Dissecting the Biological Relevance and Clinical Impact of lncRNA MIAT in Multiple Myeloma

The biological impact of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) is becoming an essential aspect of the investigation, which may contribute to understanding the disease’s complex pathobiology, providing novel potential therapeutic targets. Herein, we investigated the expression pattern and the clinical relevance of the lncRNA MIAT in MM, taking advantage of the publicly available CoMMpass database. MIAT expression in MM is highly heterogeneous and significantly associated with specific molecular lesions frequently occurring in MM. Transcriptome analyses of MM PCs from patients included in the CoMMpass database indicated a potential involvement of MIAT in different signaling pathways and ribosome biogenesis and assembly. These findings suggest that MIAT deregulation may play a pathogenetic role in MM by affecting both proliferation pathways and, indirectly, the translational process. Although MIAT expression levels seem not to be significantly associated with clinical outcome in multivariate analyses, high MIAT expression levels are associated with bortezomib resistance, this suggesting that MIAT targeting could overcome drug resistance in MM. These findings strongly prompt for further studies investigating the significance of MIAT in MM.

Intein Inhibitors as Novel Antimicrobials: Protein Splicing in Human Pathogens, Screening Methods, and Off-Target Considerations

Protein splicing is a post-translational process by which an intervening polypeptide, or intein, catalyzes its own removal from the flanking polypeptides, or exteins, concomitant with extein ligation. Although inteins are highly abundant in the microbial world, including within several human pathogens, they are absent in the genomes of metazoans. As protein splicing is required to permit function of essential proteins within pathogens, inteins represent attractive antimicrobial targets. Here we review key proteins interrupted by inteins in pathogenic mycobacteria and fungi, exciting discoveries that provide proof of concept that intein activity can be inhibited and that this inhibition has an effect on the host organism’s fitness, and bioanalytical methods that have been used to screen for intein activity. We also consider potential off-target inhibition of hedgehog signaling, given the similarity in structure and function of inteins and hedgehog autoprocessing domains.

Making the Leap: from Experimental Psychopathology to Clinical Trials

One important aim of experimental psychopathology research is to inform development of new interventions derived from basic science. However, testing whether a newly developed intervention is in fact effective requires moving from experimental studies to clinical trials, and this transition can pose many problems. These problems stem not only from the inherent complexity of even the simplest clinical trial, but also from differences between experimental psychopathology and clinical trial research that may not always be obvious to researchers immersed in only one of these specialist areas. In this paper we explore some of these complexities, and discuss when a clinical trial may, or may not be, the best next step in the translational process. We then consider some of the ins and outs of clinical trials methodology, from design and planning through to reporting, with the aim of providing a guide for experimental psychopathology researchers thinking of making the leap from their experimental studies of mechanisms to clinical trials of novel interventions. We hope that this can help increase the chance of successful clinical translation and novel treatment development from basic science.

5'-UTR SNP of FGF13 causes translational defect and intellectual disability

The congenital intellectual disability (ID)-causing gene mutations remain largely unclear, although many genetic variations might relate to ID. We screened gene mutations in Chinese Han children suffering from severe ID and found a single-nucleotide polymorphism (SNP) in the 5′-untranslated region (5′-UTR) of fibroblast growth factor 13 (FGF13) mRNA (NM_001139500.1:c.-32c>G) shared by three male children. In both HEK293 cells and patient-derived induced pluripotent stem cells, this SNP reduced the translation of FGF13, which stabilizes microtubules in developing neurons. Mice carrying the homologous point mutation in 5′-UTR of Fgf13 showed delayed neuronal migration during cortical development, and weakened learning and memory. Furthermore, this SNP reduced the interaction between FGF13 5′-UTR and polypyrimidine-tract-binding protein 2 (PTBP2), which was required for FGF13 translation in cortical neurons. Thus, this 5′-UTR SNP of FGF13 interferes with the translational process of FGF13 and causes deficits in brain development and cognitive functions.

An alternative domain-swapped structure of the Pyrococcus horikoshii PolII mini-intein

Protein splicing is a post-translational process by which an intein catalyzes its own excision from flanking polypeptides, or exteins, concomitant with extein ligation. Many inteins have nested homing endonuclease domains that facilitate their propagation into intein-less alleles, whereas other inteins lack the homing endonuclease (HEN) and are called mini-inteins. The mini-intein that interrupts the DNA PolII of Pyrococcus horikoshii has a linker region in place of the HEN domain that is shorter than the linker in a closely related intein from Pyrococcus abyssi. The P. horikoshii PolII intein requires a higher temperature for catalytic activity and is more stable to digestion by the thermostable protease thermolysin, suggesting that it is more rigid than the P. abyssi intein. We solved a crystal structure of the intein precursor that revealed a domain-swapped dimer. Inteins found as domain swapped dimers have been shown to promote intein-mediated protein alternative splicing, but the solved P. horikoshii PolII intein structure has an active site unlikely to be catalytically competent.

Equivalence classes of circular codes induced by permutation groups

In the 1950s, Crick proposed the concept of so-called comma-free codes as an answer to the frame-shift problem that biologists have encountered when studying the process of translating a sequence of nucleotide bases into a protein. A little later it turned out that this proposal unfortunately does not correspond to biological reality. However, in the mid-90s, a weaker version of comma-free codes, so-called circular codes, was discovered in nature in J Theor Biol 182:45–58, 1996. Circular codes allow to retrieve the reading frame during the translational process in the ribosome and surprisingly the circular code discovered in nature is even circular in all three possible reading-frames ($$C^3$$ C 3 -property). Moreover, it is maximal in the sense that it contains 20 codons and is self-complementary which means that it consists of pairs of codons and corresponding anticodons. In further investigations, it was found that there are exactly 216 codes that have the same strong properties as the originally found code from J Theor Biol 182:45–58. Using an algebraic approach, it was shown in J Math Biol, 2004 that the class of 216 maximal self-complementary $$C^3$$ C 3 -codes can be partitioned into 27 equally sized equivalence classes by the action of a transformation group $$L \subseteq S_4$$ L ⊆ S 4 which is isomorphic to the dihedral group. Here, we extend the above findings to circular codes over a finite alphabet of even cardinality $$|\Sigma |=2n$$ | Σ | = 2 n for $$n \in {\mathbb {N}}$$ n ∈ N . We describe the corresponding group $$L_n$$ L n using matrices and we investigate what classes of circular codes are split into equally sized equivalence classes under the natural equivalence relation induced by $$L_n$$ L n . Surprisingly, this is not always the case. All results and constructions are illustrated by examples.

Translational Hermeneutics Meets Cognitive Science: On the Notion of Performance, Intersubjectivity, and Space in the Translational Process

This paper is a preliminary attempt to connect, within the field of translation studies, the following: firstly, the results of the latest empirical studies on the role of mental simulation in the processing of the text; secondly, Hans-Georg Gadamer’s ideas concerning effective history; thirdly, the main tenets of spatiality and of cognitive narratology. One of the goals of the paper is also to attempt to demonstrate how the legacy of both hermeneutics and cognitive sciences might be reconciled in order to offer a new analytical approach and investigative framework which could suggest an interesting developmental trajectory within translational hermeneutics. Building on Magdalena Rembowska-Płuciennik’s (2012) views on intersubjectivity – that is, the ability to adopt someone else’s perspective as well as to read someone’s mind – I will attempt to demonstrate to what extent the target text (here, the earliest Polish translation of Anne of Green Gables from 1912) might be analysed by translation scholars in the light of the translator’s ability to empathize with the author in regards to the narratological devices used in the source text, as well as in light of the target text reader’s and the translator’s potential sensorimotor and perceptual activities being performed in their minds while creating a translation and while receiving it by the reader of the translation.

Insights Into Translatomics in the Nervous System

Most neurological disorders are caused by abnormal gene translation. Generally, dysregulation of elements involved in the translational process disrupts homeostasis in neurons and neuroglia. Better understanding of how the gene translation process occurs requires detailed analysis of transcriptomic and proteomic profile data. However, a lack of strictly direct correlations between mRNA and protein levels limits translational investigation by combining transcriptomic and proteomic profiling. The much better correlation between proteins and translated mRNAs than total mRNAs in abundance and insufficiently sensitive proteomics approach promote the requirement of advances in translatomics technology. Translatomics which capture and sequence the mRNAs associated with ribosomes has been effective in identifying translational changes by genetics or projections, ribosome stalling, local translation, and transcript isoforms in the nervous system. Here, we place emphasis on the main three translatomics methods currently used to profile mRNAs attached to ribosome-nascent chain complex (RNC-mRNA). Their prominent applications in neurological diseases including glioma, neuropathic pain, depression, fragile X syndrome (FXS), neurodegenerative disorders are outlined. The content reviewed here expands our understanding on the contributions of aberrant translation to neurological disease development.

The SARS-CoV-2 conserved macrodomain is a mono-ADP-ribosylhydrolase

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-related CoVs encode 3 tandem macrodomains within non-structural protein 3 (nsp3). The first macrodomain, Mac1, is conserved throughout CoVs, and binds to and hydrolyzes mono-ADP-ribose (MAR) from target proteins. Mac1 likely counters host-mediated anti-viral ADP-ribosylation, a posttranslational modification that is part of the host response to viral infections. Mac1 is essential for pathogenesis in multiple animal models of CoV infection, implicating it as a virulence factor and potential therapeutic target. Here we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose. SARS-CoV-2, SARS-CoV and MERS-CoV Mac1 exhibit similar structural folds and all 3 proteins bound to ADP-ribose with low μM affinities. Importantly, using ADP-ribose detecting binding reagents in both a gel-based assay and novel ELISA assays, we demonstrated de-MARylating activity for all 3 CoV Mac1 proteins, with the SARS-CoV-2 Mac1 protein leading to a more rapid loss of substrate compared to the others. In addition, none of these enzymes could hydrolyze poly-ADP-ribose. We conclude that the SARS-CoV-2 and other CoV Mac1 proteins are MAR-hydrolases with similar functions, indicating that compounds targeting CoV Mac1 proteins may have broad anti-CoV activity. IMPORTANCE SARS-CoV-2 has recently emerged into the human population and has led to a worldwide pandemic of COVID-19 that has caused greater than 1.2 million deaths worldwide. With, no currently approved treatments, novel therapeutic strategies are desperately needed. All coronaviruses encode for a highly conserved macrodomain (Mac1) that binds to and removes ADP-ribose adducts from proteins in a dynamic post-translational process increasingly recognized as an important factor that regulates viral infection. The macrodomain is essential for CoV pathogenesis and may be a novel therapeutic target. Thus, understanding its biochemistry and enzyme activity are critical first steps for these efforts. Here we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose, and describe its ADP-ribose binding and hydrolysis activities in direct comparison to SARS-CoV and MERS-CoV Mac1 proteins. These results are an important first step for the design and testing of potential therapies targeting this unique protein domain.