Analysis of Edit Operations for Post-editing Systems

Post-editing has become an important part not only of translation research but also in the global translation industry. While computer-aided translation tools, such as translation memories, are considered to be part of a translator's work, lately, machine translation (MT) systems have also been accepted by human translators. However, many human translators are still adopting the changes brought by translation technologies to the translation industry. This paper introduces a novel approach for seeking suitable pairs of n-grams when recommending n-grams (corresponding n-grams between MT and post-edited MT) based on the type of text (manual or administrative) and MT system used for machine translation. A tool that recommends and speeds up the correction of MT was developed to help the post-editors with their work. It is based on the analysis of words with the same lemmas and analysis of n-gram recommendations. These recommendations are extracted from sequence patterns of the mismatched words (MisMatch) between MT output and post-edited MT output. The paper aims to show the usage of morphological analysis for recommending the post-edit operations. It describes the usage of mismatched words in the n-gram recommendations for the post-edited MT output. The contribution consists of the methodology for seeking suitable pairs of words, n-grams and additionally the importance of taking into account metadata (the type of the text and/or style and MT system) when recommending post-edited operations.

DHX30 Coordinates Cytoplasmic Translation and Mitochondrial Function Contributing to Cancer Cell Survival

DHX30 was recently implicated in the translation control of mRNAs involved in p53-dependent apoptosis. Here, we show that DHX30 exhibits a more general function by integrating the activities of its cytoplasmic isoform and of the more abundant mitochondrial one. The depletion of both DHX30 isoforms in HCT116 cells leads to constitutive changes in polysome-associated mRNAs, enhancing the translation of mRNAs coding for cytoplasmic ribosomal proteins while reducing the translational efficiency of the nuclear-encoded mitoribosome mRNAs. Furthermore, the depletion of both DHX30 isoforms leads to higher global translation but slower proliferation and lower mitochondrial energy metabolism. Isoform-specific silencing supports a role for cytoplasmic DHX30 in modulating global translation. The impact on translation and proliferation was confirmed in U2OS and MCF7 cells. Exploiting RIP, eCLIP, and gene expression data, we identified fourteen mitoribosome transcripts we propose as direct DHX30 targets that can be used to explore the prognostic value of this mechanism in cancer. We propose that DHX30 contributes to cell homeostasis by coordinating ribosome biogenesis, global translation, and mitochondrial metabolism. Targeting DHX30 could, thus, expose a vulnerability in cancer cells.

Noether Currents and Maxwell-Type Equations of Motion in Higher Derivative Gravity Theories

In general coordinate invariant gravity theories whose Lagrangians contain arbitrarily high order derivative fields, the Noether currents for the global translation and for the Nakanishi’s IOSp(8|8) choral symmetry containing the BRS symmetry as its member are constructed. We generally show that for each of these Noether currents, a suitable linear combination of equations of motion can be brought into the form of a Maxwell-type field equation possessing the Noether current as its source term.

The transcription factor Xrp1 orchestrates both reduced translation and cell competition upon defective ribosome assembly or function

Ribosomal Protein (Rp) gene haploinsufficiency affects overall translation rate, leads to cell elimination by competition with wild type cells in mosaic tissues, and sometimes leads to accumulation of protein aggregates. The changes in ribosomal subunit levels observed are not sufficient for these effects, which all depend on the AT-hook, bZip domain protein Xrp1. In Rp+/- cells, Xrp1 reduced global translation through PERK-dependent phosphorylation of eIF2α. eIF2α phosphorylation was sufficient to reduce translation in, and also enable cell competition of, otherwise wild type cells. Unexpectedly, however, many other defects reducing ribosome biogenesis or function (depletion of TAF1B, eIF2, eIF4G, eIF6, eEF2, eEF1α1, or eIF5A), also increased eIF2α phosphorylation and enabled cell competition. In all cases this was through the Xrp1 expression that was induced, placing Xrp1 as the downstream instigator of cell competition that also contributed to overall translation deficits. In the absence of Xrp1, translation differences between cells were not themselves sufficient to trigger cell competition. Thus, Xrp1, which is shown here to be a sequence-specific transcription factor, is the master regulator that triggers cell competition and other consequences of multiple ribosomal stresses.

Convolutional Neural Network with an Elastic Matching Mechanism for Time Series Classification

Recently, some researchers adopted the convolutional neural network (CNN) for time series classification (TSC) and have achieved better performance than most hand-crafted methods in the University of California, Riverside (UCR) archive. The secret to the success of the CNN is weight sharing, which is robust to the global translation of the time series. However, global translation invariance is not the only case considered for TSC. Temporal distortion is another common phenomenon besides global translation in time series. The scale and phase changes due to temporal distortion bring significant challenges to TSC, which is out of the scope of conventional CNNs. In this paper, a CNN architecture with an elastic matching mechanism, which is named Elastic Matching CNN (short for EM-CNN), is proposed to address this challenge. Compared with the conventional CNN, EM-CNN allows local time shifting between the time series and convolutional kernels, and a matching matrix is exploited to learn the nonlinear alignment between time series and convolutional kernels of the CNN. Several EM-CNN models are proposed in this paper based on diverse CNN models. The results for 85 UCR datasets demonstrate that the elastic matching mechanism effectively improves CNN performance.

Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

Background We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder. Methods Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays. Results We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype. Conclusions Our study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories.

Suppression of Global Protein Translation in SARS-CoV-2 Infection

The relationship of SARS-CoV-2 with the host translation remains largely unexplored. Using polysome profiling of SARS-CoV-2 infected Caco2 cells, we here demonstrate that the virus induces a strong suppression of global translation by 48 hours of infection. Heavy polysome fractions displayed substantial depletion in the infected cells, indicating the loss of major translational activities in them. Further assessment of the major pathways regulating translation in multiple permissive cell lines revealed strong eIF4E dephosphorylation accompanied by Mnk1 depletion and ERK1/2 dephosphorylations. p38MAPK showed consistent activation and its inhibition lowered viral titers, indicating its importance in viral survival. No significant change was noticed in eIF2 α phosphorylation. mTORC1 pathway showed the most profound inhibition, indicating its potential contribution to the suppression of global translation associated with the infection. Pharmacological activation of mTORC1 caused a drop in viral titers while inhibition resulted in higher viral RNA levels, confirming a critical role of mTORC1 in regulating viral replication. Surprisingly, the infection did not cause a general suppression of 5′-TOP translation, as evident from the continued expression of ribosomal proteins. Our results collectively indicate that the differential suppression of mTORC1 might allow SARS-CoV-2 to hijack translational machinery in its favor and specifically target a set of host mRNAs.

Treatment with surfactants enables quantification of translational activity by O-propargyl-puromycin labelling in yeast

Background Translation is an important point of regulation in protein synthesis. However, there is a limited number of methods available to measure global translation activity in yeast. Recently, O-propargyl-puromycin (OPP) labelling has been established for mammalian cells, but unmodified yeasts are unsusceptible to puromycin. Results We could increase susceptibility by using a Komagataella phaffii strain with an impaired ergosterol pathway (erg6Δ), but translation measurements are restricted to this strain background, which displayed growth deficits. Using surfactants, specifically Imipramine, instead, proved to be more advantageous and circumvents previous restrictions. Imipramine-supplemented OPP-labelling with subsequent flow cytometry analysis, enabled us to distinguish actively translating cells from negative controls, and to clearly quantify differences in translation activities in different strains and growth conditions. Specifically, we investigated K. phaffii at different growth rates, verified that methanol feeding alters translation activity, and analysed global translation in strains with genetically modified stress response pathways. Conclusions We set up a simple protocol to measure global translation activity in yeast on a single cell basis. The use of surfactants poses a practical and non-invasive alternative to the commonly used ergosterol pathway impaired strains and thus impacts a wide range of applications where increased drug and dye uptake is needed.