The syntax of peripheral adverbial clauses

This paper explores the relation between the interpretations of while in English and mentre in Italian introducing adverbial clauses. Central while/mentre clauses express a temporal/aspectual modification of the proposition in the host clause. Peripheral while/mentre clauses make accessible a proposition from the discourse context enhancing the relevance of the host proposition. In one approach, clauses introduced by adversative while/mentre are analyzed as ‘less integrated’ with the associated clause than those introduced by temporal while/mentre. In another approach, adverbial clauses introduced by adversative while/mentre are considered not syntactically integrated with the host clause. This paper re-examines the nature of the syntactic integration of the adverbial clauses with the host clause, revealing a parallelism between the adversative peripheral while/mentre clauses and speaker-related sentential adverbs, leading to the conclusion that the non-integration analysis is not appropriate for this type of peripheral clauses and that any analysis must be aligned with that of the relevant non-clausal adverbials, supporting Frey (2018, 2020a, b). We also argue that central adverbial clauses recycled as speech event modifiers must be considered non-integrated. Concretely, we propose that they are integrated in discourse, through a specialized layer FrameP (Haegeman & Greco 2018).

Omics Approaches to Assess Flavor Development in Cheese

Cheese is characterized by a rich and complex microbiota that plays a vital role during both production and ripening, contributing significantly to the safety, quality, and sensory characteristics of the final product. In this context, it is vital to explore the microbiota composition and understand its dynamics and evolution during cheese manufacturing and ripening. Application of high-throughput DNA sequencing technologies have facilitated the more accurate identification of the cheese microbiome, detailed study of its potential functionality, and its contribution to the development of specific organoleptic properties. These technologies include amplicon sequencing, whole-metagenome shotgun sequencing, metatranscriptomics, and, most recently, metabolomics. In recent years, however, the application of multiple meta-omics approaches along with data integration analysis, which was enabled by advanced computational and bioinformatics tools, paved the way to better comprehension of the cheese ripening process, revealing significant associations between the cheese microbiota and metabolites, as well as their impact on cheese flavor and quality.

Integration Analysis of Pharmacokinetics and Metabolomics to Predict Metabolic Phenotype and Drug Exposure of Remdesivir

Remdesivir has displayed pharmacological activity against SARS-CoV-2. However, no pharmacometabolomics (PM) or correlation analysis with pharmacokinetics (PK) was revealed. Rats were intravenously administered remdesivir, and a series of blood samples were collected before and after treatment. Comprehensive metabolomics profile and PK were investigated and quantitated simultaneously using our previous reliable HPLC-MS/MS method. Both longitudinal and transversal metabolic analyses were conducted, and the correlation between PM and PK parameters was evaluated using Pearson’s correlation analysis and the PLS model. Multivariate statistical analysis was employed for discovering candidate biomarkers which predicted drug exposure or toxicity of remdesivir. The prominent metabolic profile variation was observed between pre- and posttreatment, and significant changes were found in 65 metabolites. A total of 15 metabolites—12 carnitines, one N-acetyl-D-glucosamine, one allantoin, and one corticosterone—were significantly correlated with the concentration of Nuc (active metabolite of remdesivir). Adenosine, spermine, guanosine, sn-glycero-3-phosphocholine, and l-homoserine may be considered potential biomarkers for predicting drug exposure or toxicity. This study is the first attempt to apply PM and PK to study remdesivir response/toxicity, and the identified candidate biomarkers might be used to predict the AUC and Cmax, indicating capability of discriminating good or poor responders. Currently, this study originally offers considerable evidence to metabolite reprogramming of remdesivir and sheds light on precision therapy development in fighting COVID-19.

GDS: A Genomic Database for Strawberries (Fragaria spp.)

Strawberry species (Fragaria spp.) are known as the “queen of fruits” and are cultivated around the world. Over the past few years, eight strawberry genome sequences have been released. The reuse of these large amount of genomic data, and the more large-scale comparative analyses are very challenging to both plant biologists and strawberry breeders. To promote the reuse and exploration of strawberry genomic data and enable extensive analyses using various bioinformatics tools, we have developed the Genome Database for Strawberry (GDS). This platform integrates the genome collection, storage, integration, analysis, and dissemination of large amounts of data for researchers engaged in the study of strawberry. We collected and formatted the eight published strawberry genomes. We constructed the GDS based on Linux, Apache, PHP and MySQL. Different bioinformatic software were integrated. The GDS contains data from eight strawberry species, as well as multiple tools such as BLAST, JBrowse, synteny analysis, and gene search. It has a designed interface and user-friendly tools that perform a variety of query tasks with a few simple operations. In the future, we hope that the GDS will serve as a community resource for the study of strawberries.

Impact of Institutions and Human Capital on CO2 Emissions in EU Transition Economies

Environmental degradation is one of the most significant problems of the globalized world. This paper explores the impact of institutional development and human capital on CO2 emissions in 11 EU transition economies over the period of 2000–2018 through co-integration analysis. The co-integration analysis revealed that human capital negatively affected CO2 emissions in Croatia, the Czech Republic, Hungary, and Slovenia, and that institutions had a negative impact on CO2 emissions in the Czech Republic. However, both institutions and human capital positively affected CO2 emissions in Latvia and Lithuania.

Diverse tumorigenic consequences of human papillomavirus integration in primary oropharyngeal cancers

Human papillomavirus (HPV) causes 5% of all cancers and frequently integrates into host chromosomes. The HPV oncoproteins E6 and E7 are necessary but insufficient for cancer formation, indicating that additional secondary genetic events are required. Here, we investigate potential oncogenic impacts of virus integration. Analysis of 105 HPV-positive oropharyngeal cancers by whole-genome sequencing detects virus integration in 77%, revealing five statistically significant sites of recurrent integration near genes that regulate epithelial stem cell maintenance (i.e., SOX2, TP63, FGFR, MYC) and immune evasion (i.e., CD274). Genomic copy number hyperamplification is enriched 16-fold near HPV integrants, and the extent of focal host genomic instability increases with their local density. The frequency of genes expressed at extreme outlier levels is increased 86-fold within ±150 kb of integrants. Across 95% of tumors with integration, host gene transcription is disrupted via intragenic integrants, chimeric transcription, outlier expression, gene breaking, and/or de novo expression of noncoding or imprinted genes. We conclude that virus integration can contribute to carcinogenesis in a large majority of HPV-positive oropharyngeal cancers by inducing extensive disruption of host genome structure and gene expression.

Single-Cell Integration Analysis of Heterotopic Ossification and Fibrocartilage Developmental Lineage: Endoplasmic Reticulum Stress Effector Xbp1 Transcriptionally Regulates the Notch Signaling Pathway to Mediate Fibrocartilage Differentiation

Introduction. Regeneration of fibrochondrocytes is essential for the healing of the tendon-bone interface (TBI), which is similar to the formation of neurogenic heterotopic ossification (HO). Through single-cell integrative analysis, this study explored the homogeneity of HO cells and fibrochondrocytes. Methods. This study integrated six datasets, namely, GSE94683, GSE144306, GSE168153, GSE138515, GSE102929, and GSE110993. The differentiation trajectory and key transcription factors (TFs) for HO occurrence were systematically analyzed by integrating single-cell RNA (scRNA) sequencing, bulk RNA sequencing, and assay of transposase accessible chromatin seq. The differential expression and enrichment pathways of TFs in heterotopically ossified tissues were identified. Results. HO that mimicked pathological cells was classified into HO1 and HO2 cell subsets. Results of the pseudo-temporal sequence analysis suggested that HO2 is a differentiated precursor cell of HO1. The analysis of integrated scRNA data revealed that ectopically ossified cells have similar transcriptional characteristics to cells in the fibrocartilaginous zone of tendons. The modified SCENIC method was used to identify specific transcriptional regulators associated with ectopic ossification. Xbp1 was defined as a common key transcriptional regulator of ectopically ossified tissues and the fibrocartilaginous zone of tendons. Subsequently, the CellPhoneDB database was completed for the cellular ligand-receptor analysis. With further pathway screening, this study is the first to propose that Xbp1 may upregulate the Notch signaling pathway through Jag1 transcription. Twenty-four microRNAs were screened and were found to be potentially associated with upregulation of XBP1 expression after acute ischemic stroke. Conclusion. A systematic analysis of the differentiation landscape and cellular homogeneity facilitated a molecular understanding of the phenotypic similarities between cells in the fibrocartilaginous region of tendon and HO cells. Furthermore, by identifying Xbp1 as a hub regulator and by conducting a ligand–receptor analysis, we propose a potential Xbp1/Jag1/Notch signaling pathway.