Circr, a Computational Tool to Identify miRNA:circRNA Associations

Circular RNAs (circRNAs) are known to act as important regulators of the microRNA (miRNA) activity. Yet, computational resources to identify miRNA:circRNA interactions are mostly limited to already annotated circRNAs or affected by high rates of false positive predictions. To overcome these limitations, we developed Circr, a computational tool for the prediction of associations between circRNAs and miRNAs. Circr combines three publicly available algorithms for de novo prediction of miRNA binding sites on target sequences (miRanda, RNAhybrid, and TargetScan) and annotates each identified miRNA:target pairs with experimentally validated miRNA:RNA interactions and binding sites for Argonaute proteins derived from either ChIPseq or CLIPseq data. The combination of multiple tools for the identification of a single miRNA recognition site with experimental data allows to efficiently prioritize candidate miRNA:circRNA interactions for functional studies in different organisms. Circr can use its internal annotation database or custom annotation tables to enhance the identification of novel and not previously annotated miRNA:circRNA sites in virtually any species. Circr is written in Python 3.6 and is released under the GNU GPL3.0 License at https://github.com/bicciatolab/Circr

Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory

Metastasis arises from disseminated tumour cells (DTCs) that are characterized by intrinsic phenotypic plasticity and the capability of seeding to secondary organs. DTCs can remain latent for years before giving rise to symptomatic overt metastasis. In this context, DTCs fluctuate between a quiescent and proliferative state in response to systemic and microenvironmental signals including immune-mediated surveillance. Despite its relevance, how intrinsic mechanisms sustain DTCs plasticity has not been addressed. By interrogating the epigenetic state of metastatic cells, we find that tumour progression is coupled with the activation of oncogenic enhancers that are organized in variable interconnected chromatin domains. This spatial chromatin context leads to the activation of a robust transcriptional response upon repeated exposure to retinoic acid (RA). We show that this adaptive mechanism sustains the quiescence of DTCs through the activation of the master regulator SOX9. Finally, we determine that RA-stimulated transcriptional memory increases the fitness of metastatic cells by supporting the escape of quiescent DTCs from NK-mediated immune surveillance. Overall, these findings highlight the contribution of oncogenic enhancers in establishing transcriptional memories as an adaptive mechanism to reinforce cancer dormancy and immune escape, thus amenable for therapeutic intervention

RESCUE OF HIPPO CO-ACTIVATOR YAP1 TRIGGERS DNA DAMAGE-INDUCED APOPTOSIS IN HEMATOLOGICAL CANCERS

Oncogene–induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53–independent, pro-apoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway co–activator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1–induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine–threonine kinase, STK4. Importantly, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a novel synthetic–lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels

Upregulation of α7 Nicotinic Receptors by Acetylcholinesterase C-Terminal Peptides

BACKGROUND: The alpha-7 nicotinic acetylcholine receptor (alpha7-nAChR) is well known as a potent calcium ionophore that, in the brain, has been implicated in excitotoxicity and hence in the underlying mechanisms of neurodegenerative disorders such as Alzheimer's disease. Previous research implied that the activity of this receptor may be modified by exposure to a peptide fragment derived from the C-terminal region of the enzyme acetylcholinesterase. This investigation was undertaken to determine if the functional changes observed could be attributed to peptide binding interaction with the alpha7-nAChR, or peptide modulation of receptor expression. METHODOLOGY/PRINCIPAL FINDINGS: This study provides evidence that two peptides derived from the C-terminus of acetylcholinesterase, not only selectively displace specific bungarotoxin binding at the alpha7-nAChR, but also alter receptor binding properties for its familiar ligands, including the alternative endogenous agonist choline. Of more long-term significance, these peptides also induce upregulation of alpha7-nAChR mRNA and protein expression, as well as enhancing receptor trafficking to the plasma membrane. CONCLUSIONS/SIGNIFICANCE: The results reported here demonstrate a hitherto unknown relationship between the alpha7-nAChR and the non-enzymatic functions of acetylcholinesterase, mediated independently by its C-terminal domain. Such an interaction may prove valuable as a pharmacological tool, prompting new approaches for understanding, and combating, the process of neurodegeneration

Upregulation of α7 Nicotinic Receptors by Acetylcholinesterase C-Terminal Peptides

BACKGROUND: The alpha-7 nicotinic acetylcholine receptor (alpha7-nAChR) is well known as a potent calcium ionophore that, in the brain, has been implicated in excitotoxicity and hence in the underlying mechanisms of neurodegenerative disorders such as Alzheimer's disease. Previous research implied that the activity of this receptor may be modified by exposure to a peptide fragment derived from the C-terminal region of the enzyme acetylcholinesterase. This investigation was undertaken to determine if the functional changes observed could be attributed to peptide binding interaction with the alpha7-nAChR, or peptide modulation of receptor expression. METHODOLOGY/PRINCIPAL FINDINGS: This study provides evidence that two peptides derived from the C-terminus of acetylcholinesterase, not only selectively displace specific bungarotoxin binding at the alpha7-nAChR, but also alter receptor binding properties for its familiar ligands, including the alternative endogenous agonist choline. Of more long-term significance, these peptides also induce upregulation of alpha7-nAChR mRNA and protein expression, as well as enhancing receptor trafficking to the plasma membrane. CONCLUSIONS/SIGNIFICANCE: The results reported here demonstrate a hitherto unknown relationship between the alpha7-nAChR and the non-enzymatic functions of acetylcholinesterase, mediated independently by its C-terminal domain. Such an interaction may prove valuable as a pharmacological tool, prompting new approaches for understanding, and combating, the process of neurodegeneration

Unpublished Mediterranean and Black Sea records of marine alien, cryptogenic, and neonative species

To enrich spatio-temporal information on the distribution of alien, cryptogenic, and neonative species in the Mediterranean and the Black Sea, a collective effort by 173 marine scientists was made to provide unpublished records and make them open access to the scientific community. Through this effort, we collected and harmonized a dataset of 12,649 records. It includes 247 taxa, of which 217 are Animalia, 25 Plantae and 5 Chromista, from 23 countries surrounding the Mediterranean and the Black Sea. Chordata was the most abundant taxonomic group, followed by Arthropoda, Mollusca, and Annelida. In terms of species records, Siganus luridus, Siganus rivulatus, Saurida lessepsianus, Pterois miles, Upeneus moluccensis, Charybdis (Archias) longicollis, and Caulerpa cylindracea were the most numerous. The temporal distribution of the records ranges from 1973 to 2022, with 44% of the records in 2020–2021. Lethrinus borbonicus is reported for the first time in the Mediterranean Sea, while Pomatoschistus quagga, Caulerpa cylindracea, Grateloupia turuturu, and Misophria pallida are first records for the Black Sea; Kapraunia schneideri is recorded for the second time in the Mediterranean and for the first time in Israel; Prionospio depauperata and Pseudonereis anomala are reported for the first time from the Sea of Marmara. Many first country records are also included, namely: Amathia verticillata (Montenegro), Ampithoe valida (Italy), Antithamnion amphigeneum (Greece), Clavelina oblonga (Tunisia and Slovenia), Dendostrea cf. folium (Syria), Epinephelus fasciatus (Tunisia), Ganonema farinosum (Montenegro), Macrorhynchia philippina (Tunisia), Marenzelleria neglecta (Romania), Paratapes textilis (Tunisia), and Botrylloides diegensis (Tunisia).peer-reviewe

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Integration of Bioinformatic Predictions and Experimental Data to Identify circRNA-miRNA Associations

Circular RNAs (circRNAs) have recently emerged as a novel class of transcripts, characterized by covalently linked 3′–5′ ends that result in the so-called backsplice junction. During the last few years, thousands of circRNAs have been identified in different organisms. Yet, despite their role as disease biomarker started to emerge, depicting their function remains challenging. Different studies have shown that certain circRNAs act as miRNA sponges, but any attempt to generalize from the single case to the “circ-ome” has failed so far. In this review, we explore the potential to define miRNA “sponging” as a more general function of circRNAs and describe the different approaches to predict miRNA response elements (MREs) in known or novel circRNA sequences. Moreover, we discuss how experiments based on Ago2-IP and experimentally validated miRNA:target duplexes can be used to either prioritize or validate putative miRNA-circRNA associations

EphB6 Regulates TFEB-Lysosomal Pathway and Survival of Disseminated Indolent Breast Cancer Cells

Late relapse of disseminated cancer cells is a common feature of breast and prostate tumors. Several intrinsic and extrinsic factors have been shown to affect quiescence and reawakening of disseminated dormant cancer cells (DDCCs); however, the signals and processes sustaining the survival of DDCCs in a foreign environment are still poorly understood. We have recently shown that crosstalk with lung epithelial cells promotes survival of DDCCs of estrogen receptor-positive (ER+) breast tumors. By using a lung organotypic system and in vivo dissemination assays, here we show that the TFEB-lysosomal axis is activated in DDCCs and that it is modulated by the pro-survival ephrin receptor EphB6. TFEB lysosomal direct targets are enriched in DDCCs in vivo and correlate with relapse in ER+ breast cancer patients. Direct coculture of DDCCs with alveolar type I-like lung epithelial cells and dissemination in the lung drive lysosomal accumulation and EphB6 induction. EphB6 contributes to survival, TFEB transcriptional activity, and lysosome formation in DDCCs in vitro and in vivo. Furthermore, signaling from EphB6 promotes the proliferation of surrounding lung parenchymal cells in vivo. Our data provide evidence that EphB6 is a key factor in the crosstalk between disseminated dormant cancer cells and the lung parenchyma and that the TFEB-lysosomal pathway plays an important role in the persistence of DDCCs