Estrogen-related receptor alpha and Rplp1 ribosome protein-dependent translation coordinately regulate starvation response and decrease NASH progression

Although general translation declines during fasting, maintaining the translation of a subset or proteins is necessary for metabolic homeostasis and cell viability. Using unbiased proteome analysis of hepatic cells during starvation, we identified a novel pathway in which Esrra-mediated transcription of Rplp1-dependent translation of lysosomal proteins declined during early starvation and recovered after prolonged starvation to restore autophagy-lysosome function. Interestingly, hepatic Esrra-Rplp1-dependent translation rate of lysosomal proteins also was impaired in patients and mice with non-alcoholic steatohepatitis (NASH), and translational response to starvation was dysregulated in mice with NASH. Remarkably, activation of Esrra pharmacologically, genetically, or by alternate day fasting restored protein translation, increased expression of lysosomal proteins, induced autophagy, and reduced lipotoxicity, inflammation, and fibrosis in cell culture and in vivo models of NASH. Thus, hepatic Esrra is essential for ribosome-dependent translation of lysosomal proteins during starvation, and prevention of lipotoxicity and progression in NASH.

Do Fragile X Syndrome and Other Intellectual Disorders Converge at Aberrant Pre-mRNA Splicing?

Fragile X Syndrome is a neuro-developmental disorder caused by the silencing of the FMR1 gene, resulting in the loss of its protein product, FMRP. FMRP binds mRNA and represses general translation in the brain. Transcriptome analysis of the Fmr1-deficient mouse hippocampus reveals widespread dysregulation of alternative splicing of pre-mRNAs. Many of these aberrant splicing changes coincide with those found in post-mortem brain tissue from individuals with autism spectrum disorders (ASDs) as well as in mouse models of intellectual disability such as PTEN hamartoma syndrome (PHTS) and Rett Syndrome (RTT). These splicing changes could result from chromatin modifications (e.g., in FXS, RTT) and/or splicing factor alterations (e.g., PTEN, autism). Based on the identities of the RNAs that are mis-spliced in these disorders, it may be that they are at least partly responsible for some shared pathophysiological conditions. The convergence of splicing aberrations among these autism spectrum disorders might be crucial to understanding their underlying cognitive impairments.

Card-Based Cryptography Meets Formal Verification

Card-based cryptography provides simple and practicable protocols for performing secure multi-party computation with just a deck of cards. For the sake of simplicity, this is often done using cards with only two symbols, e.g., $$\clubsuit $$ ♣ and $$\heartsuit $$ ♡ . Within this paper, we also target the setting where all cards carry distinct symbols, catering for use-cases with commonly available standard decks and a weaker indistinguishability assumption. As of yet, the literature provides for only three protocols and no proofs for non-trivial lower bounds on the number of cards. As such complex proofs (handling very large combinatorial state spaces) tend to be involved and error-prone, we propose using formal verification for finding protocols and proving lower bounds. In this paper, we employ the technique of software bounded model checking (SBMC), which reduces the problem to a bounded state space, which is automatically searched exhaustively using a SAT solver as a backend. Our contribution is threefold: (a) we identify two protocols for converting between different bit encodings with overlapping bases, and then show them to be card-minimal. This completes the picture of tight lower bounds on the number of cards with respect to runtime behavior and shuffle properties of conversion protocols. For computing AND, we show that there is no protocol with finite runtime using four cards with distinguishable symbols and fixed output encoding, and give a four-card protocol with an expected finite runtime using only random cuts. (b) We provide a general translation of proofs for lower bounds to a bounded model checking framework for automatically finding card- and run-minimal (i.e., the protocol has a run of minimal length) protocols and to give additional confidence in lower bounds. We apply this to validate our method and, as an example, confirm our new AND protocol to have its shortest run for protocols using this number of cards. (c) We extend our method to also handle the case of decks on symbols $$\clubsuit $$ ♣ and $$\heartsuit $$ ♡ , where we show run-minimality for two AND protocols from the literature.

Distinct features of the Leishmania cap-binding protein LeishIF4E2 revealed by CRISPR-Cas9 mediated hemizygous deletion

Leishmania parasites cycle between sand-fly vectors and mammalian hosts adapting to alternating environments by stage-differentiation accompanied by changes in the proteome profiles. Translation regulation plays a central role in driving the differential program of gene expression since control of gene regulation in Leishmania is mostly post-transcriptional. The Leishmania genome encodes six eIF4E candidates, some of which bind a dedicated eIF4G candidate, and each eIF4E is assumed to have specific functions with perhaps some overlap. However, LeishIF4E2 does not bind any known eIF4G ortholog and was previously shown to comigrate with the polysomal fractions of sucrose gradients in contrast to the other initiation factors that usually comigrate with pre-initiation and initiation complexes. Here we deleted one of the two LeishIF4E2 gene copies using the CRISPR-Cas9 methodology. The deletion caused severe alterations in the morphology of the mutant cells that became round, small, and equipped with a very short flagellum that did not protrude from its pocket. Reduced expression of LeishIF4E2 had no global effect on translation and growth, unlike other LeishIF4Es; however, there was a change in the proteome profile of the LeishIF4E2(+/-) cells. Upregulated proteins were related mainly to general metabolic processes including enzymes involved in fatty acid metabolism, DNA repair and replication, signaling, and cellular motor activity. The downregulated proteins included flagellar rod and cytoskeletal proteins, as well as surface antigens involved in virulence. Moreover, the LeishIF4E2(+/-) cells were impaired in their ability to infect cultured macrophages. Overall, LeishIF4E2 does not behave like a general translation factor and its function remains elusive. Our results also suggest that the individual LeishIF4Es perform unique functions.

⋆-cohomology, third type Chern character and anomalies in general translation-invariant noncommutative Yang–Mills

A representation of general translation-invariant star products ⋆ in the algebra of [Formula: see text] is introduced which results in the Moyal–Weyl–Wigner quantization. It provides a matrix model for general translation-invariant noncommutative quantum field theories in terms of the noncommutative calculus on differential graded algebras. Upon this machinery a cohomology theory, the so-called ⋆-cohomology, with groups [Formula: see text], [Formula: see text], is worked out which provides a cohomological framework to formulate general translation-invariant noncommutative quantum field theories based on the achievements for the commutative fields, and is comparable to the Seiberg–Witten map for the Moyal case. Employing the Chern–Weil theory via the integral classes of [Formula: see text] a noncommutative version of the Chern character is defined as an equivariant form which contains topological information about the corresponding translation-invariant noncommutative Yang–Mills theory. Thereby, we study the mentioned Yang–Mills theories with three types of actions of the gauge fields on the spinors, the ordinary, the inverse, and the adjoint action, and then some exact solutions for their anomalous behaviors are worked out via employing the homotopic correlation on the integral classes of ⋆-cohomology. Finally, the corresponding consistent anomalies are also derived from this topological Chern character in the ⋆-cohomology.

Theoretical Aspects in Spanish>English Translation for University Students: Monitoring Teaching Tools and Further Suggestions for Translation Students

Spanish>English Translation for Spanish students is one of the most challenging subjects for non-native English translators. Thanks to these subjects, university students have a practical possibility to translate texts from several general and specialised topics. Owing to this fact, every theoretical study is important in other to reach optimal results in these practical courses. Unfortunately, the COVID19 outbreak at the end of the year 2019 and its subsequent worldwide spread has brought additional adaptations to our university studies. The aim of this study is to explain how these adaptations were introduced in our practical subject “Traducción General C2. Inglés” (General Translation C2. English), which focuses on Spanish>English Translation, and taught in the third course of Translation and Interpreting studies at the Universidad Autónoma de Madrid, Spain. In addition to this, this research includes some translation methods and conclusions observed during the course: analysis of Translation Cards of every text included in the subject, how the students mentioned problems and comments of every text, and how these problems can be corrected in the subject by considering every feedback from students and teachers. This final objective can, therefore, bring to light essential aspects coming from both sides of the translation teaching process in our universities.

An Inventory of the Problems Related to Translating and Revising Legal Texts Issued by an African Court: A Case Study

The aim of this paper is to make an inventory of the problems that translators encounter when they translate the documents issued by a specific African human rights court. More specifically translating at the ACHPR requires the knowledge of legal language and familiarity with a particular type of legal texts as well as competence in human rights conventions and charters and general translation skills. In an attempt to address these issues, this paper adopts a threefold approach, namely a historical approach recalling some legal systems and traditions upheld by courts, a theoretical approach throwing light on some key concepts and a lexical approach that makes it possible to extract legal terms from texts issued by the court and match them with their equivalents in the target language. The result of this research work is that legal translation is a specialised area due to the legal terms and systems involved in it. Unlike other specialised areas where the link between the signifier and the signified is fixed, in legal translation, the signified may be inflected due to differences between legal systems. Finding an equivalent for a legal term in another legal system or in a target language may beat times difficult and even impossible.

Distinct features of the Leishmania cap-binding protein LeishIF4E2 revealed by CRISPR-Cas9 mediated heterozygous deletion

Leishmania parasites cycle between sand-fly vectors and mammalian hosts, adapting to alternating environments by stage-differentiation, accompanied by changes in the proteome profiles. Translation regulation plays a central role in driving the differential program of gene expression, since control of gene regulation in Leishmania is mostly post-transcriptional. The Leishmania genome encodes six eIF4E candidates, each assumed to have specific functions, although overlaps are expected. It is noted that some of them can bind to a dedicated eIF4G candidate partners, and LeishIF4E2 does not bind any known eIF4G ortholog. LeishIF4E2 was previously shown to comigrate in the polysomal fractions of sucrose gradients, whereas initiation factors usually comigrate with pre-initiation and initiation complexes. Using the CRISPR-Cas9 methodology, we deleted one of the two LeishIF4E2 gene copies. The deletion caused severe alterations in the morphology of mutant cells that turned round and equipped with a very short flagellum, but their growth rate and general translation remained unaffected. Proteomic analysis of the LeishIF4E2(+/-) mutant cells compared to wild type controls showed that the number of proteins that were upregulated exceeded the number of downregulated proteins, possibly indicating that a repressor function was eliminated. The upregulated proteins were related mainly to general metabolic processes, DNA repair and replication, signaling, and cellular motor activity. The downregulated proteins included several groups, including cytoskeletal and ribosomal proteins. Despite the fact that only one of the two LeishIF4E2 alleles was deleted, the mutant cells were impaired in their ability to infect cultured macrophages. LeishIF4E2 does not behave like a general translation factor and its function remains elusive. Although it could have a repressive function, we cannot exclude the possibility that it is responsible for translation of a specific set of transcripts. Overall, our results are in line with the possibility that the different LeishIF4Es are assigned unique functions.Author summaryLeishmania parasites cause a broad spectrum of diseases that lead to different pathological symptoms. During their life cycle, the parasites shuffle between sand-fly vectors and mammalian hosts, while adapting to changing environments via a stage specific program of gene expression that assists the survival of Leishmania under the changing conditions. Translation initiation plays a key role in control of gene expression, in Leishmania this is exemplified by the presence of multiple cap-binding complexes that interact with mRNAs. The parasites encode multiple paralogs of the cap-binding translation initiation factor eIF4E, and of its corresponding binding partner eIF4G, forming complexes with different potential functions. Using the CRISPR-Cas9 methodology, we generated a heterozygous mutant of the least studied cap-binding paralog, LeishIF4E2, eliminating one of its two alleles. The mutation caused morphological defects, resulting in short and rounded up cells with a significant reduction in their flagellar length. Although general translation rates and growth of the mutant parasite were not affected, total proteome analysis and translation assay suggested that LeishIF4E2 could possibly function as a translation repressor. Alternatively, LeishIF4E-2 could be responsible for promoting translation of a specific set of transcripts.