Splicing is functionally coupled to transcription, linking the rate of RNA polymerase II (Pol II) elongation and the ability of splicing factors to recognize splice sites (ss) of various strengths. ...In most cases, slow Pol II elongation allows weak splice sites to be recognized, leading to higher inclusion of alternative exons. Using CFTR alternative exon 9 (E9) as a model, we show here that slowing down elongation can also cause exon skipping by promoting the recruitment of the negative factor ETR-3 onto the UG-repeat at E9 3′ splice site, which displaces the constitutive splicing factor U2AF65 from the overlapping polypyrimidine tract. Weakening of E9 5′ ss increases ETR-3 binding at the 3′ ss and subsequent E9 skipping, whereas strengthening of the 5′ ss usage has the opposite effect. This indicates that a delay in the cotranscriptional emergence of the 5′ ss promotes ETR-3 recruitment and subsequent inhibition of E9 inclusion.
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•Alternative splicing is coupled to transcriptional elongation•Slow elongation either up- or downregulates exon inclusion depending on the exon•In CFTR exon 9, slow elongation favors recruiting the negative splicing factor ETR3•Delaying transcription of exon 9 5′ ss favors ETR-3 binding and exon 9 skipping
Splicing takes place cotranscriptionally and is coupled to transcription. Many alternative splicing decisions depend on the rate RNA Pol II elongation. Although the prevailing paradigm indicates that slow elongation promotes exon inclusion, Dujardin et al. describe a mechanism explaining why, in some exons, slow elongation has the opposite effect.
Recent international literature has demonstrated that the public stigma suffered by women victims of intimate partner violence (IPV) makes them less likely to disclose the abuse and to seek help and ...has a negative influence on third-party responses, with professionals working in the judicial system and law enforcement agencies being particularly susceptible to its impact. The absence of theories explaining how this stigma works and the legal and cultural differences that exist between countries prompted us to explore the process by which professionals working in law enforcement and the judicial system in Spain stigmatize this specific group of victims. Constructivist grounded theory was used to establish meanings and relationships between the components and processes involved in stigmatization, based on the data collected from individual, semi-structured, in-depth interviews with 11 professionals working in the aforementioned fields. In addition to the stigmatization that the interviewees claimed to have observed in coworkers, we also analyzed the conscious and/or unconscious stigmatization that they themselves exercised, which became evident during the course of the interview. The results confirmed the existence of stigma among professionals, with the said stigma often being unintentional and implicit in nature. The theoretical model that emerged from the data comprised four broad categories linked to the origin of the stigma, stigmatizing myths about victims and IPV, stigmatizing responses to victims who are seeking help, and the consequences of the stigma for the victims. In the study, we outline the associations observed between these factors and the subcategories included in each, and highlight the need to design training programs for professionals who are designed to fight against the stigma and which include self-analysis exercises as well as theoretical contents. We also discuss other implications of the results for both research and practice.
MicroRNAs (miRNAs) regulate target mRNAs by silencing them. Reciprocally, however, target mRNAs can also modulate miRNA stability. Here, we uncover a remarkable efficacy of target RNA‐directed miRNA ...degradation (TDMD) in rodent primary neurons. Coincident with degradation, and while still bound to Argonaute, targeted miRNAs are 3′ terminally tailed and trimmed. Absolute quantification of both miRNAs and their decay‐inducing targets suggests that neuronal TDMD is multiple turnover and does not involve co‐degradation of the target but rather competes with miRNA‐mediated decay of the target. Moreover, mRNA silencing, but not TDMD, relies on cooperativity among multiple target sites to reach high efficacy. This knowledge can be harnessed for effective depletion of abundant miRNAs. Our findings bring insight into a potent miRNA degradation pathway in primary neurons, whose TDMD activity greatly surpasses that of non‐neuronal cells and established cell lines. Thus, TDMD may be particularly relevant for miRNA regulation in the nervous system.
Synopsis
This quantitative study of target‐directed miRNA degradation (TDMD) reveals its potency in primary neurons and distinguishes TDMD and mRNA degradation as independent processes, the balance of which can be tilted toward depletion of even abundant miRNAs by appropriate target design.
Target‐induced non‐templated nucleotide addition (tailing) occurs on miRNAs, while they are bound to Argonaute.
TDMD and mRNA silencing are independent processes, permitting one target to induce degradation of several miRNA molecules.
mRNA silencing, but not TDMD, requires cooperativity among multiple target sites to reach high efficiency.
This quantitative study of target‐directed miRNA degradation (TDMD) reveals its potency in primary neurons and distinguishes TDMD and mRNA degradation as independent processes, the balance of which can be tilted toward depletion of even abundant miRNAs by appropriate target design.
Severe mental illnesses (SMI) in general, and schizophrenia in particular, have been characterized as alterations of the experience of self and identity. When first diagnosed with SMI, the subjective ...experiences and specific narrative challenges faced by this population are particularly important. Therefore, qualitative approaches which allow to analyze these subjective experiences should be developed. This article presents in detail a specific method, called Social Positioning Analysis, which makes the complexity of narratives and life stories with multiple turning points understandable. To develop this methodological proposal, it has been taken into account the performative aspects of social interaction in which narratives are constructed. The methodology has previously been used in other health contexts and is innovative in the field of mental health. Linguistic criteria, definitions, and multiple examples are included to facilitate its application, as well as some reflections about its potential and possible benefits.
Abstract
Context
Nonalcoholic fatty liver disease (NAFLD) is a common obesity-associated pathology characterized by hepatic fat accumulation, which can progress to fibrosis, cirrhosis, and ...hepatocellular carcinoma. Obesity is associated with profound changes in gene-expression patterns of the liver, which could contribute to the onset of comorbidities.
Objective
As these alterations might be linked to a dysregulation of the splicing process, we aimed to determine whether the dysregulation in the expression of splicing machinery components could be associated with NAFLD.
Participants
We collected 41 liver biopsies from nonalcoholic individuals with obesity, with or without hepatic steatosis, who underwent bariatric surgery.
Interventions
The expression pattern of splicing machinery components was determined using a microfluidic quantitative PCR-based array. An in vitro approximation to determine lipid accumulation using HepG2 cells was also implemented.
Results
The liver of patients with obesity and steatosis exhibited a severe dysregulation of certain splicing machinery components compared with patients with obesity without steatosis. Nonsupervised clustering analysis allowed the identification of three molecular phenotypes of NAFLD with a unique fingerprint of alterations in splicing machinery components, which also presented distinctive hepatic and clinical-metabolic alterations and a differential response to bariatric surgery after 1 year. In addition, in vitro silencing of certain splicing machinery components (i.e., PTBP1, RBM45, SND1) reduced fat accumulation and modulated the expression of key de novo lipogenesis enzymes, whereas conversely, fat accumulation did not alter spliceosome components expression.
Conclusion
There is a close relationship between splicing machinery dysregulation and NAFLD development, which should be further investigated to identify alternative therapeutic targets.
Dysregulations of the splicing machinery precede the development of steatosis and define different molecular phenotypes of nonalcoholic fatty liver disease (NAFLD). This study provides information to explore strategies for NAFLD.
Migration can be understood as a breach in life experience, creating a transition, and identity narratives as a strategy to repair this breach. Our study focuses on how two classical dilemmas that ...characterize this process are navigated in the narrative of migration of the participant (An Ecuadorian migrant woman in Andalusia): self versus others, and continuity of the self over time, despite changes. A semi-structured interview was conducted to achieve the objectives of the study. The interview was transcribed and analyzed on three axes: 1) Migration settings, identifying the dominant spaces of interaction where the migration narrative takes place; 2) Migration I-positions and voices, identifying the I-positions and voices involved in the narrative; and 3) Continuities and discontinuities in the identity narrative. The results demonstrated that the main settings and positions in the narrative were related to nationality, gender, and religion in relation to the dilemmas of self versus others and continuity versus change. These positions help the participant negotiate self-continuity in front of the changes associated with migration and the resistance against xenophobic discourses and positions in the host country. Results support the analysis of the transition processes associated to migration based on the concept of proculturation.
This article develops a theoretical approach to the study of identity narratives from the concept of the bordering process. The first section describes the theoretical concepts that sustain the ...proposal, in particular, the concept of border as a mediating artifact, the theoretical concept of the bordering process as a social practice, and finally, identity narratives and the dialogical perspective of the self. The second section analyzes the proposals and limitations of some studies on identity narratives in international borderlands. In the same section, we develop our theoretical proposal for studying border identity narratives, which attempts to overcome some limitations of previous studies and respond to the debate on the role of others in the construction of the self. We conclude that the inclusion of the border as a semiotic artifact and the bordering process in the construction of the self provide a new perspective of identity narratives as border narratives for the study of border experiences throughout human development.
Abstract
A subset of circular RNAs (circRNAs) and linear RNAs have been proposed to ‘sponge’ or block microRNA activity. Additionally, certain RNAs induce microRNA destruction through the process of ...Target RNA-Directed MicroRNA Degradation (TDMD), but whether both linear and circular transcripts are equivalent in driving TDMD is unknown. Here, we studied whether circular/linear topology of endogenous and artificial RNA targets affects TDMD. Consistent with previous knowledge that Cdr1as (ciRS-7) circular RNA protects miR-7 from Cyrano-mediated TDMD, we demonstrate that depletion of Cdr1as reduces miR-7 abundance. In contrast, overexpression of an artificial linear version of Cdr1as drives miR-7 degradation. Using plasmids that express a circRNA with minimal co-expressed cognate linear RNA, we show differential effects on TDMD that cannot be attributed to the nucleotide sequence, as the TDMD properties of a sequence often differ when in a circular versus linear form. By analysing RNA sequencing data of a neuron differentiation system, we further detect potential effects of circRNAs on microRNA stability. Our results support the view that RNA circularity influences TDMD, either enhancing or inhibiting it on specific microRNAs.
Graphical Abstract
Graphical Abstract
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and occurs mainly in patients with liver cirrhosis. The mammalian target of rapamycin (mTOR) signaling pathway is involved in ...many hallmarks of cancer including cell growth, metabolism re-programming, proliferation and inhibition of apoptosis. The mTOR pathway is upregulated in HCC tissue samples as compared with the surrounding liver cirrhotic tissue. In addition, the activation of mTOR is more intense in the tumor edge, thus reinforcing its role in HCC proliferation and spreading. The inhibition of the mTOR pathway by currently available pharmacological compounds (i.e., sirolimus or everolimus) is able to hamper tumor progression both in vitro and in animal models. The use of mTOR inhibitors alone or in combination with other therapies is a very attractive approach, which has been extensively investigated in humans. However, results are contradictory and there is no solid evidence suggesting a true benefit in clinical practice. As a result, neither sirolimus nor everolimus are currently approved to treat HCC or to prevent tumor recurrence after curative surgery. In the present comprehensive review, we analyzed the most recent scientific evidence while providing some insights to understand the gap between experimental and clinical studies.
The COVID-19 pandemic created a unique set of circumstances in which to investigate collective memory and future simulations of events reported during the onset of a potentially historic event. ...Between early April and late June 2020, we asked over 4,000 individuals from 15 countries across four continents to report on remarkable (a) national and (b) global events that (i) had happened since the first cases of COVID-19 were reported, and (ii) they expected to happen in the future. Whereas themes of infections, lockdown, and politics dominated global and national past events in most countries, themes of economy, a second wave, and lockdown dominated future events. The themes and phenomenological characteristics of the events differed based on contextual group factors. First, across all conditions, the event themes differed to a small yet significant degree depending on the severity of the pandemic and stringency of governmental response at the national level. Second, participants reported national events as less negative and more vivid than global events, and group differences in emotional valence were largest for future events. This research demonstrates that even during the early stages of the pandemic, themes relating to its onset and course were shared across many countries, thus providing preliminary evidence for the emergence of collective memories of this event as it was occurring. Current findings provide a profile of past and future collective events from the early stages of the ongoing pandemic, and factors accounting for the consistencies and differences in event representations across 15 countries are discussed.
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