotrophic Factor (BDNF) salivary biomarkers, audiometric and neuropsychological parameters
Authors: Lippolis M. , Lenti R. , Mantuano P. , De Luca A. , Pantaleo A. , Quaranta N. , Pilotto A. , Solfrizzi V. , Vuust P. , Brattico E. 
Published: December 2024

AbstractBrain-Derived Neurotrophic Factor (BDNF) plays a crucial role in neuroplasticity, supporting brain health along life and even during aging. This longitudinal study investigates the impact of a 9-month multidomain intervention, including choral practice, on BDNF levels, audiometric and neuropsychological outcomes, in older adults, assessed also for their multidimensional frailty, based on their physical, cognitive and nutritional conditions. BDNF levels, along with geriatric, neuropsychological, audiometric and neurophysiological measures, are taken, via saliva samples, both pre- and post-intervention. For BDNF longitudinal analyses, up to 80 elderly will be randomly assigned to an experimental group participating in a 9 month long multidomain program of activities including choir, physical, intellectual and manual activities or to an active control group participating in physical, intellectual or manual non-musical activities for 9 months or to a passive control group. Participation in daily activities for all groups will be monitored via diaries. Our primary goal is to investigate whether engaging in physical, cognitive and social multidomain activities can enhance neuroplasticity as measured by BDNF levels, to contrast aspects of multidimensional frailty (as assessed by the multidimensional prognostic score, MPI) in the aging population. Secondly, we aim to relate changes in BDNF levels to the perceptual and cognitive domains and psychosocial well-being. Although previous studies point out the positive effects of musical training and active aging on brain health, the scarcity of longitudinal research on effects on BDNF for older individuals keeps the issue open. Moreover, we aim to test whether non-invasive, accessible saliva-based BDNF measurements, despite some reliability limitations, could offer indications of neuroprotection in aging.
A unified model of gene expression control by cohesin and CTCF
Authors: Narita Takeo , Kilic Sinan , Higashijima Yoshiki , Pappas Georgios , Maskey Elina , Choudhary Chunaram 
Published: December 2024

AbstractCohesin and CTCF fold vertebrate genomes into loops and topologically associating domains (TADs). The genome folding by cohesin and CTCF is considered crucial for enhancer-promoter communication and gene regulation. However, the extent of cohesin and CTCF-dependent looping in global enhancer function and their potential non-architectural roles in gene activation have remained unclear. Here, we demonstrate that the acute removal of cohesin or CTCF in mouse cells dysregulates hundreds of genes, albeit subtly. Among various possible enhancer types, cohesin almost exclusively facilitates gene activation by one enhancer type—the CBP/p300-dependent enhancers. Interestingly, CTCF plays a dual role, operating both with and without cohesin, and promoting gene activation both in an enhancer-dependent and independent manner. By anchoring cohesin loops, CTCF directs enhancers to specific target genes and prevents their mistargeting. Independently of cohesin and enhancers, CTCF acts as a transcriptional activator or repressor, depending on its precise binding position near promoters. Acting as a canonical transcription activator, CTCF directly activates hundreds of housekeeping genes, including those essential for mammalian cell proliferation. Mechanistically, promoter-bound CTCF controls DNA accessibility and RNA polymerase II recruitment. The transcriptional activator function of CTCF appears unique to vertebrates and is shared by its vertebrate-specific paralog, CTCFL, despite CTCFL’s inability to anchor cohesin loops. These findings reveal the scope of cohesin and CTCF in gene regulation, delineate their shared and unique functions, define a specific class of enhancers using cohesin-mediated looping, and establish a crucial function of CTCF in gene regulation independent of its architectural role. The work reconciles conflicting views and provides a unified model for gene regulation by cohesin and CTCF.