Expanding uncapped translation and emerging function of circular RNA in carcinomas and noncarcinomas

Circular RNAs (circRNAs) are classified as noncoding RNAs because they are devoid of a 5’ end cap and a 3’ end poly (A) tail necessary for cap-dependent translation. However, increasing numbers of translated circRNAs identified through high-throughput RNA sequencing overlapping with polysome profiling indicate that this rule is being broken. CircRNAs can be translated in cap-independent mechanism, including IRES (internal ribosome entry site)-initiated pattern, MIRES (m6A internal ribosome entry site) -initiated patterns, and rolling translation mechanism (RCA). CircRNA-encoded proteins harbour diverse functions similar to or different from host proteins. In addition, they are linked to the modulation of human disease including carcinomas and noncarcinomas. CircRNA-related translatomics and proteomics have attracted increasing attention. This review discusses the progress and exclusive characteristics of circRNA translation and highlights the latest mechanisms and regulation of circRNA translatomics. Furthermore, we summarize the extensive functions and mechanisms of circRNA-derived proteins in human diseases, which contribute to a better understanding of intricate noncanonical circRNA translatomics and proteomics and their therapeutic potential in human diseases.

A DAP5/eIF3d alternate mRNA translation mechanism promotes differentiation and immune suppression by human regulatory T cells

Regulatory T cells (Treg cells) inhibit effector T cells and maintain immune system homeostasis. Treg cell maturation in peripheral sites requires inhibition of protein kinase mTORC1 and TGF-beta-1 (TGF-beta). While Treg cell maturation requires protein synthesis, mTORC1 inhibition downregulates it, leaving unanswered how Treg cells achieve essential mRNA translation for development and immune suppression activity. Using human CD4+ T cells differentiated in culture and genome-wide transcription and translation profiling, here we report that TGF-beta transcriptionally reprograms naive T cells to express Treg cell differentiation and immune suppression mRNAs, while mTORC1 inhibition impairs translation of T cell mRNAs but not those induced by TGF-beta. Rather than canonical mTORC1/eIF4E/eIF4G translation, Treg cell mRNAs utilize the eIF4G homolog DAP5 and initiation factor eIF3d in a non-canonical translation mechanism that requires cap-dependent binding by eIF3d directed by Treg cell mRNA 5’ noncoding regions. Silencing DAP5 in isolated human naive CD4+ T cells impairs their differentiation into Treg cells. Treg cell differentiation is mediated by mTORC1 downregulation and TGF-beta transcriptional reprogramming that establishes a DAP5/eIF3d-selective mechanism of mRNA translation.

Circular RNAs’ cap-independent translation protein and its roles in carcinomas

Circular RNAs a kind of covalently closed RNA and widely expressed in eukaryotes. CircRNAs are involved in a variety of physiological and pathological processes, but their regulatory mechanisms are not fully understood. Given the development of the RNA deep-sequencing technology and the improvement of algorithms, some CircRNAs are discovered to encode proteins through the cap-independent mechanism and participate in the important process of tumorigenesis and development. Based on an overview of CircRNAs, this paper summarizes its translation mechanism and research methods, and reviews the research progress of CircRNAs translation in the field of oncology in recent years. Moreover, this paper aims to provide new ideas for tumor diagnosis and treatment through CircRNAs translation.

The Downregulation of eIF3a Contributes to Vemurafenib Resistance in Melanoma by Activating ERK via PPP2R1B

Vemurafenib, a BRAF V600E inhibitor, provides therapeutic benefits for patients with melanoma, but the frequent emergence of drug resistance remains a challenge. An understanding of the mechanisms underlying vemurafenib resistance may generate novel therapeutic strategies for patients with melanoma. Here, we showed that eIF3a, a translational regulatory protein, was an important mediator involved in vemurafenib resistance. eIF3a was expressed at significantly lower levels in vemurafenib-resistant A375 melanoma cells (A375R) than in parental A375 cells. Overexpression of eIF3a enhanced the sensitivity to BRAF inhibitors by reducing p-ERK levels. Furthermore, eIF3a controlled ERK activity by regulating the expression of the phosphatase PPP2R1B via a translation mechanism, thus determining the sensitivity of melanoma cells to vemurafenib. In addition, a positive correlation between eIF3a and PPP2R1B expression was also observed in tumor samples from the Human Protein Atlas and TCGA databases. In conclusion, our studies reveal a previously unknown molecular mechanism of BRAF inhibitor resistance, which may provide a new strategy for predicting vemurafenib responses in clinical treatment.

Construction of innovation and entrepreneurship teaching scene under the background of numeral intelligence: Based on the theory of actor-network

With the continuous deepening of innovation and entrepreneurship education, innovation and entrepreneurship education is faced with the problem of upgrading. The construction of the innovation and entrepreneurship teaching scene is the key to solving “teaching and learning” in the process of upgrading. Based on the translation mechanism of actor-network theory, this paper probes into the three paths of “structure scene, classroom teaching scene and learning mode” to construct the teaching scene of innovation and entrepreneurship, which is a new path to explore the innovation and reform of innovation and entrepreneurship teaching by integrating numeral intelligence technology.

TPGen: Prescription Generation Using Knowledge-guided Translator

Background: Prescriptions contain a lot of clinical information and play a pivotal role in the clinical diagnosis of Traditional Chinese Medicine (TCM), which is a combination of herb to treat the symptoms of a patient from decision-making of doctors. In the process of clinical decision-making, a large number of prescriptions have been invented and accumulated based on TCM theories. Mining complex and the regular relationships between symptoms and herbs in the prescriptions are important for both clinical practice and novel prescription development. Previous work used several machine learning methods to discover regularities and generate prescriptions but rarely used TCM knowledge to guide prescription generation and described why each herb is predicted for treating a symptom. Methods: In this work, we employ a machine translation mechanism and propose a novel sequence-to-sequence (seq2seq) architecture termed TPGen to generate prescriptions. TPGen consisting of an encoder and a decoder is a well-known framework for resolving the machine translation problem in the natural language processing (NLP) domain. We use the lite transformer and Bi-directional Gate Recurrent Units(Bi-GRUS) as a fundamental model in TPGen, and integrate TCM clinical knowledge to guide the model improvement termed TPGen+. Results: We conduct extensive experiments on a public TCM dataset and clinical data. The experimental results demonstrate that our proposed model is effective and outperforms other state-of-the-art methods in TCM expert evaluation. The approach will be beneficial for clinical prescription discovery and diagnosis

A machine translation mechanism of Brazilian Portuguese to Libras with syntactic-semantic adequacy

Deaf people communicate naturally using visual-spatial languages, called sign languages (SL). Although SLs are recognized as a language in many countries, the problems faced by Deaf people for accessing information remain. As a result, they have difficulties exercising their citizenship and access information in SLs, which usually leads to linguistic and knowledge acquisition delays. Some scientific works have been developed to address these problems related to the machine translation of spoken languages to sign languages. However, the existing machine translation platforms have some limitations, especially in syntactic and lexical nature. Thus, this work aims to develop a mechanism for machine translation to Libras, the Brazilian Sign Language, with syntactic-semantic adequacy. It consists of an automatic translation component for Libras based on syntactic-semantic translation rules and a formal syntactic-semantic rule description language. As proof of concept of the proposed approach, we created a specific grammar for Libras translation exploring these aspects and integrating these elements into VLibras Suite, a service for machine translation of digital content in Brazilian Portuguese (BP) to Libras. We performed several tests using this modified version of VLibras to measure the level of comprehension of the output generated by the new translator mechanism. In the computational experiments, as well as in the actual tests with Deaf and hearing users, the proposed approach was able to improve the results of the current VLibras version.

Loss of Cnot6l Impairs Inosine RNA Modifications in Mouse Oocytes

Mammalian oocytes must degrade maternal transcripts through a process called translational mRNA decay, in which maternal mRNA undergoes translational activation, followed by deadenylation and mRNA decay. Once a transcript is translationally activated, it becomes deadenylated by the CCR4-NOT complex. Knockout of CCR4-NOT Transcription Complex Subunit 6 Like (Cnot6l), a deadenylase within the CCR4-NOT complex, results in mRNA decay defects during metaphase I (MI) entry. Knockout of B-cell translocation gene-4 (Btg4), an adaptor protein of the CCR4-NOT complex, results in mRNA decay defects following fertilization. Therefore, mechanisms controlling mRNA turnover have significant impacts on oocyte competence and early embryonic development. Post-transcriptional inosine RNA modifications can impact mRNA stability, possibly through a translation mechanism. Here, we assessed inosine RNA modifications in oocytes, eggs, and embryos from Cnot6l-/- and Btg4-/- mice, which display stabilization of mRNA and over-translation of the stabilized transcripts. If inosine modifications have a role in modulating RNA stability, we hypothesize that in these mutant backgrounds, we would observe changes or a disruption in inosine mRNA modifications. To test this, we used a computational approach to identify inosine RNA modifications in total and polysomal RNA-seq data during meiotic maturation (GV, MI, and MII stages). We observed pronounced depletion of inosine mRNA modifications in samples from Cnot6l-/-, but not in Btg4-/- mice. Additionally, analysis of ribosome-associated RNA revealed clearance of inosine modified mRNA. These observations suggest a novel mechanism of mRNA clearance during oocyte maturation, in which inosine-containing transcripts decay in an independent, but parallel mechanism to CCR4-NOT deadenylation.

Is it Possible that Cells have had More than One Origin?

Cells occupy a prominent place in the history of life on planet Earth. The central role of cellular organization is observed by the fact that “cellular life” is often used as a synonym for life itself. Thus, most characteristics used to define cells overlap with the ones used to define life. Notwithstanding, new scenarios about the origin of life are bringing alternative views to describe how cells may have evolved from the open biological systems named progenotes. Here, using a logical and conceptual analysis, we re-evaluate the characteristics used to infer a single origin for cells. We argue that some evidences used to support cell monophyly, such as the presence of elements from both the translation mechanism and the universality of the genetic code, actually indicate a unique origin for all “biological systems”, a term used to define not only cells, but also virus and progenotes. Besides, we present evidence that at least two biochemical pathways as important as (i) DNA replication and (ii) lipid biosynthesis may not homologous between Bacteria and Archaea. The identities observed between the proteins involved in those pathways along representatives of these two ancestral Domains are too low to indicate common genic ancestry. Altogether these facts can be seen as an indication that cellular organization has possibly evolved two or more times and that LUCA (the Last Universal Common Ancestor) might not have existed as a cellular entity. Thus, we aim to consider the possibility that different strategies acquired by biological systems to exist, such as viral, bacterial and archaeal were originated independently from the evolution of different progenote populations.

A Study on the Present Situation and Countermeasures of Translation Practice for English Majors in China

This paper mainly uses the methods of questionnaire and qualitative analysis. A questionnaire survey was conducted among the last and current English majors. Mainly to understand their translation practice in school, including their attitude towards translation practice, the teaching mode of translation course, the time spent in translation practice after class and the main fields involved, and whether the school has provided translation practice platform and its practicability. The survey of 240 English majors reflects the present situation of English Majors in translation practice: 1) Strong willingness to translate; 2) Lack of practice in class; 3) Lack of extracurricular practice; 4) Lack of translation practice platform. To solve the problems in the translation practice of English majors analyzed by the survey results, this paper puts forward some countermeasures: including establishing a translation practice platform within the University, encouraging translation volunteer activities and building a cooperative translation mechanism between the University and the enterprise.