bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regional Integration Projects in Venezuela’s Foreign Policy under the Presidency of Nicolas Maduro (2013-2018)
Authors: Oleksenko Roman , Villasmil Espinoza Jorge J. , Andriukaitiene Regina 
Published: May 2023

The purpose of the research paper is to highlight the development, changes, and results that occurred in Venezuela’s regional integration during President Nicolas Maduro’s first term of office (2013-2018).
The novelty of the research paper is in a comprehensive analysis of Venezuela’s regional policy within the framework of the leading integration associations ALBA, CELAC, and UNASUR, which, according to Hugo Chavez’s plan, were supposed to turn the Bolivarian Republic of Venezuela into a regional leader in Latin America. Instead, N. Maduro was unable to take advantage of his predecessor’s foreign policy successes and lost the opportunities he had planned.
Conclusions. Taking into consideration the theoretical and ideological foundations of Venezuela’s foreign policy, the conclusion can be made that the regional vector of foreign policy has remained one of the focal points for President Nicolas Maduro. Thanks to its resources and ideological dominance, the country could rightfully claim regional leadership, as it united the countries of the region on the wave of anti-Americanism, initiated many integration movements, and made most countries in the region dependent on its energy supplies and credits.
‘Pockets of resistance’ to US expansion in Latin America and regional integration were concentrated in three organizations where Venezuela was one of the founders or key players: ALBA, CELAC, and UNASUR.
The economic and political crisis that hit Venezuela sharply raised the question of the continuity of the ‘Bolivarian Project’, which affected the change in the state’s priorities, including in the international arena. N. Maduro had to focus on the country’s internal problems.
In the regional integration policy of Venezuela during N. Maduro’s first term of office, we can distinguish two qualitative periods: 1. 2013-2015, the time of relatively successful implementation of the regional integration course, and, 2. 2016-2018, the decline and actual collapse of the regional vector of Venezuela’s foreign policy. It was just the loss of democratic tendencies in Maduro’s domestic policy that led to the loss of regional leadership and global stature.
The three integration projects analyzed by the authors started losing their credibility and effectiveness during 2013-2018, which happened mostly due to the crisis in Venezuela. CELAC and UNASUR de facto ceased their activities, and ALBA remained the only instrument of N. Maduro’s regional influence.
Translator learners' strategies in local and textual metaphors
Authors: Gebbia Chiara Astrid 
Published: May 2023

IntroductionMetaphor is more than understanding and expressing an abstract concept in terms of a concrete one. Pre-linguistically, it is the conceptual creativity that resides in the entities yet to be expressed. Linguistically, it is the invention that expands the boundaries of words. Contextually, it is the preservation or generation of polysemy that brings about a confrontation of meanings. As such, metaphor is also a universal creative mechanism of semantic innovation and an artful discourse feature. Both Metaphor and Translation Studies, however, have mostly addressed conventional metaphors and professional translators, thereby neglecting students' behaviors when translating creative metaphors, especially at discourse level.Methods/AimThe main objective of this task-based descriptive study is therefore to investigate to what extent and how the translation strategies spontaneously adopted by 73 translator students are influenced by local, creative metaphors and by their textual patterning. The analysis of the data showed that while isolated, non-conflictual metaphors did not pose any challenges, the diverse patterns of conflictual ones hampered the translation outcome. At the micro-level, literal and explicitation strategies result in neutral, less connotative renditions. When omission prevails in correlation to metaphor clusters, the target texts appear more condensed, overtly informative, and lack the metaphorical diversity and cohesion of the source ones. As a result, the appealing linguistic jocularity deriving from exploiting metaphors and puns is toned down.DiscussionSince students tend to avoid creative solutions, these findings will serve as a preliminary discussion on how students' strategic and textual competence can benefit from cognitive-informed, conflict-based inferencing skills by exploiting the metalinguistic nature of creative metaphors and puns.
CMR left ventricular strains beyond global longitudinal strain in differentiating light-chain cardiac amyloidosis from hypertrophic cardiomyopathy
Authors: Wang Fangqing , Deng Yan , Li Shunjia , Cheng Qichao , Wang Qing , Yu Dexin , Wang Qian 
Published: May 2023

BackgroundThe clinical value of left ventricular (LV) global longitudinal strain (GLS) in the differential diagnosis of light-chain cardiac amyloidosis (AL-CA) and hypertrophic cardiomyopathy (HCM) has been previously reported. In this study, we analyzed the potential clinical value of the LV long-axis strain (LAS) to discriminate AL-CA from HCM. Furthermore, we analyzed the association between all the LV global strain parameters derived from cardiac magnetic resonance (CMR) feature tracking and LAS in both the AL-CA and HCM patients to assess the differential diagnostic efficacies of these global peak systolic strains.Materials and methodsThus, this study enrolled 89 participants who underwent cardiac MRI (CMRI), consisting of 30 AL-CA patients, 30 HCM patients, and 29 healthy controls. The intra- and inter-observer reproducibility of the LV strain parameters including GLS, global circumferential strain (GCS), global radial strain (GRS), and LAS were assessed in all the groups and compared. Receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic performances of the CMR strain parameters in discriminating AL-CA from HCM.ResultsThe intra- and inter-observer reproducibility of the LV global strains and LAS were excellent (range of interclass correlation coefficients: 0.907–0.965). ROC curve analyses showed that the differential diagnostic performances of the global strains in discriminating AL-CA from HCM were good to excellent (GRS, AUC = 0.921; GCS, AUC = 0.914; GLS, AUC = 0.832). Furthermore, among all the strain parameters analyzed, LAS showed the highest diagnostic efficacy in differentiating between AL-CA and HCM (AUC = 0.962).ConclusionCMRI-derived strain parameters such as GLS, LAS, GRS, and GCS are promising diagnostic indicators that distinguish AL-CA from HCM with high accuracy. LAS showed the highest diagnostic accuracy among all the strain parameters.
Analysis of immunogenic cell death in ascending thoracic aortic aneurysms based on single-cell sequencing data
Authors: Tian Zemin , Zhang Peng , Li Xinyang , Jiang Delong 
Published: May 2023

BackgroundAt present, research on immunogenic cell death (ICD) is mainly associated with cancer therapy. Little is known about the role of ICD in cardiovascular disease, especially in ascending thoracic aortic aneurysms (ATAA).MethodATAA single-cell RNA (scRNA) sequencing data were analyzed to identify the involved cell types and determine their transcriptomic characteristics. The chi-square test, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, Gene Set Enrichment Analysis (GSEA), and CellChat for cell-to-cell communication analysis from the Gene Expression Omnibus (GEO) database were used.ResultA total of 10 cell types were identified, namely, monocytes, macrophages, CD4 T/NK (CD4+ T cells and natural killer T cells), mast cells, B/Plasma B cells, fibroblasts, endothelial cells, cytotoxic T cells (CD8+ T cells, CTLs), vascular smooth muscle cells (vSMCs), and mature dendritic cells (mDCs). A large number of inflammation-related pathways were present in the GSEA results. A large number of ICD-related pathways were found in the KEGG enrichment analysis of differentially expressed genes in endothelial cells. The number of mDCs and CTLs in the ATAA group was significantly different from that in the control group. A total of 44 pathway networks were obtained, of which 9 were associated with ICD in endothelial cells (CCL, CXCL, ANNEXIN, CD40, IL1, IL6, TNF, IFN-II, GALECTIN). The most important ligand−receptor pair by which endothelial cells act on CD4 T/NK cells, CTLs and mDCs is CXCL12-CXCR4. The most important ligand−receptor pair by which endothelial cells act on monocytes and macrophages is ANXA1-FPR1. The most important ligand−receptor pair by which CD4 T/NK cells and CTLs act on endothelial cells is CCL5-ACKR1. The most important ligand−receptor pair that myeloid cells (macrophages, monocytes and mDCs) act on endothelial cells is CXCL8-ACKR1. Moreover, vSMCs and fibroblasts mainly promote inflammatory responses through the MIF signaling pathway.ConclusionICD is present in ATAA and plays an important role in the development of ATAA. The target cells of ICD may be mainly endothelial cells, in which the aortic endothelial cell ACKR1 receptor can not only promote T-cell infiltration through the CCL5 ligand but also promote myeloid cell infiltration through the CXCL8 ligand. ACKR1 and CXCL12 may become target genes for ATAA drug therapy in the future.
Case Report: Interindividual variability and possible role of heterozygous variants in a family with deficiency of adenosine deaminase 2: are all heterozygous born equals?
Authors: Pulvirenti Federica , Cinicola Bianca Laura , Ferrari Simona , Guadagnolo Daniele , Sculco Eleonora , Capponi Martina , Loffredo Lorenzo , Sciannamea Maddalena , Insalaco Antonella , Quinti Isabella , De Benedetti Fabrizio , Zicari Anna Maria 
Published: May 2023

Deficiency of adenosine deaminase 2 (DADA2) is a rare systemic autoinflammatory disease, typically with autosomal recessive inheritance, usually caused by biallelic loss of function mutations in the ADA2 gene. The phenotypic spectrum is broad, generally including fever, early-onset vasculitis, stroke, and hematologic dysfunction. Heterozygous carriers may show related signs and symptoms, usually milder and at an older age. Here we describe the case of two relatives, the proband and his mother, bearing an ADA2 homozygous pathogenic variant, and a heterozygous son. The proband was a 17-year-old boy with intermittent fever, lymphadenopathies, and mild hypogammaglobulinemia. He also had sporadic episodes of aphthosis, livedo reticularis and abdominal pain. Hypogammaglobulinemia was documented when he was 10 years old, and symptoms appeared in his late adolescence. The mother demonstrated mild hypogammaglobulinemia, chronic pericarditis since she was 30 years old and two transient episodes of diplopia without lacunar lesions on MRI. ADA2 (NM_001282225.2) sequencing identified both mother and son as homozygous for the c.1358A&gt;G, p.(Tyr453Cys) variant. ADA2 activity in the proband and the mother was 80-fold lower than in the controls. Clinical features in both patients improved on anti-tumor necrosis factor therapy. An older son was found to be heterozygous for the same mutation post-mortem. He died at the age of 12 years due to a clinical picture of fever, lymphadenitis, skin rash and hypogammaglobulinemia evolving toward fatal multiorgan failure. Biopsies of skin, lymph nodes, and bone marrow excluded lymphomas and vasculitis. Despite being suspected of symptomatic carrier, the contribution of an additional variant in compound heterozygosity, or further genetic could not be ruled out, due to poor quality of DNA samples available. In conclusion, this familiar case demonstrated the wide range of phenotypic variability in DADA2. The search for ADA2 mutations and the assessment of ADA2 activity should be considered also in patients with the association of hypogammaglobulinemia and inflammatory conditions, also with late presentation and in absence of vasculitis. Furthermore, the clinical picture of the deceased carrier suggests a possible contribution of heterozygous pathogenic variants to inflammation.
Leptin deficiency in CD8+ T cells ameliorates non-segmental vitiligo by reducing interferon-γ and Granzyme B
Authors: Wu Meiyu , Wang Lu , Wu Haijing , Yang Ming , He Zhenghao , Chen Yiran , Zhang Huiming 
Published: May 2023

BackgroundVitiligo is an autoimmune skin disease mainly mediated by CD8+ T cells, which affects about 0.1%-2% population of the world. Leptin plays a critical role in regulating the activation of CD8+ T cells. However, the effect of Leptin on vitiligo remains unclear.ObjectivesTo explore the effect of leptin on CD8+ T cells and its influence on vitiligo.MethodsRNA sequencing and Quantitative Real-time PCR (RT-qPCR) were used to explore the differentially expressed genes. Immunofluorescence staining was performed on skin lesions. Leptin in serum was detected by enzyme linked immunosorbent assay (ELISA). The peripheral blood mononuclear cells were detected by flow cytometry after leptin stimulation for 72 hours. A vitiligo model was established by monobenzone on Leptin KO mice.Results557 differentially expressed genes were found, including 154 up-regulated and 403 down-regulated genes. Lipid metabolism pathways showed a close relationship to the pathogenesis of vitiligo, especially the PPAR signaling pathway. RT-qPCR (p = 0.013) and immunofluorescence staining (p = 0.0053) verified that LEPR expressed significantly higher in vitiligo. The serum leptin level of vitiligo patients was significantly lower than that of healthy controls (p = 0.0245). The interferon-γ subset of CD8+LEPR+ T cells from vitiligo patients was significantly higher (p = 0.0189). The protein level of interferon-γ was significantly increased after leptin stimulation in vitro (p = 0.0217). In mice, Leptin deficiency resulted in less severe hair depigmentation. Leptin deficiency also resulted in significantly lower expressed vitiligo-related genes, such as Cxcl9 (p = 0.0497), Gzmb (p &lt; 0.001), Ifng (p = 0.0159), and Mx1 (p &lt; 0.001) after modeling.ConclusionLeptin could promote the progression of vitiligo by enhancing the cytotoxic function of CD8+ T cells. Leptin may become a new target for vitiligo treatment.
Knowledge mapping of immune thrombocytopenia: a bibliometric study
Authors: Wu Feifeng , Li Cuifang , Mao Jueyi , Zhu Junquan , Wang Yang , Wen Chuan 
Published: May 2023

BackgroundImmune thrombocytopenia (ITP) is an autoimmune disease characterized by isolated thrombocytopenia. Recently, the pathophysiology and novel drugs of ITP have been the focus of researchers with plenty of publications emerging. Bibliometrics is the process of extracting measurable data through statistical analysis of published research studies to provide an insight into the trends and hotspots.ObjectiveThis study aimed to provide an insight into developing trends and hotspots in the field of ITP by bibliometric analysis.MethodsBy using three bibliometric mapping tools (bibliometrix R package, VOSviewer, CiteSpace), we summarized the overview information of retrieved publications, as well as the analysis of keyword co-occurrence and reference co-citation.ResultsA total of 3299 publications with 78066 citations on ITP research were included in the analysis. The keyword co-occurrence network identified 4 clusters relating to the diagnosis, pathophysiology, and treatment of ITP respectively. Then the reference co-citation analysis produced 12 clusters with a well-structured and highly credible clustering model, and they can be divided into 5 trends: second-line treatment, chronic ITP, novel therapy and pathogenesis, COVID-19 vaccine. Treg cells, spleen tyrosine kinase, and mesenchymal stem cells were the latest hotspots with strong burstness.ConclusionThis bibliometric analysis provided a comprehensive insight into research hotspots and trends on ITP, which would enrich the review of the ITP research.
Integrating machine learning and single-cell trajectories to analyze T-cell exhaustion to predict prognosis and immunotherapy in colon cancer patients
Authors: Shen Xiaogang , Zuo Xiaofei , Liang Liang , Wang Lin , Luo Bin 
Published: May 2023

IntroductionThe incidence of colon adenocarcinoma (COAD) has recently increased, and patients with advanced COAD have a poor prognosis due to treatment resistance. Combining conventional treatment with targeted therapy and immunotherapy has shown unexpectedly positive results in improving the prognosis of patients with COAD. More study is needed to determine the prognosis for patients with COAD and establish the appropriate course of treatment.MethodsThis study aimed to explore the trajectory of T-cell exhaustion in COAD to predict the overall survival and treatment outcome of COAD patients. Clinical data were derived from the TCGA-COAD cohort through "UCSC", as well as the whole genome data. Prognostic genes driving T-cell trajectory differentiation were identified on the basis of single-cell trajectories and univariate Cox regression. Subsequently, T-cell exhaustion score (TES) was created by iterative LASSO regression. The potential biological logic associated with TES was explored through functional analysis, immune microenvironment assessment, immunotherapy response prediction, and in vitro experiments.ResultsData showed that patients with significant TES had fewer favorable outcomes. Expression, proliferation, and invasion of COAD cells treated with TXK siRNA were also examined by cellular experiments. Both univariate and multivariate Cox regression indicated that TES was an independent prognostic factor in patients with COAD; in addition, subgroup analysis supported this finding. Functional assay revealed that immune response and cytotoxicity pathways are associated with TES, as the subgroup with low TES has an active immune microenvironment. Furthermore, patients with low TES responded better to chemotherapy and immunotherapy.ConclusionIn this study, we systematically explored the T-cell exhaustion trajectory in COAD and developed a TES model to assess prognosis and provide guidelines for the treatment decision. This discovery gave rise to a fresh concept for novel therapeutic procedures for the clinical treatment of COAD.
Clinically practical pharmacometrics computer model to evaluate and personalize pharmacotherapy in pediatric rare diseases: application to Graves' disease
Authors: Steffens Britta , Koch Gilbert , Gächter Pascal , Claude Fabien , Gotta Verena , Bachmann Freya , Schropp Johannes , Janner Marco , l'Allemand Dagmar , Konrad Daniel , Welzel Tatjana , Szinnai Gabor , Pfister Marc 
Published: May 2023

ObjectivesGraves' disease (GD) with onset in childhood or adolescence is a rare disease (ORPHA:525731). Current pharmacotherapeutic approaches use antithyroid drugs, such as carbimazole, as monotherapy or in combination with thyroxine hormone substitutes, such as levothyroxine, as block-and-replace therapy to normalize thyroid function and improve patients' quality of life. However, in the context of fluctuating disease activity, especially during puberty, a considerable proportion of pediatric patients with GD is suffering from thyroid hormone concentrations outside the therapeutic reference ranges. Our main goal was to develop a clinically practical pharmacometrics computer model that characterizes and predicts individual disease activity in children with various severity of GD under pharmacotherapy.MethodsRetrospectively collected clinical data from children and adolescents with GD under up to two years of treatment at four different pediatric hospitals in Switzerland were analyzed. Development of the pharmacometrics computer model is based on the non-linear mixed effects approach accounting for inter-individual variability and incorporating individual patient characteristics. Disease severity groups were defined based on free thyroxine (FT4) measurements at diagnosis.ResultsData from 44 children with GD (75% female, median age 11 years, 62% receiving monotherapy) were analyzed. FT4 measurements were collected in 13, 15, and 16 pediatric patients with mild, moderate, or severe GD, with a median FT4 at diagnosis of 59.9 pmol/l (IQR 48.4, 76.8), and a total of 494 FT4 measurements during a median follow-up of 1.89 years (IQR 1.69, 1.97). We observed no notable difference between severity groups in terms of patient characteristics, daily carbimazole starting doses, and patient years. The final pharmacometrics computer model was developed based on FT4 measurements and on carbimazole or on carbimazole and levothyroxine doses involving two clinically relevant covariate effects: age at diagnosis and disease severity.DiscussionWe present a tailored pharmacometrics computer model that is able to describe individual FT4 dynamics under both, carbimazole monotherapy and carbimazole/levothyroxine block-and-replace therapy accounting for inter-individual disease progression and treatment response in children and adolescents with GD. Such clinically practical and predictive computer model has the potential to facilitate and enhance personalized pharmacotherapy in pediatric GD, reducing over- and underdosing and avoiding negative short- and long-term consequences. Prospective randomized validation trials are warranted to further validate and fine-tune computer-supported personalized dosing in pediatric GD and other rare pediatric diseases.
Alteration of gastric microbiota and transcriptome in a rat with gastric intestinal metaplasia induced by deoxycholic acid
Authors: Xu Zijing , Xiao Ling , Wang Shuaishuai , Cheng Yuqin , Wu Jianping , Meng Yufen , Bao Kaifan , Zhang Junfeng , Cheng Chun 
Published: May 2023

ObjectiveBile reflux plays a key role in the development of gastric intestinal metaplasia (GIM), an independent risk factor of gastric cancer. Here, we aimed to explore the biological mechanism of GIM induced by bile reflux in a rat model.MethodsRats were treated with 2% sodium salicylate and allowed to freely drink 20 mmol/L sodium deoxycholate for 12 weeks, and GIM was confirmed by histopathological analysis. Gastric microbiota was profiled according to the 16S rDNA V3–V4 region, gastric transcriptome was sequenced, and serum bile acids (BAs) were analyzed by targeted metabolomics. Spearman's correlation analysis was used in constructing the network among gastric microbiota, serum BAs, and gene profiles. Real-time polymerase chain reaction (RT-PCR) measured the expression levels of nine genes in the gastric transcriptome.ResultsIn the stomach, deoxycholic acid (DCA) decreased the microbial diversity but promoted the abundances of several bacterial genera, such as Limosilactobacillus, Burkholderia–Caballeronia–Paraburkholderia, and Rikenellaceae RC9 gut group. Gastric transcriptome showed that the genes enriched in gastric acid secretion were significantly downregulated, whereas the genes enriched in fat digestion and absorption were obviously upregulated in GIM rats. The GIM rats had four promoted serum BAs, namely cholic acid (CA), DCA, taurocholic acid, and taurodeoxycholic acid. Further correlation analysis showed that the Rikenellaceae RC9 gut group was significantly positively correlated with DCA and RGD1311575 (capping protein-inhibiting regulator of actin dynamics), and RGD1311575 was positively correlated with Fabp1 (fatty acid-binding protein, liver), a key gene involved in fat digestion and absorption. Finally, the upregulated expression of Dgat1 (diacylglycerol acyltransferase 1) and Fabp1 related to fat digestion and absorption was identified by RT-PCR and IHC.ConclusionDCA-induced GIM enhanced gastric fat digestion and absorption function and impaired gastric acid secretion function. The DCA–Rikenellaceae RC9 gut group–RGD1311575/Fabp1 axis might play a key role in the mechanism of bile reflux-related GIM.