bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deficiency of the purinergic receptor P2X4 limits atherosclerosis in mice
Authors: Koenig S , Peikert A , Merz J , Rofa K , Schaefer I , Dimanski D , Karnbrock L , Von Garlen S , Aleid R , Bulatova K , Hoppe N , Bode C , Zirlik A , Stachon P 
Published: November 2020

Abstract

Introduction
Extracellular nucleotides like ATP promote inflammation as danger signals in various chronic diseases via purinergic receptors. In our previous work we identified P2X4 expression in murine atherosclerotic lesions. Therefore, we hypothesized a contribution of the ATP-P2X4 axis to vascular inflammation in atherosclerosis.

Methods
To investigate the functional role of P2X4 in atherogenesis, wild-type LDL-receptor deficient mice (LDLR−/−) and P2X4-deficient LDLR−/− mice (P2X4−/−LDLR−/−) were fed a high cholesterol diet for 16 weeks. Plaque progression in aortic arches was monitored by echography at intervals of 4 weeks, and leukocyte subsets in blood samples were analysed by flow cytometry. Atherosclerotic lesions were then assessed histologically in aortic root, arch, and abdominal aorta. In order to assess leukocyte recruitment, intravital microscopy was performed after injection of ATP in P2X4−/− or wildtype mice (WT). Regarding transferability to human disease, atherosclerotic plaque from carotid endarterectomy has been stained immunohistochemically for P2X4-receptor expression.

Results
After 16 weeks, P2X4-deficient mice showed significantly reduced atherosclerotic lesions in the aortic root (n=40, LDLR−/−: 0.47 mm2, P2X4−/−LDLR−/−: 0.39 mm2, p=0.04). Ly6C- monocyte count in peripheral blood was higher in P2X4−/−LDLR−/− (n=32, LDLR−/−: 241/μl, P2X4−/−LDLR−/−: 542/μl, p=0.0088), shifting the balance to a more anti-inflammatory subset. Memory-cell generation of CD4-T-cells is significantly higher in knockout-mice, suggesting an involvement of T-helper cells (n=25, LDLR−/−: 27%, P2X4−/−LDLR−/−: 46%, p=0.0003). Peritoneally injected ATP induced leukocyte rolling in WT, but not in P2X4-deficient mice. In human carotid arteries, atherosclerotic plaque shows higher staining for P2X4−/− receptor than not diseased areas.

Conclusion
P2X4-deficiency enhances anti-inflammatory leukocytes in peripheral blood and reduces atherosclerosis. Therefore, blocking the ATP-P2X4 axis may prevent leukocyte recruitment to atherosclerotic lesions and could present a potential new target for anti-atherogenic therapy.

Funding Acknowledgement
Type of funding source: Public grant(s) – National budget only. Main funding source(s): This work was supported by a research grant of the German Research Foundation (DFG) to Peter Stachon. Sebastian König was supported by a research grant of the German Cardiac Society (DGK)
Modification of histone 3 lysine 27 (H3K27) trimethylation in EZH2 and JMJD3 deficient T cells attenuates atherosclerosis through polarization towards anti-inflammatory phenotypes
Authors: Lacy M , Nitz K , Janjic A , Wu Y , Venkatasubramani A , Imhof A , Enard W , Weber C , De Winther M , Atzler D , Lutgens E 
Published: November 2020

Abstract

Background
The trimethylation status of Histone 3 Lysine 27 (H3K27), which is regulated by the methylating enzyme Enchancer of zeste homolog 2 (EZH2) and the demethylating enzyme Jumonji domain containing 3 (JMJD3), is a critical epigenetic signature for the differentiation and polarization of T cells. During atherogenesis, T cells initiate and propagate lesion formation through imbalanced polarization of T helper (Th) cells leading to the accumulation of pro-atherogenic T cell subsets, including Th1, that exacerbate inflammation.

Purpose
We hypothesize that T-cell EZH2 and JMJD3 may contribute to inflammation and atherosclerotic plaque formation through opposing polarization of T helper cells.

Methods
We generated transgenic mice with either Ezh2 or Jmjd3 flanked by loxP-sites that were sensitive to Cre-mediated inactivation. Mice were backcrossed to apolipoprotein E (ApoE−/−) mice expressing Cre in T cells (Cd4Cretg) to generate hypercholesterolemic Ezh2fl/fl-Cd4Cre-ApoE−/− (Ezh2fl/fl) and Jmjd3fl/fl-Cd4Cre-ApoE−/− (Jmjd3fl/fl) mice. Following a 6 week high fat diet, the immune status and atherosclerotic progression of the mice were assessed by histology, flow cytometry, and RNA sequencing.

Results
Mass spectrometry of histones isolated from CD4+ T cells confirmed a decrease in H3K27 trimethylation in Ezh2fl/fl mice and an increase in Jmjd3fl/fl mice (p=0.0002 and p=0.01, respectively). In the aortic root, both Ezh2fl/fl and Jmjd3fl/fl mice developed significantly less atherosclerosis (p=0.001 and p=0.0006, respectively). A shift from naive T cells to effectors was observed in the lymph nodes and spleens in both models (p&lt;0.0001 for all). Flow cytometric analysis revealed a systemic accumulation of Th2 in Ezh2fl/flmice (p&lt;0.0001), which was corroborated by a 2.75 log2 fold change of IL-4 expression (padj&lt;0.0001) (RNA-sequencing) in CD4+ T cells as well as elevated IL-4 plasma concentrations (p=0.04). Ingenuity pathway analysis revealed the canonical Th1 pathway was inhibited in Ezh2fl/fl mice. In Jmjd3fl/fl mice, flow cytometric analysis revealed a 2 fold increase of Foxp3-expressing T regulatory (Treg) cells in the blood (p=0.005), lymph nodes (p&lt;0.0001), and spleen (p&lt;0.0001).

Conclusions
Our data demonstrate deficiency of either EZH2 or JMJD3 strongly reduce lesion progression in atherosclerosis through polarization of T cells towards anti-atherogenic Th2 or Treg populations, respectively. Targeting T-cell H3K27 trimethylation may be a promising candidate for further investigation to treat atherosclerosis.

Funding Acknowledgement
Type of funding source: Public grant(s) – National budget only. Main funding source(s): German Research Foundation (DFG)
Anthracyclines and regional myocardial damage in breast cancer patients. A multicentre study from the Working Group on Drug Cardiotoxicity and Cardioprotection, Italian Society of Cardiology (SIC)
Authors: Zito Concetta , Manganaro Roberta , Cusmà Piccione Maurizio , Madonna Rosalinda , Monte Ines , Novo Giuseppina , Mercurio Valentina , Longobardo Luca , Cadeddu Dessalvi Christian , Deidda Martino , Pagliaro Pasquale , Spallarossa Paolo , Costantino Rossella , Santarpia Mariacarmela , Altavilla Giuseppe , Carerj Scipione , Tocchetti Carlo Gabriele 
Published: November 2020

Abstract

Aims
In breast cancer (BC) patients treated with anthracyclines-based therapies, we aim at assessing whether adjuvant drugs impact cardiac function differently and whether their cardiotoxicity has a regional pattern.

Methods and results
In a multicentre study, 146 BC patients (56 ± 11 years) were prospectively enrolled and divided into three groups according to the received treatments: AC/EC-Group (doxorubicin or epirubicin + cyclophosphamide), AC/EC/Tax-Group (AC/EC + taxanes), FEC/Tax-Group (fluorouracil + EC + taxanes). Fifty-six patients of the total cohort also received trastuzumab. Left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were calculated before starting chemotherapy (T0), at 3 months (T3), at 6 (T6), and 12 months (T12). A ≥10% drop of EF, while remaining within the normal range, was reached at T6 in 25.3% of patients from the whole cohort with an early decrease only in FEC/Tax-Group (P = 0.04). A ≥15% GLS reduction was observed in many more (61.6%) patients. GLS decreased early both in the whole population (P &lt; 0.001) and in the subgroups. The FEC-Tax Group showed the worst GLS at T6. Trastuzumab further worsened GLS at T12 (P = 0.031). A significant reduction of GLS was observed in all LV segments and was more relevant in the anterior septum and apex.

Conclusions
The decrease of GLS is more precocious and pronounced in BC patients who received FEC + taxanes. Cardiac function further worsens after 6 months of adjuvant trastuzumab. All LV segments are damaged, with the anterior septum and the apex showing the greatest impairments.
Trajectories, bifurcations, and pseudo-time in large clinical datasets: applications to myocardial infarction and diabetes data
Authors: Golovenkin Sergey E , Bac Jonathan , Chervov Alexander , Mirkes Evgeny M , Orlova Yuliya V , Barillot Emmanuel , Gorban Alexander N , Zinovyev Andrei 
Published: November 2020

Abstract

Background
Large observational clinical datasets are becoming increasingly available for mining associations between various disease traits and administered therapy. These datasets can be considered as representations of the landscape of all possible disease conditions, in which a concrete disease state develops through stereotypical routes, characterized by “points of no return" and “final states" (such as lethal or recovery states). Extracting this information directly from the data remains challenging, especially in the case of synchronic (with a short-term follow-up) observations.

Results
Here we suggest a semi-supervised methodology for the analysis of large clinical datasets, characterized by mixed data types and missing values, through modeling the geometrical data structure as a bouquet of bifurcating clinical trajectories. The methodology is based on application of elastic principal graphs, which can address simultaneously the tasks of dimensionality reduction, data visualization, clustering, feature selection, and quantifying the geodesic distances (pseudo-time) in partially ordered sequences of observations. The methodology allows a patient to be positioned on a particular clinical trajectory (pathological scenario) and the degree of progression along it to be characterized with a qualitative estimate of the uncertainty of the prognosis. We developed a tool ClinTrajan for clinical trajectory analysis implemented in the Python programming language. We test the methodology in 2 large publicly available datasets: myocardial infarction complications and readmission of diabetic patients data.

Conclusions
Our pseudo-time quantification-based approach makes it possible to apply the methods developed for dynamical disease phenotyping and illness trajectory analysis (diachronic data analysis) to synchronic observational data.
Testing for Endogeneity of Covid-19 Patient Assignments
Authors: Gourieroux C , Djogbenou A , Jasiak J 
Published: November 2020

Abstract
A considerable number of individuals infected by COVID-19 died in self-isolation. This paper uses a graphical inference method to examine if patients were endogenously assigned to self-isolation during the early phase of COVID-19 epidemic in Ontario. The endogeneity of patient assignment is evaluated from a dependence measure revealing relationships between patients’ characteristics and their location at the time of death. We test for absence of assignment endogeneity in daily samples and study the dynamic of endogeneity. This methodology is applied to patients’ characteristics, such as age, gender, location of the diagnosing health unit, presence of symptoms, and underlying health conditions.
Case review of severe acute radiation syndrome from whole body exposure: concepts of radiation-induced multi-organ dysfunction and failure
Authors: Tanigawa Koichi 
Published: November 2020

ABSTRACT
Acute radiation syndrome (ARS) due to whole body exposure (WBE) presents various clinical pictures, occasionally leading to fatal consequences. In this report, the literature providing details of the clinical course of severe ARS owing to WBE is reviewed and the lessons learned from recent accidents are discussed, to better prepare for another radiological event. Studies investigating radiological accidents that provided details of medical care for severe ARS were searched in official reports from the International Atomic Energy Agency and through the databases of PubMed, Medline, CiNii and Google Scholar and reviewed. Four fatal cases of severe ARS due to WBE in Soreq 1990 and Nesvizh 1992, and two cases in JCO Tokaimura 1999 were reviewed. A common set of medical interventions was carried out, that put a focus on medical management assuming the occurrence of hematopoietic disorders. However, clinicians were faced with a mixture of chronic hematological and non-hematological events including persistent gastrointestinal disorders, gradual and progressive skin disorders, liver and renal dysfunction and respiratory failure. Clinical pictures following high-dose WBE have become more complicated as treatment modalities improve. To address these issues, a concept of severe ARS due to WBE has been proposed with respect to radiation-induced multi-organ dysfunction syndrome (RI-MODS) and failure (RI-MOF). These patients need to be managed at institutions where multidisciplinary, resource-intensive therapy can be provided.
Re-assessing the role of the fecalith in acute appendicitis in adults: case report, case series and literature review
Authors: Tran Nguyen , Emuakhagbon Valerie-Sue , Baker Bradford T , Huerta Sergio 
Published: November 2020

Abstract
Appendicitis in adults is thought to occur because of luminal obstruction from a fecalith. We present a unique case of a patient who had her entire appendiceal lumen occupied by a fecalith (5.0 cm long) but had no appendicitis. We reviewed the records of 257 veterans who underwent surgical intervention at our institution for the management of acute appendicitis. Fecaliths occurred in 15.6% of patients. At laparotomy, 20.6% had a perforated appendix; pathology showed fecaliths in 20.8% of specimens. A review of the literature inclusive of 25 series showed fecaliths in 33.3% of patients with a normal appendix, 23.5% of patients with acute appendicitis and 24.9% with perforated appendicitis. These data show that appendicitis is not a common cause of fecalith obstruction in adults.
Separatrix divergence of stellar streams in galactic potentials
Authors: Yavetz Tomer D , Johnston Kathryn V , Pearson Sarah , Price-Whelan Adrian M , Weinberg Martin D 
Published: November 2020

ABSTRACTFlattened axisymmetric galactic potentials are known to host minor orbit families surrounding orbits with commensurable frequencies. The behaviour of orbits that belong to these orbit families is fundamentally different than that of typical orbits with non-commensurable frequencies. We investigate the evolution of stellar streams on orbits near the boundaries between orbit families (separatrices) in a flattened axisymmetric potential. We demonstrate that the separatrix divides these streams into two groups of stars that belong to two different orbit families, and that as a result, these streams diffuse more rapidly than streams that evolve elsewhere in the potential. We utilize Hamiltonian perturbation theory to estimate both the time-scale of this effect and the likelihood of a stream evolving close enough to a separatrix to be affected by it. We analyse two prior reports of stream-fanning in simulations with triaxial potentials, and conclude that at least one of them is caused by separatrix divergence. These results lay the foundation for a method of mapping the orbit families of galactic potentials using the morphology of stellar streams. Comparing these predictions with the currently known distribution of streams in the Milky Way presents a new way of constraining the shape of our Galaxy’s potential and distribution of dark matter.
Incidence and Impact of Persistent Viremia on SVR Rates in Patients Receiving Direct-Acting Antiviral Therapy
Authors: Carver Alicia B , Zuckerman Autumn D , DeClercq Joshua , Choi Leena , Chastain Cody A 
Published: November 2020

Abstract
Rates of persistent viremia (PV) while on direct-acting antiviral therapy were low (5.7%) in a real-world cohort of 983 patients. High sustained virologic response rates were achieved both in patients with PV (92.9%) and those with rapid virologic response (96.5%), without significant differences.
A functional module states framework reveals cell states for drug and target prediction
Authors: Qin Guangrong , Knijnenburg Theo , Gibbs David , Moser Russell , Monnat Raymond J. , Kemp Christopher , Shmulevich Ilya 
Published: November 2020

SummaryCells are complex systems in which many functions are performed by different genetically-defined and encoded functional modules. To systematically understand how these modules respond to drug or genetic perturbations, we developed a Functional Module States framework. Using this framework, we 1) defined the drug induced transcriptional state space for breast cancer cell lines using large public gene expression datasets, and revealed that the transcriptional states are associated with drug concentration and drug targets; 2) identified potential targetable vulnerabilities through integrative analysis of transcriptional states after drug treatment and gene knockdown associated cancer dependency; and 3) used functional module states to predict transcriptional state-dependent drug sensitivity and built prediction models using the functional module states for drug response. This approach demonstrates a similar prediction performance as do approaches using high dimensional gene expression values, with the added advantage of more clearly revealing biologically relevant transcriptional states and key regulators.
ProteoSushi: a software tool to biologically annotate and quantify modification-specific, peptide-centric proteomics datasets
Authors: Seymour Robert W. , van der Post Sjoerd , Mooradian Arshag D. , Held Jason M. 
Published: November 2020

AbstractLarge-scale proteomic profiling of protein post-translational modifications has provided important insights into the regulation of cell signaling and disease. These modification-specific proteomics workflows nearly universally enrich modified peptides prior to mass spectrometry analysis, but protein-centric proteomic software tools have many limitations evaluating and interpreting these peptide-centric datasets. We therefore developed ProteoSushi, a software tool tailored to the analysis of each modified site in peptide-centric proteomic datasets that is compatible with any post-translational modification or chemical label. ProteoSushi uses a unique approach to assign identified peptides to shared proteins and genes, minimizing redundancy by prioritizing shared assignments based on UniProt annotation score and optional user-supplied protein/gene lists. ProteoSushi simplifies quantitation by summing or averaging intensities, merging overlapping peptide charge states, missed cleavages, peptide spectral matches, and variable modifications into a single value for each modified site. ProteoSushi annotates each PTM site with the most up-to-date biological information available from UniProt, such as functional roles or known modifications, the protein domain in which the site resides, the protein’s subcellular location and function and more. ProteoSushi has a graphical user interface for ease of use. ProteoSushi’s flexibility and combination of features streamlines peptide-centric data processing and knowledge mining of large modification-specific proteomics datasets.
Th17 cells provide direct protective effects that limit stomach parasite burden following orogastric mucosalTrypanosoma cruziinfection
Authors: Cai Catherine W. , Eickhoff Christopher S. , Meza Krystal A. , Blase Jennifer R. , Audette Rebecca E. , Chan David H. , Bockerstett Kevin A. , DiPaolo Richard J. , Hoft Daniel F. 
Published: November 2020

AbstractTrypanosoma cruziis the intracellular parasite of Chagas disease, a chronic condition characterized by cardiac and gastrointestinal morbidity. Protective immunity requires CD4+ T cells, and Th1 cells and IFN-γ are important players in host defense. More recently, Th17 cells and IL-17 have been shown to exert protective functions in systemicT. cruziinfection. However, it remains unclear whether Th17 cells and IL-17A protect against mucosal infection, which is an important cause of human outbreaks. We found that IL-17RA knock-out (KO) mice are highly susceptible to orogastric infection, indicating an important function for this cytokine in mucosal immunity toT. cruzi. To investigate the specific role of Th17 cells for mucosal immunity, we reconstituted RAG1 KO mice withT. cruzi-specificT cell receptor transgenic Th17 cells prior to orogastricT. cruzichallenges. We found that Th17 cells provided protection against gastric mucosalT. cruziinfection, indicated by significantly lower stomach parasite burdens.In vitromacrophage infection assays revealed that protection by Th17 cells is reversed with IL-17A neutralization or loss of macrophage NADPH oxidase activity. Consistent with this,in vivo, mice lacking functional NADPH oxidase were not protected by Th17 cell transfer. These data are the first report that Th17 cells protect against mucosalT. cruziinfection, and identify a novel protective mechanism involving the induction of NADPH oxidase activity in macrophages by IL-17A. These studies provide important insights for Chagas vaccine development, and more broadly, increase our understanding of the diverse roles of Th17 cells in host defense.
The HSPG Syndecan is a core organizer of cholinergic synapses inC. elegans
Authors: Zhou Xin , Vachon Camille , Cizeron Mélissa , Romatif Océane , Bülow Hannes E. , Jospin Maëlle , Bessereau Jean-Louis 
Published: November 2020

SUMMARYThe extracellular matrix has emerged as an active component of chemical synapses regulating synaptic formation, maintenance and homeostasis. The heparan sulfate proteoglycan syndecans are known to regulate cellular and axonal migration in the brain. They are also enriched at synapses, but their synaptic functions remain more elusive. Here we show that SDN-1, the sole ortholog of syndecan inC. elegans, is absolutely required for the synaptic clustering of homomeric α7-like N-acetylcholine receptors (AChR) and regulates the synaptic content of heteromeric L-AChRs. SDN-1 is concentrated at neuromuscular junctions (NMJs) by the neurally-secreted synaptic organizer Ce-Punctin/MADD-4, which also activates the transmembrane netrin receptor DCC. Those cooperatively recruit the FARP and CASK orthologues that localize N-AChRs at cholinergic NMJs through physical interactions. Therefore, SDN-1 stands at the core of the cholinergic synapse organization by bridging the extracellular synaptic determinants to the intracellular synaptic scaffold that controls the postsynaptic receptor content.