bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trafficking dynamics of VEGFR1, VEGFR2, and NRP1 in human endothelial cells
Authors: Sarabipour Sarvenaz , Kinghorn Karina , Quigley Kaitlyn M , Kovacs-Kasa Anita , Annex Brian H , Bautch Victoria L , Mac Gabhann Feilim 
Published: October 2022

AbstractThe vascular endothelial growth factor (VEGF) family of cytokines are key drivers of blood vessel growth and remodeling. These ligands act via multiple VEGF receptors (VEGFR) and co-receptors such as Neuropilin (NRP) expressed on endothelial cells. These membrane-associated receptors are not solely expressed on the cell surface, they move between the surface and intracellular locations, where they can function differently. The location of the receptor alters its ability to ‘see’ (access and bind to) its ligands, which regulates receptor activation; location also alters receptor exposure to subcellularly localized phosphatases, which regulates its deactivation. Thus, receptors in different subcellular locations initiate different signaling, both in terms of quantity and quality. Similarly, the local levels of co-expression of other receptors alters competition for ligands. Subcellular localization is controlled by intracellular trafficking processes, which thus control VEGFR activity; therefore, to understand VEGFR activity, we must understand receptor trafficking. Here, for the first time, we simultaneously quantify the trafficking of VEGFR1, VEGFR2, and NRP1 on the same cells - specifically human umbilical vein endothelial cells (HUVECs). We build a computational model describing the expression, interaction, and trafficking of these receptors, and use it to simulate cell culture experiments. We use new quantitative experimental data to parameterize the model, which then provides mechanistic insight into the trafficking and localization of this receptor network. We show that VEGFR2 and NRP1 trafficking is not the same on HUVECs as on non-human ECs; and we show that VEGFR1 trafficking is not the same as VEGFR2 trafficking, but rather is faster in both internalization and recycling. As a consequence, the VEGF receptors are not evenly distributed between the cell surface and intracellular locations, with a very low percentage of VEGFR1 being on the cell surface, and high levels of NRP1 on the cell surface. Our findings have implications both for the sensing of extracellular ligands and for the composition of signaling complexes at the cell surface versus inside the cell.
Phenotypic and genomic comparison of human outbreak and cattle-associated Shiga toxin-producing Escherichia coli O157:H7
Authors: Peroutka-Bigus Nathan , Nielsen Daniel W. , Trachsel Julian , Mou Kathy T. , Sharma Vijay K. , Kudva Indira T. , Loving Crystal L. 
Published: October 2022

AbstractEscherichia coli O157:H7 (O157)-adulterated food products, including beef and produce, are associated with disease outbreaks in humans. Although cattle feces are a source for the contamination, it is unclear if diverse O157 human-associated outbreak isolates expressing a specific virulence phenotype can colonize and shed in the feces of cattle at a quantitatively similar levels to non-outbreak isolates. It is also unclear if other phenotypes, such as biofilm, cell attachment, and toxin production, differentiate environmental O157 isolates from O157 isolates associated with human illness. Genomic profiling of O157 isolates acquired through routine surveillance can inform if the isolates encode virulence genes associated with human disease, but many genotype-phenotype relationships remain unclear for O157. Therefore, the objective of this study was to compare a diverse set of O157 isolates, with the intent of identifying potential genotypic differences that could inform phenotypes such as cattle colonization and fecal shedding, in vitro cell attachment, biofilm production, and Shiga toxin production. In addition, the relationship between phenotypes and potential for foodborne illness as it relates to genomic virulence traits was explored. No significant differences in cattle colonization and fecal shedding were detected for the tested isolates, despite broad genomic differences. In addition, the in vitro phenotypic differences noted in biofilm and cell attachment did not associate with one LSPA-6 lineage compared to another. Overall, no differences in cattle shedding were observed, yet variations in genotype and phenotype were identified indicating further work is warranted to better understand the relationship between O157 genome and virulence.ImportanceFoodborne illness has a major impact on the health and wellbeing of the global population, besides creating substantial financial hardships for industry. While many bacteria and viruses are implicated in foodborne illness, Escherichia coli serotype O157:H7 (O157) is a common food adulterant that can cause human disease and food recalls. Cattle feces are a significant source of food-adulterating O157. A greater understanding of O157 genetics and its relation to phenotype is needed to develop mitigation strategies to limit spread of O157 into the food chain. The goal of the research was to identify O157 genomic and phenotypic attributes of O157 associated with cattle colonization and fecal shedding along with other factors involved in environmental persistence and illness in humans. It was observed that variations in biofilm formation and in vitro cellular adherence did not associate with enhanced cattle colonization or fecal shedding, indicating that the processes involved in cattle colonization are complex and not well understood.
16S rRNA sequencing for profiling microbial communities in idiopathic granulomatous mastitis
Authors: Ong Seeu Si , Xu Jia , Sim Choon Kiat , Khng Alexis Jiaying , Ho Peh Joo , Kwan Philip Kam Weng , Ravikrishnan Aarthi , Tan Kiat-Tee Benita , Tan Qing Ting , Tan Ern Yu , Tan Su-Ming , Putti Thomas Choudary , Lim Swee Ho , Serene Tang Ee Ling , Nagarajan Niranjan , Karnani Neerja , Li Jingmei , Hartman Mikael 
Published: October 2022

ABSTRACTBackgroundIdiopathic granulomatous mastitis (IGM) is a rare, chronic, and benign inflammatory breast disease with ambiguous aetiology. Contrastingly, lactational mastitis (LM) is commonly diagnosed in breastfeeding women. To investigate IGM aetiology, we profiled the microbial flora of pus and skin in IGM and LM patients.MethodsIGM patients were recruited from 2018 to 2020; LM patients were recruited as controls. 16S rRNA sequencing libraries were constructed from 16S rRNA gene amplified from total DNA extracted from pus and skin swabs. Metagenomic analysis was conducted using modified microbiome abundance analysis-suite customised R-resource for paired pus and skin samples. Microbiome multivariable association analyses were performed using linear models.Results21 IGM and 3 LM paired pus and skin samples underwent metagenomic analysis. Bray-Curtis ecological dissimilarity distance showed dissimilarity across four sample types (IGM-pus, IGM-skin, LM-pus, LM-skin; PERMANOVA, p<0.001). No characteristic dominant genus was observed across IGM samples. IGM pus samples were more diverse than corresponding IGM skin samples (Shannon and Simpson index; Wilcoxon paired signed-rank tests, p=0.022 and p=0.07). Corynebacterium kroppenstedtii, reportedly associated with IGM in literature, was higher in IGM pus samples than paired skin sample (Wilcoxon, p=0.022). Three other species and nineteen genera were statistically significant in paired IGM pus-skin comparison after antibiotic treatment adjustment, and multiple comparisons correction.ConclusionsMicrobial profiles are unique between IGM and LM patients. Inter-patient variability and polymicrobial IGM pus samples cannot implicate specific genus or species as an infectious cause for IGM.
Radiomic Profiling of Chest CT in a Cohort of Sarcoidosis Cases
Authors: Carlson Nichole E , Lippitt William , Ryan Sarah M , Mroz Margaret , Barkes Briana , Liao Shu-Yi , Maier Lisa A , Fingerlin Tasha E 
Published: October 2022

AbstractBackgroundHigh resolution computed tomography (HRCT) of the chest is increasingly used in clinical practice for sarcoidosis. Visual assessment of chest HRCTs in patients with sarcoidosis has high inter- and intra-rater variation. Radiomics offers a reproducible quantitative assessment of HRCT lung parenchyma and could be useful as an additional summary measure of disease. We develop radiomic profiles on HRCT and map them to radiologic, clinical, and patient reported outcomes.Research QuestionCan radiomic analysis of chest HRCT cluster patients into groups that are related to radiologic, clinical, and patient reported outcomes?Study Design and MethodsThree-dimensional radiomic features were calculated on chest HRCT for both lungs from sarcoidosis cases enrolled in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study (N=320). Robust and sparse K-means was used to cluster sarcoidosis cases using their radiomic profiles. Differences in patterns on visual assessment (VAS) by cluster were identified using chi-squared tests. Linear regression investigated how pulmonary function tests and patient reported outcomes differed between clusters with and without adjustment for other radiologic quantification.ResultsRadiomic-based clustering identified four clusters associated with both Scadding stage and Oberstein score (P<0.001). One of the clusters had markedly few abnormalities. Another cluster had consistently more abnormalities along with more Scadding stage IV. Average pulmonary function testing (PFT) differed between clusters, even after accounting for Scadding stage and Oberstein score (P<0.001), with one cluster having more obstructive disease. The most discriminative radiomic measures explained 10-15% of the variation in PFT beyond demographic variables. Shortness of breath, fatigue, and physical health differed by cluster (P<0.014).InterpretationRadiomic quantification of sarcoidosis identifies new subtypes representative of existing radiologic assessment and more predictive of pulmonary function. These findings provide evidence that radiomics may be useful for identifying new imaging-based disease phenotypes.
Validation of diagnosis of acute myocardial infarction and stroke in electronic medical records: a primary care cross-sectional study in Madrid, Spain (the e-MADVEVA Study)
Authors: de Burgos-Lunar C , del Cura-González I , Cárdenas-Valladolid JC , Gómez-Campelo P , Abánades-Herranz JC , López-de Andrés A , Sotos-Prieto M , Iriarte-Campo V , Salinero-Fort MA 
Published: October 2022

AbstractObjectivesTo validate the diagnoses of AMI and stroke recorded in EMR and to estimate the population prevalence of both diseases in people aged ≥ 18 yearsDesignCross-sectional validation study Setting: 45 primary care centresParticipantsSimple random sampling of diagnoses of AMI and stroke (ICPC-2 codes K75 and K90, respectively) registered by 55 physicians and random age- and sex-matched sampling of the records that included in primary care EMRs in Madrid (Spain).Primary and Secondary Outcomes MeasuresSensitivity, specificity, positive and negative predictive values, and overall agreement were calculated using the kappa statistic. Applied gold standards were electrocardiograms, brain imaging studies, hospital discharge reports, cardiology reports, and neurology reports. In the case of AMI, the ESC/ACCF/AHA/WHF Expert Consensus Document was also used. Secondary outcomes were the estimated prevalence of both diseases considering the sensitivity and specificity obtained (true prevalence).ResultsThe sensitivity of a diagnosis of AMI was 98.11% (95% CI, 96.29-99.03), and the specificity was 97.42% (95% CI, 95.44-98.55). The sensitivity of a diagnosis of stroke was 97.56% (95% CI, 95.56-98.68), and the specificity was 94.51% (95% CI, 91.96-96.28). No differences in the results were found after stratification by age and sex (both diseases). The prevalence of AMI and stroke was 1.38% and 1.27%, respectively.ConclusionThe validation results show that diagnoses of AMI and stroke in primary care EMRs constitute a helpful tool in epidemiological studies. The prevalence of AMI and stroke was lower than 2% in the population aged over 18 years.Strengths and limitations of this studyThe major strength of the e-MADVEVA study is the individual validation (manual validation) of electronic medical records by comparing each case and non-case, matched by age, with an accepted reference gold standard.The validation method allows for calculating PPV, NPV, Sensitivity, and Specificity, in contrast with other methods such as questionnaires for healthcare practitioners or patients and comparing rates in a comparable population.In-hospital mortality due to AMI and stroke may not have been recorded in primary care EMRs, with the result that the prevalence of patients who die in hospital due to a first AMI or stroke may be underestimated.The ICPC-2 codes studied for AMI (ICPC-2 K75) and stroke (ICPC-2 K90) do not allow differentiation between the different types of AMI and stroke.
AMU: Using mRNA Embedding in Self-Attention Network to Predict Melanoma Immune Checkpoint Inhibitor Response
Authors: Yin Yi , Wu Qing , Wang Ziming , Kang Yu , Xie Xianhe 
Published: October 2022

AbstractBackgroundTo precisely predict drug response and avoid unnecessary treatment have been urgent needs to be resolved in the age of melanoma immunotherapy. Deep learning model is a powerful instrument to predict drug response. Simultaneously extracting the function and expression data characteristics of mRNA may help to improve the prediction performance of the model.MethodsWe designed a deep learning model named AMU with self-attention structure which were fed with the mRNA expression values for predicting melanoma immune checkpoint inhibitor clinical responses.ResultsComparing with SVM, Random Forest, AdaBoost, XGBoost and the classic convolutional network, AMU showed the preferred performance with the AUC of 0.941 and mAP of 0.960 in validation dataset and AUC of 0.672, mAP of 0.800 in testing dataset, respectively. In model interpretation work, TNF-TNFRSF1A pathway were indicated as a key pathway to influence melanoma immunotherapy responses. Further, gene features extracted from embedding layer and calculated by t-SNE algorithm, showed a local similarity with Functional Protein Association Network (STRING, https://cn.string-db.org/), AMU could predict gene functions and interactions simultaneously.ConclusionsDeep learning model built with self-attention structure has strong power to process mRNA expression data and gene vector representation is a promising work in biomedical field.What is already known on this topicThe types of biomarkers for immunotherapy are very complex and transcriptomics biomarker research is one part of it, but currently it is lack of generally acknowledged results with practical value. Combining deep learning models with transcriptomics biomarker markers can help us to predict drug sensitivity. However, the powerful capabilities of deep learning models have not been fully exploited and utilized.What this study addsThe expression of 160 genes could well predict the efficacy of immunotherapy, even if the tissue samples were after drug administration, and through model training, we could also extract the interactions and connections between genes. The deep learning model could not only do prediction, but were also promising in performing gene vector representation learning.How this study might affect research, practice or policyOur research is not only to provide a model with high predictive value, but also to extract gene interaction relations during model training, which is very enlightening for gene vector representation learning. The research of gene vector representation learning can promote the prediction accuracy of deep learning models in various biomedical fields because it can become the common upstream of many biomedical tasks.
Enteroendocrine cells protect the stem cell niche by regulating crypt metabolism in response to nutrients
Authors: McCauley Heather A. , Riedman Anne Marie , Enriquez Jacob R. , Zhang Xinghao , Watanabe-Chailland Miki , Sanchez J. Guillermo , Kechele Daniel O. , Paul Emily F. , Riley Kayle , Burger Courtney , Lang Richard A. , Wells James M. 
Published: October 2022

AbstractBackground and aimsThe intestinal stem cell niche is exquisitely sensitive to changes in diet, with high fat diet, caloric restriction, and fasting resulting in altered crypt metabolism and intestinal stem cell function. Unlike cells on the villus, cells in the crypt are not immediately exposed to the dynamically changing contents of the lumen. We hypothesized that enteroendocrine cells (EECs), which sense environmental cues and in response release hormones and metabolites, are essential for relaying the nutrient status of the animal to cells deep in the crypt.MethodsWe used the tamoxifen-inducible VillinCreERT2 mouse model to deplete EECs (Neurog3fl/fl) from adult intestinal epithelium and we generated human intestinal organoids from wild-type and NEUROG3-null human pluripotent stem cells. We used indirect calorimetry, 1H-NMR metabolomics, mitochondrial live imaging, and the Seahorse bioanalyzer to assess metabolism. Intestinal stem cell activity was measured by proliferation and enteroid-forming capacity. Transcriptional changes were assessed using 10X Genomics single-cell sequencing.ResultsLoss of EECs resulted in increased energy expenditure in mice, an abundance of active mitochondria, and a shift of crypt metabolism to fatty acid oxidation. Crypts from mouse and human intestinal organoids lacking EECs displayed increased intestinal stem cell activity and failed to activate phospho-S6 ribosomal protein, a marker for activity of the master metabolic regulator mammalian target of rapamycin (mTOR). These phenotypes were similar to those observed when wild-type mice were deprived of nutrients.ConclusionsDeletion of EECs recapitulated a fasting phenotype despite normal levels of ingested nutrients. These data suggest that EECs are required to relay nutritional information to the stem cell niche and are essential regulators of intestinal metabolism.
Effects of generations in captivity and elevated rearing temperature on Ontario hatchery brook trout (Salvelinus fontinalis) fry quality and survival
Authors: Wilder A.S. , Wilson C.C. , Warriner T. R. , Semeniuk C.A.D. 
Published: October 2022

AbstractWith increasing environmental temperatures causing concern for the status of freshwater fishes, captive breeding programs may become increasingly important for conservation efforts as well as to support fisheries. Although captive broodstocks provide reliable gamete sources for production stocking, prolonged generations under hatchery conditions selection for hatchery conditions (domestication) and reduced phenotypic plasticity to novel environmental stressors. We assessed the effects of rearing temperature and number of generations spent in captivity on the survival and quality (indicated by lack of malformations) of long-term (F20+) and newly-captive (F1) strains of Ontario hatchery brook trout (Salvelinus fontinalis) with shared genetic history. We found that elevated temperatures decreased likelihood of survival between the hatched and fry stages. Additionally, we found that elevated temperature reduced fry quality of F1fish whereas F20+fish were less thermally sensitive, suggesting no reduction in plasticity due to captivity. The combined effects of elevated rearing temperatures and number of hatchery generations suggest that selection for captivity can occur rapidly (in one generation) even under benign conditions, and that additive stressor effects of captivity and temperature may impact newly established strains.
Three-dimensional structure of inner ear hair cell mitochondrial networks and ribbon synapses in a zebrafish model of Usher syndrome type 1B
Authors: Riley Kenneth C. , Koleilat Alaa , Dugdale Joseph , Cooper Shawna A. , Christensen Trace A. , Schimmenti Lisa A. 
Published: October 2022

AbstractInner ear hair cells are the fundamental unit of sound and vibration detection in inner ear and lateral line structures. Our understanding of the structure and ultrastructure of hair cells has heretofore relied upon two-dimensional imaging. The development of serial block-face scanning electron microscopy (SBFSEM) changes this paradigm and allows for ultrastructural evaluation of hair cells in three-dimensions. This is the first report of SBFSEM analysis in the myo7aa-/- mutant where we evaluated several attributes of zebrafish hair cells from the inner ear cristae in both wildtype and myo7aa-/- mutant zebrafish through three-dimensional reconstruction. We describe ribbon synapse number, location, and volume, mitochondrial localization, and innervation for individual hair cells. We determined that myo7aa-/- mutant ribbon synapses have a smaller volume and surface area; however, all other hair cell attributes investigated were not significantly different between the mutant and wildtype zebrafish. These findings are critical for the development of therapies for deafness caused by mutations in myo7aa, as this study supports that the necessary hair cell machinery for hearing is largely intact. In addition, the methodology and measurements developed in this study provide a guide for the evaluation of zebrafish hair cells using SBFSEM.
Molecular basis of stepwise cyclic tetra-adenylate cleavage by the type III CRISPR ring nuclease Crn1/Sso2081
Authors: Du Liyang , Luo Zhipu , Lin Zhonghui 
Published: October 2022

ABSTRACTThe cyclic oligoadenylates (cOAs) act as second messengers of type III CRISPR immunity system through activating the auxiliary nucleases for indiscriminate RNA degradation. The cOA-degrading nucleases (ring nucleases) provide an ‘off-switch’ regulation of the signaling, thereby preventing cell dormancy or cell death. Here, we describe the crystal structures of the CRISPR-associated ring nuclease 1 (Crn1) from Saccharolobus solfataricus (Sso) 2081 in its apo or bound to cA4 in both pre-cleavage and transient intermediate states. Sso2081 harbors a unique helical insert that encloses cA4 in the central cavity. Two free phosphates symmetrically bind the catalytic site of apo Sso2081 and overlap with the two scissile phosphates of cA4, supporting a bilaterally symmetrical cleavage. The structure of transient intermediate state captured by Ser11Ala mutation immediately illustrates a stepwise cleavage of cA4 by Sso2081. Our study establishes atomic mechanisms of cA4 recognition and degradation by the type III CRISPR ring nuclease Crn1/Sso2081.