bluuebunny/crossref_metadata_2025_split huggingface dataset:
The MARECA (national study of management of breast cancer locoregional recurrence and oncological outcomes) study: protocol for a prospective, multicentre cohort study
Authors: Hartup Sue M. , Morgan Jenna L. , Cheng Vinton WT , Barry Peter A. , Copson Ellen , Cutress Ramsey I. , Dave Rajiv , Elsberger Beatrix , Fairbrother Patricia , Hogan Brian , Horgan Kieran , Kirwan Cliona C. , McIntosh Stuart A. , O’Connell Rachel L. , Patani Neill , Potter Shelley , Rattay Tim , Sheehan Lisa , Wyld Lynda , Kim Baek 
Published: January 2024

Background:
Despite a UK 5-year breast cancer survival rate of 86.6%, patients may develop breast cancer recurrence within the same breast after breast conserving surgery, as well as in the remaining skin or chest wall after mastectomy or in the ipsilateral lymph glands. These recurrences, collectively termed locoregional recurrence (LRR), occur in around 8% of patients within 10 years of their original diagnosis. Currently, there is a lack of robust information on the presentation and prevalence of LRR with no UK-specific clinical guidelines available for the optimal management of this patient group. Additionally, there is a need to identify patterns of LRR presentation and their progression, which will enable prognostic factors to be determined. This will subsequently enable the tailoring of treatment and improve patient outcome.

Methods:
The MARECA study is a prospective, multicentre cohort study recruiting patients diagnosed with breast cancer LRR +/- associated distant metastases. Over 50 UK breast units are participating in the study with the aim of recruiting at least 500 patients over a recruitment period of 24 months. The data collected will detail the tumour pathology, imaging results, surgical treatment, radiotherapy and systemic therapy of the primary and recurrent breast cancer. Study follow-up will be for up to 5 years following LRR diagnosis to determine subsequent oncological outcomes and evaluate potential prognostic factors.

Discussion:
This study will address the current knowledge gap and identify subgroups of patients who have less successful treatment outcomes. The results will determine the current management of LRR and the prognosis of patients diagnosed with breast cancer LRR +/- distant metastases in the UK, with the aim of establishing best practice and informing future national guidelines. The results will direct future research and inform the design of additional interventional trials and translational studies.
Proteomic Analysis and Sex-Specific Changes in Chronically Ischemic Swine Myocardium Treated with Sodium-Glucose Cotransporter-2 Inhibitor Canagliflozin
Authors: Harris Dwight D , Sabe Sharif A , Broadwin Mark , Stone Christopher , Malhotra Akshay , Xu Cynthia M , Sabra Mohamed , Abid M Ruhul , Sellke Frank W 
Published: January 2024

BACKGROUND:
Although sodium-glucose cotransporter-2 inhibitors have been shown to improve cardiovascular outcomes in general, little is presently known about any sex-specific changes that may result from this therapy. We sought to investigate and quantify potential sex-specific changes seen with the sodium-glucose cotransporter-2 inhibitor canagliflozin (CAN) in a swine model of chronic myocardial ischemia.

STUDY DESIGN:
Eighteen Yorkshire swine underwent left thoracotomy with placement of an ameroid constrictor. Two weeks postop, swine were assigned to receive either control (F = 5 and M = 5) or CAN 300 mg daily (F = 4 and M = 4). After 5 weeks of therapy, swine underwent myocardial functional measurements, and myocardial tissue was sent for proteomic analysis.

RESULTS:
Functional measurements showed increased cardiac output, stroke volume, ejection fraction, and ischemic myocardial flow at rest in male swine treated with CAN compared with control male swine (all p < 0.05). The female swine treated with CAN had no change in cardiac function as compared with control female swine. Proteomic analysis demonstrated 6 upregulated and 97 downregulated proteins in the CAN female group compared with the control female group. Pathway analysis showed decreases in proteins in the tricarboxylic acidic cycle. The CAN male group had 639 upregulated and 172 downregulated proteins compared with control male group. Pathway analysis showed increases in pathways related to cellular metabolism and decreases in pathways relevant to the development of cardiomyopathy and to oxidative phosphorylation.

CONCLUSIONS:
Male swine treated with CAN had significant improvements in cardiac function that were not observed in female swine treated with CAN. Moreover, CAN treatment in male swine was associated with significantly more changes in protein expression than in female swine treated with CAN. The increased proteomic changes seen in the CAN male group likely contributed to the more robust changes in cardiac function seen in male swine treated with CAN.
A practical guide to time-resolved fluorescence microscopy and spectroscopy
Authors: Clark Benjamin S. , Silvernail Irene , Gordon Kenya , Castaneda Jose F. , Morgan Andi N. , Rolband Lewis A. , LeBlanc Sharonda J. 
Published: January 2024

ABSTRACTTime-correlated single photon counting (TCSPC) coupled with confocal microscopy is a versatile biophysical tool that enables real-time monitoring of biomolecular dynamics across many timescales. With TCSPC, Fluorescence correlation spectroscopy (FCS) and pulsed interleaved excitation-Förster resonance energy transfer (PIE-FRET) are collected simultaneously on diffusing molecules to extract diffusion characteristics and proximity information. This article is a guide to calibrating FCS and PIE-FRET measurements with several biological samples including liposomes, streptavidin-coated quantum dots, proteins, and nucleic acids for reliable determination of diffusion coefficients and FRET efficiency. The FRET efficiency results are also compared to surface-attached single molecules using fluorescence lifetime imaging microscopy (FLIM-FRET). Combining the methods is a powerful approach to revealing mechanistic details of biological processes and pathways.
A method for mining condition-specific co-expressed genes inCamellia sinensisbased on K-means clustering: A case study of “Anji Baicha” tea cultivar
Authors: Zheng Xinghai , Lim Peng Ken , Mutwil Marek , Wang Yuefei 
Published: January 2024

AbstractAs one of the world’s most important beverage crops, tea plants (Camellia sinensis) are renowned for their unique flavors and numerous beneficial secondary metabolites, attracting researchers to investigate the formation of tea quality. With the increasing availability of transcriptome data on tea plants in public databases, conducting large-scale co-expression analyses has become feasible to meet the demand for functional characterization of tea plant genes. However, as the multidimensional noise increases, larger-scale co-expression analyses are not always effective. Analyzing a subset of samples generated by effectively downsampling and reorganizing the global sample set often leads to more accurate results in co-expression analysis. Meanwhile, global-based co-expression analyses are more likely to overlook condition-specific gene interactions, which may be more important and worthy of exploration and research. Here, we employed the k-means clustering method to organize and classify the global samples of tea plants, resulting in clustered samples. Metadata annotations were then performed on these clustered samples to determine the “conditions” represented by each cluster. Subsequently, we conducted gene co-expression network analysis (WGCNA) separately on the global samples and the clustered samples, resulting in global modules and cluster-specific modules. Comparative analyses of global modules and cluster-specific modules have demonstrated that cluster-specific modules exhibit higher accuracy in co-expression analysis. To measure the degree of condition specificity of genes within condition-specific clusters, we introduced the correlation difference value (CDV). By incorporating the CDV into co-expression analyses, we can assess the condition specificity of genes. This approach proved instrumental in identifying a PPR-type RNA editing factor gene (CWM1) that specifically functions during the bud-prealbinism stage of theCamellia sinensiscultivar “Anji Baicha”. We hypothesize that this gene may be upregulated and play a role in inhibiting chloroplast development, ultimately resulting in albino phenotypes in “Anji Baicha”.
The spatial structure of the tumor immune microenvironment can explain and predict patient response in high-grade serous carcinoma
Authors: Kleunen Lucy Van , Ahmadian Mansooreh , Post Miriam D , Wolsky Rebecca J , Rickert Christian , Jordan Kimberly , Hu Junxiao , Richer Jennifer K. , Marjon Nicole A. , Behbakht Kian , Sikora Matthew J. , Bitler Benjamin G. , Clauset Aaron 
Published: January 2024

AbstractDespite ovarian cancer being the deadliest gynecological malignancy, there has been little change to therapeutic options and mortality rates over the last three decades. Recent studies indicate that the composition of the tumor immune microenvironment (TIME) influences patient outcomes but are limited by a lack of spatial understanding. We performed multiplexed ion beam imaging (MIBI) on 83 human high-grade serous carcinoma tumors — one of the largest protein-based, spatially-intact, single-cell resolution tumor datasets assembled — and used statistical and machine learning approaches to connect features of the TIME spatial organization to patient outcomes. Along with traditional clinical/immunohistochemical attributes and indicators of TIME composition, we found that several features of TIME spatial organization had significant univariate correlations and/or high relative importance in high-dimensional predictive models. The top performing predictive model for patient progression-free survival (PFS) used a combination of TIME composition and spatial features. Results demonstrate the importance of spatial structure in understanding how the TIME contributes to treatment outcomes. Furthermore, the present study provides a generalizable roadmap for spatial analyses of the TIME in ovarian cancer research.
TFEB-Mediated Pro-inflammatory Response in Murine Macrophages Induced by Acute Alpha7 Nicotinic Receptor Activation
Authors: Honwad Havisha H. , Najibi Mehran , Koscso Balazs , Bogunovic Milena , Irazoqui Javier E. 
Published: January 2024

AbstractTranscription factors TFEB and TFE3 are crucial for regulating autophagy, lysosomal biogenesis, and lipid metabolism, and have significant roles in macrophage function and innate immunity. The alpha7 nicotinic acetylcholine receptor (α7nAChR), a ligand-gated Ca2+channel known for its therapeutic potential in neurological and inflammatory disorders, has been implicated in modulating immune responses by modulating macrophage function. Stimulation of α7nAChR with chemical agonists has been claimed to activate TFEB in pancreatic acinar cells and neurons. However, the impact of α7nAChR activation on TFEB and TFE3 in macrophages remained unknown, posing an important question due to the potential implications for inflammation regulation. This study investigates the effects of acute α7nAChR activation on TFEB-mediated responses in murine macrophages using the specific agonist PNU-282987. We demonstrate that α7nAChR stimulation triggers TFEB nuclear translocation and lysosomal expansion. Surprisingly, PNU-282987 induces a broad pro-inflammatory gene signature without concomitant cytokine secretion, suggesting an uncoupling of gene expression from cytokine release. Mechanistically, TFEB activation requires the lysosomal Ca2+exporter MCOLN1 and the Ca2+-dependent phosphatase PPP3/calcineurin. Additionally, PNU-282987 elevates reactive oxygen species (ROS) levels, and ROS are involved in TFEB activation by PNU-282987. Notably, even with α7nAChR deletion, compensatory ROS-mediated TFEB activation persists, suggesting the involvement of additional nicotinic receptors. Our findings reveal a novel α7nAChR-TFEB signaling axis in macrophages, offer new insights into the cholinergic regulation of immune responses, establish a baseline for comparison with disease states, and identify potential therapeutic targets for modulating inflammation.
Suspension Electrospinning of Decellularized Extracellular Matrix
Authors: Jones Sarah , VandenHeuval Sabrina , Martinez Andres Luengo , Burgeson Eric , Raghavan Shreya , Rogers Simon , Cosgriff-Hernandez Elizabeth 
Published: January 2024

AbstractDecellularized extracellular matrices (dECM) have strong regenerative potential as tissue engineering scaffolds; however, current clinical options for dECM are limited to freeze-drying its native form into sheets. Electrospinning is a versatile scaffold fabrication technique that allows control of macro- and microarchitecture. It remains challenging to electrospin dECM; which has led researchers to either blend it with synthetic materials or use enzymatic digestion to fully solubilize the dECM. Both strategies reduce the innate bioactivity of dECM and limit its regenerative potential. Herein, we developed a new suspension electrospinning method to fabricate a pure dECM scaffold that retains its innate bioactivity. Systematic investigation of suspension parameters was used to identify critical rheological properties required to instill “spinnability,” including homogenization, concentration, and particle size. Homogenization enhanced particle interaction to impart the requisite elastic behavior to withstand electrostatic drawing without breaking. A direct correlation between concentration and viscosity was observed that altered fiber morphology; whereas, particle size had minimal impact on suspension properties and fiber morphology. The versatility of this new method was demonstrated by electrospinning dECM with three common decellularization techniques (Abraham, Badylak, Luo) and tissue origins (intestinal submucosa, heart, skin). Bioactivity retention after electrospinning was confirmed using cell proliferation, angiogenesis, and macrophage assays. Collectively, these findings provide a framework for researchers to electrospin dECM for diverse tissue engineering applications.Abstract Figure
Polycaprolactone-based shape memory foams as self-fitting vaginal stents
Authors: Hicks Ashley , Roberts Courteney , Robinson Andrew , Wilson Kailey , Kotamreddy Varsha , LaRue Trace , Veyssi Arian , Beltran Felipe , Hakim Julie , Rausch Manuel , Grunlan Melissa , Cosgriff-Hernandez Elizabeth 
Published: January 2024

AbstractThere is an urgent critical need for a patient-forward vaginal stent that can prevent debilitating vaginal stenosis that occurs in up to 75% of patients who undergo pelvic radiation treatments and adolescent patients after vaginal reconstruction. To this end, we developed a self-fitting vaginal stent based on a shape-memory polymer (SMP) foam that can assume a secondary, compressed shape for ease of deployment. Upon insertion, the change in temperature and hydration initiates foam expansion to shape fit to the individual patient and restore the lumen of the stent to allow egress of vaginal secretions. To achieve rapid actuation at physiological temperature, we investigated the effect of architecture of two photocurable, polycaprolactone (PCL) macromers. Star-PCL-tetraacrylate displayed reduced melting temperature in the target range as compared to the linear-PCL-diacrylate. Emulsion-templating was then used to fabricate foams from 75:25 water-in-oil (W/O) emulsions that were subsequently annealed to yield high-porosity SMP foams. Upon axial shape memory testing, both foams displayed excellent shape fixity (90%); however, only the PCLstar-foams displayed shape recovery (∼84%) at 37°C to its permanent shape. A custom mold and curing system was then used to fabricate PCLstar-foams into hollow, cylindrical stents. The stent was crimped to its temporary insertion shape (50% reduction in diameter, OD ∼ 11 mm) with a custom radial crimper and displayed excellent shape fixity for deployment (> 95%) and shape recovery (∼ 100%). To screen vaginal stents, we developed a custom benchtop pelvic model that simulated vaginal anatomy, temperatures, and pressures with an associated computational model. A hysteroscope was used to visualize stent expansion and deformation via a scope port near the cervix of the benchtop model. A crimped SMP vaginal stent was deployed in the model and expanded to walls of the canal (∼70% increase in cross-sectional area) in less than 5 minutes after irrigation with warm water. The vaginal stent demonstrated retention of vaginal caliber with less than 1% decrease in cross-sectional area under physiological pressure. Collectively, this work demonstrates the potential for SMP foams as self-fitting vaginal stents to prevent stenosis. Additionally, this work provides new open-source tools for the iterative design of other gynecological devices.Abstract FigureCreated in BioRender
A Multiscale Spatial Modeling Framework for the Germinal Center Response
Authors: Mu Derek P. , Scharer Christopher D. , Kaminski Norbert E. , Zhang Qiang 
Published: January 2024

AbstractThe germinal center response or reaction (GCR) is a hallmark event of adaptive humoral immunity. Unfolding in the B cell follicles of the secondary lymph organs, a GC culminates in the production of high-affinity antibody-secreting plasma cells along with memory B cells. By interacting with follicular dendritic cells (FDC) and T follicular helper (Tfh) cells, GC B cells exhibit complex spatiotemporal dynamics. Driving the B cell dynamics are the intracellular signal transduction and gene regulatory network that responds to cell surface signaling molecules, cytokines, and chemokines. As our knowledge of the GC continues to expand in depth and in scope, mathematical modeling has become an important tool to help disentangle the intricacy of the GCR and inform novel mechanistic and clinical insights. While the GC has been modeled at different granularities, a multiscale spatial simulation framework – integrating molecular, cellular, and tissue-level responses – is still rare. Here, we report our recent progress toward this end with a hybrid stochastic GC framework developed on the Cellular Potts Model-based CompuCell3D platform. Tellurium is used to simulate the B cell intracellular molecular network comprising NF-κB, FOXO1, MYC, AP4, CXCR4, and BLIMP1 that responds to B cell receptor (BCR) and CD40-mediated signaling. The molecular outputs of the network drive the spatiotemporal behaviors of B cells, including cyclic migration between the dark zone (DZ) and light zone (LZ) via chemotaxis; clonal proliferative bursts, somatic hypermutation, and DNA damage-induced apoptosis in the DZ; and positive selection, apoptosis via a death timer, and emergence of plasma cells in the LZ. Our simulations are able to recapitulate key molecular, cellular, and morphological GC events including B cell population growth, affinity maturation, and clonal dominance. This novel modeling framework provides an open-source, customizable, and multiscale virtual GC simulation platform that enables qualitative and quantitativein silicoinvestigations of a range of mechanic and applied research questions in future.
yQTL Pipeline: a structured computational workflow for large scale quantitative trait loci discovery and downstream visualization
Authors: Li Mengze , Song Zeyuan , Gurinovich Anastasia , Schork Nicholas , Sebastiani Paola , Monti Stefano 
Published: January 2024

1AbstractQuantitative trait loci (QTL) denote regions of DNA whose variation is associated with variations in quantitative traits. QTL discovery is a powerful approach to understand how changes in molecular and clinical phenotypes may be related to DNA sequence changes. However, QTL discovery analysis encompasses multiple analytical steps and the processing of multiple input files, which can be laborious, error prone, and hard to reproduce if performed manually. In order to facilitate and automate large-scale QTL analysis, we developed theyQTL Pipeline, where the ‘y’indicates the dependent quantitative variable being modeled.Prior to genome-wide association test, the pipeline supports the calculation or the direct input of pre-defined genome-wide principal components and genetic relationship matrix when applicable. User-specified covariates can also be provided. Depending on whether familial relatedness exists among the subjects, genome-wide association tests will be performed using either a linear mixed-effect model or a linear model. Using the workflow management tool Nextflow, the pipeline parallelizes the analysis steps to optimize run-time and ensure results reproducibility. In addition, a user-friendly R Shiny App is developed to facilitate result visualization. Upon uploading the result file, it can generate Manhattan plots of user-selected phenotype traits and trait-QTL connection networks based on user-specified p-value thresholds.We applied theyQTL Pipelineto analyze metabolomics profiles of blood serum from the New England Centenarians Study (NECS) participants. A total of 9.1M SNPs and 1,052 metabolites across 194 participants were analyzed. Using a p-value cutoff 5e-8, we found 14,983 mQTLs cumulatively associated with 312 metabolites. The built-in parallelization of our pipeline reduced the run time from ∼90 min to ∼26 min. Visualization using the R Shiny App revealed multiple mQTLs shared across multiple metabolites. TheyQTL Pipelineis available with documentation on GitHub athttps://github.com/montilab/yQTL-Pipeline.
Identification of anisotropy in chromosome dynamics by principal component analysis using integrated spatial genomics
Authors: Nara Takuya , Takahashi Haruko , Awazu Akinori , Kikuchi Yutaka 
Published: January 2024

AbstractEukaryotic interphase chromosomes maintain a three-dimensional structure within the nucleus and undergo fluctuations. It has been reported that such dynamics are involved in transcription, replication, and DNA repair. However, the analysis of chromosomal dynamics has been limited to high-throughput chromosome conformation capture data, which records the contact frequencies between chromosomal regions and lack direct information about the dynamic. Herein, we investigated chromosome fluctuations as polymers based on experimental data from sequential fluorescencein situhybridization (seqFISH)+ using a multiomics methodology. To describe the principal modes of chromosome fluctuations, we applied principal component analysis to the three-dimensional structure information of single chromosomes in 446 mouse embryonic stem cells (mESCs) obtained from seqFISH+ data analysis for spatial genomics and signals of nuclear factors (SNFs: histone marks, repeat DNAs, and nuclear compartments). We found that chromosome fluctuations exhibit both isotropic and anisotropic modes. The properties of anisotropy in chromosome fluctuation vary among chromosomes and appear to depend on the interaction between repeat DNAs on the chromosomes and nuclear compartments. Furthermore, our principal component analysis revealed anisotropic chromosome fluctuations before and after the mitotic phase, specifically when chromosomes adopt a spindle-like shape. This result suggests the potential involvement of anisotropic chromosomal fluctuations in the transition of nuclear organization during the cell cycle. Our results represent the first study to elucidate the dynamics of chromosomes as polymers based on real multiomics data.