bluuebunny/crossref_metadata_2025_split huggingface dataset:
Morpho-functional timeline of progressive cystic fibrosis pancreatic exocrine and endocrine pathology derived from semi-quantitative scoring and AI-driven quantitative image analysis
Authors: Al-Selwi Yara , Tiniakos Dina , Richardson Sarah J , Flaxman Christine S , Russell Lydia , Palmer Matthew , Coulthard Rowan , Maheshwari Rashmi , Dyson Nicola , Honkanen-Scott Minna , Klöppel Günter , Shaw James AM , Kattner Nicole 
Published: January 2025

AbstractCystic fibrosis (CF) is associated with pancreatic exocrine insufficiency (PEI) early in life and diabetes in up to 50% of adults. The underlying CF-related sequential changes within the pancreas associated with exocrine and endocrine insufficiency remain incompletely understood due to scarcity of available human tissue, protracted disease course and absence of established robust and reproducible analytical approaches. This study aimed to develop and apply a systematic analysis cross-sectionally to CF pancreatic tissue samples from donors over a wide age range to construct a timeline related to the main exocrine and endocrine changes underlying progressive disease. Based on a histopathological semi-quantitative scoring system and AI-driven quantitative image analysis pancreatic changes were individually evaluated and classified according to three patterns: fibrotic; fibrotic and lipotic; and lipoatrophic. This systematic evaluation was applied to 29 CF and 58 control donors without pancreatic disease. Rapid loss of acinar tissue with virtually complete absence by the age of 7 years was confirmed, mirrored by fatty tissue replacement – changes underlying PEI and likely preceding progression towards diabetes. Ductal blockage by thickened secretions was associated with increasing ductal dilatation accompanied by peri-ductal fibrosis, followed by ductal loss with involution of associated fibrosis in parallel with increasing adipocyte proportional area (PA). Remaining ducts were relatively small surrounded by residual fibrosis. Islets became increasingly clustered initially surrounded by activated pancreatic stellate cells (PSCs) and fibrosis and then disorganised by interposing fibrotic tissue between endocrine cell regions and surrounded by residual collagen stranding in a ‘lipoatrophic’ pancreas. Overall islet mass was not significantly reduced but β-cell PA was significantly reduced from birth without further loss over time. We concluded that the natural history of pancreatic CF progresses inexorably from peri-ductal fibrosis to global fat replacement with relatively well-maintained islet mass but PSC-associated fibrotic islet remodelling circumstantially implicated in β-cell failure.
Lymphoid-tissue-on-chip recapitulates human antibody responses in vitro
Authors: Teufel Claudia , Schlemmer Anna-Sophie , Eiken Andrea W. , Wagoner Zachary W. , Vöhringer Dennis , Christ Lena , Dulovic Alex , Marsall Patrick , Fandrich Madeleine , Brás Eduardo J.S. , Marzi Julia , Bärhold Friederike , Philipp Julia , Becker Sven , Wagar Lisa E , Loskill Peter 
Published: January 2025

ABSTRACTIn the past decades, vaccine development has made great strides. Nevertheless, more often than not, vaccine candidates fail in advanced stages of development and clinical trials. A key reason is the poor predictive value of non-clinical in vivo and in vitro models, due to either species-specific differences in the immune response or insufficient reflection of physiological vaccine mechanisms. Reliable modeling of human adaptive immune responses is a prerequisite to understand processes leading to vaccine-induced protective immunization and to drive informed decisions in vaccine development pipelines. Here, we present a centrifugal microfluidics based organ-on-chip approach to generate an organotypic high density lymphoid tissue on-chip. The model enables long-term culture of lymphoid tissue and raised antigen-specific antibody responses against influenza vaccines even after four weeks on-chip. Antibody response of different magnitude and quality could be induced both by direct antigen exposure as well as by recruitment of antigen-presenting cells from the periphery. The model represents an attractive approach to evaluate the impact of the mode of antigen delivery on adaptive immune responses. Beyond applications in vaccine development, the lymphoid-tissue-on-chip provides a platform to study cellular interactions during homeostasis, immune responses and long-term impact of immunomodulators over several weeks.
Investigation of the HLA locus in autopsy-confirmed progressive supranuclear palsy
Authors: Wang Jinguo , Forrest Shelley L. , Dasari Sathish , Tanaka Hidetomo , Rogaeva Ekaterina , Tartaglia M. Carmela , Fox Susan , Lang Anthony E. , Kalyaanamoorthy Subha , Kovacs Gabor G. 
Published: January 2025

ABSTRACTObjectivesProgressive supranuclear palsy (PSP) is a neurodegenerative disease showing pathological tau accumulation in subcortical neurons and glial cells. The human leukocyte antigen (HLA) locus on chromosome 6 is a polymorphic region with complex linkage patterns that has been implicated in several autoimmune and neurological disorders. TheHLAlocus has not been systematically examined in PSP. It is unclear whether tau and HLA can interact to induce an autoimmune disease mechanism.MethodsWe evaluated an autopsy confirmed PSP cohort (n=44) and compared allele/haplotype frequencies to those of the reference group of a local deceased Canadian donor pool. We performed HLA/Tau peptide binding prediction and modelling of HLA Class II and Tau Peptide interactions.FindingsOdds ratio was 2.94 (95% CI 1.01 to 8.55; p=0.047) forDQB1*06:01 allele, and 2.59 (95% CI 1.39 to 4.83; p=0.0025) for the narcolepsy associated haplotype (DRB1*15:01DQB1*06:02). One patient with 4 repeat tau PSP type pathology was a carrier of the IgLON5-associated haplotype (DRB1*10:01DQB1*05:01). HLA/Tau peptide binding prediction and modelling of HLA Class II/Tau Peptide interactions revealed strong binding tau peptides but not the PSP protofilament fold for alleles DQA1*01:02DQB1*06:02 and DQA1*01:03DQB1*06:01.ConclusionOur study suggests that epitopes within the tau peptide may bind to HLA alleles that are found in a subset of PSP patients supporting the notion of an autoimmune pathophysiological component. These findings have implications for subtyping and stratifying patients for therapies, including those targeting immune modulation.
Testing the extreme plastic mycelium hypothesis: Does grazing induce developmental plasticity in saprotrophic fungi?
Authors: Aguilar-Trigueros C.A. , Boddy L. , Fricker M.D. 
Published: January 2025

AbstractPhenotypic plasticity—the ability of a genotype to alter its phenotype in response to environmental changes—can play a crucial role in maximizing fitness in fluctuating environments. However, plasticity comes at a cost, as the energy required to transform a phenotype imposes limits on its extent. While limits to plasticity are well-documented in many organisms, they are not well understood in modular organisms like filamentous fungi. Fungi have highly flexible morphologies, allowing individual organisms to adjust their phenotype in response to local environmental conditions. This flexibility has led to speculation that fungi exhibit "extreme phenotypic plasticity," making them an interesting system for studying plasticity mechanisms. To test this idea, we analyzed the grazer-induced morphological plasticity of four cord-forming fungal species exposed to different soil microfauna with varying feeding behaviors, using a phenotypic trajectory analysis framework. We hypothesized that grazing would drive convergence towards a common "grazing-resistant phenotype" across species, due to the extreme flexibility of fungal mycelia. Alternatively, we proposed that species would follow unique developmental trajectories in response to grazers, reflecting species-specific plasticity limits. Our results showed that fungal species accounted for most of the morphological variation, with grazers having only a small but significant effect. Moreover, we did not observe convergence towards a common grazing-resistant phenotype; instead, each species followed distinct developmental pathways within species-specific limits, which varied widely. Some species altered up to 30% of their phenotype in response to grazers, while others showed as little as 1% variation. These findings suggest a more nuanced view of fungal plasticity, where morphological plasticity might not be the most effective response to grazing pressure. We speculate that the observed differences in plasticity limits may correlate with the complexity of cord formation in different species. These constraints on fungal morphological plasticity offer new insights into how fungi adapt to dynamic ecological conditions and underscore the need to explore alternative phenotypic responses to environmental pressures. Our study highlights the need to refine plasticity theories, particularly for organisms with complex, modular structures like fungi.
The role of induced polarization in drug discovery applications
Authors: Mohamed Ashraf , Brooks Bernard R. , Amin Muhamed 
Published: January 2025

AbstractInduced polarization plays a pivotal role in ligand-protein binding by enhancing both the specificity and strength of molecular interactions. As a ligand approaches a protein, their respective electronic clouds redistribute in response to each other’s electrostatic fields—a phenomenon governed by induced polarization. The response of a molecule’s electron density to an external field is quantitatively described by its polarizability tensor. In this study, we calculated polarizability tensors for thousands of drug-like molecules from the CHEMBL database, focusing on compounds targeting the Thrombin, Estrogen Receptor alpha, and Phosphodiesterase 5A proteins using Density Functional Theory (DFT). We show that a machine learning model based on atomic hybridization accurately predict the polarizabilities eigenvalues, calculated with DFT. Then, we build a neural network and random forest models to predict the IC50’s based on the same features. The success of these models, despite utilizing a limited number of features, underscores the critical role of induced polarizabilities in determining binding energies.
Genome assemblies of Indiandesicattle reveals hotspots of rearrangements and immune-related genetic diversity
Authors: Azam Sarwar , Sahu Abhisek , Kadivella Mohammad , Khan Aamir Waseem , Neupane Mahesh , Tassell Curtis P Van , Rosen Benjamin D , Gandham Ravi Kumar , Rath Subha Narayan , Majumdar Subeer S 
Published: January 2025

AbstractIndia, home to the world’s largest cattle population, hosts native dairy breeds essential to its agricultural economy because of their adaptability and resilience. This study characterizes the genomes of five prominent breeds Gir, Kankrej, Red Sindhi, Sahiwal and Tharparkar, highlighting their unique genomic characteristics. Thede novoassemblies ranged from 2.70-2.78 Gb in size, with 90% of the genomes assembled in just 56 to 1,663 scaffolds. The use of reference-guided scaffolding further enhanced these genomes, resulting in 93.3-96.7% pseudomolecule coverage with strong BUSCO scores (94.1-95.5%). Comparative analyses revealed 87–95% synteny with the Brahman genome and identified 19.84–153.16 Mb of structural rearrangements per genome, including inversions, translocations, and duplications. Synteny diversity analysis uncovered 10,643 perfectly collinear regions spanning 87.3 Mb and 6,622 hotspots of rearrangement (HOT regions) covering 55.18 Mb. These HOT regions, characterized by high synteny diversity, were significantly enriched with immune-related genes. Moreover, immune-related gene clusters, including MHC, NKC, and LRC, were identified within HOT regions in thedesireference genome. Our findings provide valuable insights into the genetic diversity ofdesicattle breeds. The high-quality genome assemblies generated in this study will serve as valuable resources for future research in genetic improvement, disease resistance, and environmental adaptation.
Digital Phage Biology in Droplets
Authors: Givelet Louis , von Schönberg Sophie , Katzmeier Florian , Simmel Friedrich C. 
Published: January 2025

AbstractSince their discovery, bacteriophages – viruses that infect bacteria – have been an invaluable source of insight for molecular biology and have provided a plethora of molecular components for biotechnology. Driven by the imminent global antibiotic crisis, interest in using bacteriophages as antimicrobial agents has strongly increased in the past few years. While standard quantification of phage counts and infectivity by double-layer plaque assays (DLA) have provided foundational insights, they are limited by their inability to monitor infection dynamics over time and the inflexibility in experimental setups. Here, we introduce a novel high-throughput method using droplet microfluidics to quantify individual phage infection events, enhancing the understanding of phage-host dynamics at the single-event level. By co-encapsulating individual phages and bacteria in microfluidic droplets, we can control key experimental parameters such as exposure time and the ratio of phages to bacteria. Our system allows for precise quantification of lysis events and the direct observation of lysis kinetics unaffected by the continuous release of progeny phages that is typical in bulk cultures. Moreover, our method is potentially applicable to any phage-host pair. Our findings suggest that droplet microfluidics can provide a more accurate and dynamic understanding of phage biology. This approach could be particularly valuable in the development of phage-based antimicrobial strategies in the face of rising antibiotic resistance.
Synthetic and plant-derived multivalent galactans as modulators of cancer-associated galectins-3 and -9
Authors: Pfeifer Lukas , Mueller Kim-Kristine , Müller Maximilian Thal , Philipp Lisa-Marie , Sebens Susanne , Classen Birgit 
Published: January 2025

AbstractGalectins are β-galactoside-binding proteins with numerous functions. Some of them are involved in proliferation and metastasis of cancer, making them promising therapeutic targets. As different plant glycans have been shown to bind to galectins, plant saccharides might be potential galectin inhibitors. To produce plant galactans rich in galactose and smaller in size, we degraded arabinogalactan-proteins fromEchinacea purpureaandZostera marinaas well as arabinogalactan from larch. As galectin (Gal)-3 and -9 both have been described to be involved in cancer development, we quantified the binding capacities of the different galactans to both galectins by biolayer-interferometry. Our results revealed that all plant-derived galactans and Yariv reagents with terminal galactose and lactose residues bind to Gal-3 in micromolar ranges. Surprisingly, only the higher charged galactans fromZostera marinashowed affinity to Gal-9. Investigations of two different pancreatic cancer cell lines (Panc1 and Panc89) and different cell variants thereof revealed that Gal-3 was expressed by both cell lines with a significantly higher Gal-3 level in Panc1 cells compared to Panc89 cells. Conversely, Gal-9 was only detected in Panc89 cells. The findings revealed that galactans are promising sources to develop galectin antagonists and plant galactans from different species express specificities for distinct galectins.
An animal model of coronary microvascular dysfunction (CMD) in the female spontaneously hypertensive rat: the role of diet
Authors: Najjar Rami S. , Mehta Puja K. , Gewirtz Andrew T. 
Published: January 2025

AbstractCoronary microvascular dysfunction (CMD) drives angina in patients with ischemia non-obstructive coronary artery disease, a condition that is more prevalent in females. Effective treatment strategies and a detailed mechanistic understanding of CMD remain limited, in part, due to scarcity of physiologically relevant animal models. Indeed, while CMD has been studied in animals with diabetes and/or fed high-fat diets, in fact, hypertension is the predominant risk factor for CMD in humans but is not captured by these models. Thus, we characterized the CMD that arose in female spontaneously hypertensive rats (SHRs). We measured coronary flow reserve, alongside basic cardiovascular function in SHRs and normotensive Wistar Kyoto rats (WKYs) fed a purified diet, as well as SHRs consuming a grain-based chow (GBC) diet. SHRs on a purified diet, but not WKYs or SHRs consuming GBC, exhibited impaired coronary flow reserve as assessed by echocardiography. Thus, SHRs develop a diet-dependent CMD, which can serve as a model to study hypertension-related CMD.Graphical Abstract
A High-Throughput Bone Marrow 3D Co-Culture System to Develop Resistance to B Cell Receptor Signaling Targeted Agents in B Cell Non-Hodgkin Lymphoma
Authors: Zadro Alex , Arribas Alberto , Colombo Maria Vittoria , Cannas Eleonora , Spriano Filippo , Cascione Luciano , Mensah Afua Adjeiwaa , Simonetta Federico , Petta Dalila , Arrigoni Chiara , Candrian Christian , Moretti Matteo , Bertoni Francesco 
Published: January 2025

AbstractB cell receptor (BCR) signaling plays a central role in the pathogenesis of B cell lymphomas, making it a crucial therapeutic target. The advent of BCR-targeted inhibitors, particularly those directed at PI3K and BTK, has revolutionized treatment for B cell non-Hodgkin lymphoma (B-NHL). However, therapeutic resistance remains a significant clinical challenge. Increasing evidence suggests that the tumor microenvironment (TME), particularly the bone marrow (BM) microenvironment, is crucial in driving cancer progression and therapeutic resistance. The BM microenvironment provides a specialized niche where lymphoma cells can evade therapy through interactions with stromal cells and extracellular matrix (ECM) components. Bone marrow stromal cells (BMSCs) contribute significantly to this resistance.In this study, we developed anin vitro3D model to better understand B cell lymphoma biology and drug resistance mechanisms. We co-cultured lymphoma cell lines with primary BMSCs in a 3D fibrin gel matrix using a high-throughput and automated system. Our results revealed that BMSCs modulate lymphoma cell growth and reduce their sensitivity to the PI3K inhibitor copanlisib and the BTK inhibitor ibrutinib. Furthermore, this model allowed us to identify IGFBP-3, Serpin E1, and PTX-3 as potential mediators of therapeutic resistance. These findings underscore the value of using 3D co-culture models in preclinical settings to more accurately study drug resistance, as they more closely simulate the BM microenvironment’s complexity than traditional 2D models, thus improving the predictive value of drug testing in B cell lymphomas.Visual Abstract
Mapping spatially-resolved transcriptomes in systemic sclerosis
Authors: Li Zhijian , Rigau Aleix Rius , Xie Wenjie , Huang Linlin , Shao Xiaohang , Li Yi-Nan , Matei Alexandru-Emil , Ye Wenjing , Zou Hejian , Pinello Luca , Distler Jörg H.W. , He Rui , Liang Minrui 
Published: January 2025

AbstractSystemic sclerosis (SSc) is a prototypical fibrotic disease with high mortality and limited treatment options. Despite advances in single-cell RNA sequencing (scRNA-seq), the comprehensive understanding of cellular heterogeneity and cell-cell interaction within the fibrogenesis microenvironment remains limited. We generated spatially resolved transcriptome maps from healthy and SSc skin and built a scRNA-seq atlas to map the single-cell data to spatial space. This enabled us to identify a fibrotic niche, enriched with fibroblasts and macrophages, which is significantly expanded in SSc and correlated with clinical outcome. We revealed disease-specific cell states of fibroblasts and macrophages, and evaluated their spatial dependency on other cell types. We identified selective expression of ACKR3 in fibroblast progenitors that diminishes with SSc progression, which may serve to regulate CXCL12/CXCR4-mediated macrophage recruitment and fibrotic remodeling. Together, we provided an in-depth description at cellular and spatial levels of fine-tuned regulatory events occurring in SSc, offering spatiotemporal insights.One Sentence SummaryIntegrated spatial omics provide insight into the cellular and transcriptional landscape in spatially distinct microenvironments, which may drive fibrosis progression in SSc.
Targeting histone acetylation enables epigenetic modulation of inflammatory pathways – a novel therapeutic strategy for rheumatoid arthritis
Authors: Brinkmann Marie , Tosevska Anela , Luckerbauer Bianca , Madern Moritz , Göschl Lisa , Ellmeier Wilfried , Aletaha Daniel , Preglej Teresa , Bonelli Michael 
Published: January 2025

AbstractAutoimmune diseases like rheumatoid arthritis (RA) are characterized by a systemic inflammation caused by autoreactive immune cells. Epigenomic modulation of these cells offers a strategy to reprogram pathogenic pathways without altering the genome, potentially restoring immune balance. Epigenetic inhibitors are already utilized in oncology but often exhibit adverse effects due to lack of selectivity and cytotoxic concentrations. Applying these drugs to treat autoimmune diseases necessitates more selective inhibitors and the use of tolerable concentrations. In this study, we screened a library of 25 compounds with varying degrees of target selectivity and different concentrations. Spectral cytometry enabled the analysis of cell-subset distribution and activation, followed by bulk RNA-sequencing for transcriptomic profiling.We could demonstrate cell-subset specific and concentration-dependent immune modulation in PBMCs. Transcriptomic analysis showed that inhibitors of histone acetylation-modulating enzymes significantly altered gene expression, particularly in immune regulation pathways relevant to autoimmune diseases. Comparative analysis betweenin-vitrotreated healthy controls and RA patients demonstrated both shared and selective drug effects, with some inhibitors like Ricolinostat overlapping with established RA drug pathways.Our findings highlight the potential of epigenetic inhibitors, especially those targeting histone acetylation, to modulate immune responses in a target-selective manner.Graphical abstract
A Paper-Droplet Hybrid System for Efficient Blood Plasma Separation in Multiplex Diagnostics
Authors: Dash Amaan , Medicharla Rajeev Srikar , DasGupta Sunando 
Published: January 2025

AbstractSingle μPAD-based lateral flow blood plasma separation techniques suffer from low sensitivity, inconsistent performance, and extended turnaround times, hindering point- of-care whole blood multiplexing. Integrating multifunctional microfluidic approach could offer a paradigm shift, providing rapid, high-throughput blood testing with reduced sample alongside streamlined downstream automation. Herein we report a novel low-cost sessile-drop and paper hybrid blood plasma separation technique that achieves efficient (≥ 98 %) separation within seconds (∼70 s). Evaporation-driven natural convection within a sessile blood droplet facilitates effective mixing, while capillary forces prevalent in the paper structure selectively transport plasma to the detection zones, all without any externally applied motive force. The separated plasma is successfully analysed for simultaneous glucose and albumin detection using colorimetric assay. This method demonstrates high accuracy in predicting glucose and albumin levels in healthy and diseased samples when benchmarked against an Automated Biochemistry Analyzer. A 3D foldable all-in-one paper microfluidic device, complemented by a MATLAB based application (GPS App.) has been developed for quantitative assessment during on-field diagnostics. This study presents a rapid, efficient, and user-friendly alternative to traditional flow-based separation, providing reliable detection in resource-limited settings.