Trauma-induced coagulopathy in severely injured patients: knowledge lost in translation?

Many guidelines exist on how to treat patients with multiple injuries correctly in an accident and emergency setting. The aim of the present work was to find out how well patients are treated focusing on trauma induced coagulopathy (TIC), and what anaesthetists involved in trauma care think about their own experiences with TIC.

Dopaminergic modulation of rapid reality adaptation in thinking

Dopamine has long held a prominent role in the interpretation of schizophrenia and other psychoses. Clinical studies on confabulation and disorientation, disorders marked by a confusion of reality in thinking, indicated that the ability to keep thinking in phase with reality depends on a process suppressing the interference of upcoming memories that do not refer to ongoing reality. A host of animal studies and a recent clinical study suggested that this suppression might correspond to the phasic inhibition of dopaminergic neurons in response to the absence of expected outcomes. In this study, we tested healthy subjects with a difficult version of a memory paradigm on which confabulating patients had failed. Subjects participated in three test sessions, in which they received in double-blind, randomized fashion L-dopa, risperidone, or placebo. We found that l-dopa, in comparison with risperidone, impaired performance in a highly specific way, which corresponded to the pattern of patients with reality confusion. Specifically, they had an increase of false positive responses, while overall memory performance and reaction times were unaffected. We conclude that dopaminergic transmission influences the ability to rapidly adapt thinking to ongoing reality.

Lost in translation: the impact of publication language on citation frequency in the scientific dental literature

Citation metrics are commonly used as a proxy for scientific merit and relevance. Papers published in English, however, may exhibit a higher citation frequency than research articles published in other languages, though this issue has not yet been investigated from a Swiss perspective where English is not the native language.

Protein disulfide isomerase blocks CEBPA translation and is up-regulated during the unfolded protein response in AML

Deregulation of the myeloid key transcription factor CEBPA is a common event in acute myeloid leukemia (AML). We previously reported that the chaperone calreticulin is activated in subgroups of AML patients and that calreticulin binds to the stem loop region of the CEBPA mRNA, thereby blocking CEBPA translation. In this study, we screened for additional CEBPA mRNA binding proteins and we identified protein disulfide isomerase (PDI), an endoplasmic reticulum (ER) resident protein, to bind to the CEBPA mRNA stem loop region. We found that forced PDI expression in myeloid leukemic cells in fact blocked CEBPA translation, but not transcription, whereas abolishing PDI function restored CEBPA protein. In addition, PDI protein displayed direct physical interaction with calreticulin. Induction of ER stress in leukemic HL60 and U937 cells activated PDI expression, thereby decreasing CEBPA protein levels. Finally, leukemic cells from 25.4% of all AML patients displayed activation of the unfolded protein response as a marker for ER stress, and these patients also expressed significantly higher PDI levels. Our results indicate a novel role of PDI as a member of the ER stress-associated complex mediating blocked CEBPA translation and thereby suppressing myeloid differentiation in AML patients with activated unfolded protein response (UPR).

Alba-domain proteins of Trypanosoma brucei are cytoplasmic RNA-binding proteins that interact with the translation machinery

Trypanosoma brucei and related pathogens transcribe most genes as polycistronic arrays that are subsequently processed into monocistronic mRNAs. Expression is frequently regulated post-transcriptionally by cis-acting elements in the untranslated regions (UTRs). GPEET and EP procyclins are the major surface proteins of procyclic (insect midgut) forms of T. brucei. Three regulatory elements common to the 3' UTRs of both mRNAs regulate mRNA turnover and translation. The glycerol-responsive element (GRE) is unique to the GPEET 3' UTR and regulates its expression independently from EP. A synthetic RNA encompassing the GRE showed robust sequence-specific interactions with cytoplasmic proteins in electromobility shift assays. This, combined with column chromatography, led to the identification of 3 Alba-domain proteins. RNAi against Alba3 caused a growth phenotype and reduced the levels of Alba1 and Alba2 proteins, indicative of interactions between family members. Tandem-affinity purification and co-immunoprecipitation verified these interactions and also identified Alba4 in sub-stoichiometric amounts. Alba proteins are cytoplasmic and are recruited to starvation granules together with poly(A) RNA. Concomitant depletion of all four Alba proteins by RNAi specifically reduced translation of a reporter transcript flanked by the GPEET 3' UTR. Pulldown of tagged Alba proteins confirmed interactions with poly(A) binding proteins, ribosomal protein P0 and, in the case of Alba3, the cap-binding protein eIF4E4. In addition, Alba2 and Alba3 partially cosediment with polyribosomes in sucrose gradients. Alba-domain proteins seem to have exhibited great functional plasticity in the course of evolution. First identified as DNA-binding proteins in Archaea, then in association with nuclear RNase MRP/P in yeast and mammalian cells, they were recently described as components of a translationally silent complex containing stage-regulated mRNAs in Plasmodium. Our results are also consistent with stage-specific regulation of translation in trypanosomes, but most likely in the context of initiation.

Unique modifications of translation elongation factors

Covalent modifications of proteins often modulate their biological functions or change their subcellular location. Among the many known protein modifications, three are exceptional in that they only occur on single proteins: ethanolamine phosphoglycerol, diphthamide and hypusine. Remarkably, the corresponding proteins carrying these modifications, elongation factor 1A, elongation factor 2 and initiation factor 5A, are all involved in elongation steps of translation. For diphthamide and, in part, hypusine, functional essentiality has been demonstrated, whereas no functional role has been reported so far for ethanolamine phosphoglycerol. We review the biosynthesis, attachment and physiological roles of these unique protein modifications and discuss common and separate features of the target proteins, which represent essential proteins in all organisms.