Protein-directed ribosomal frameshifting temporally regulates gene expression

Programmed −1 ribosomal frameshifting is a mechanism of gene expression, whereby specific signals within messenger RNAs direct a proportion of translating ribosomes to shift −1 nt and continue translating in the new reading frame. Such frameshifting normally occurs at a set ratio and is utilized in the expression of many viral genes and a number of cellular genes. An open question is whether proteins might function as $\textit{trans}$-acting switches to turn frameshifting on or off in response to cellular conditions. Here we show that frameshifting in a model RNA virus, encephalomyocarditis virus, is $\textit{trans}$-activated by viral protein 2A. As a result, the frameshifting efficiency increases from 0 to 70% (one of the highest known in a mammalian system) over the course of infection, temporally regulating the expression levels of the viral structural and enzymatic proteins.This work was supported by Wellcome Trust grants (088789) and (106207), UK Biotechnology and Biological Research Council (BBSRC) grant (BB/J007072/1) and a European Research Council (ERC) European Union's Horizon 2020 research and innovation programme grant (646891) to A.E.F.; by BBSRC grant (BB/L000334/1) and UK Medical Research Council grant (MR/M011747/1) to I.B.; by a BBSRC PhD studentship to L.K.F.; and by a Wellcome Trust PhD scholarship to J.D.J

The use of multi-omics data and approaches in breast cancer immunotherapy: a review

Breast cancer is projected to be the most common cancer in women in 2020 in the USA. Despite high remission rates treatment side effects remain an issue, hence the interest in novel approaches such as immunotherapies which aim to utilize patients’ immune systems to target cancer cells. This review summarizes the basics of breast cancer including staging and treatment options, followed by a discussion on immunotherapy, including immune checkpoint blockade. After this, examples of the role of omics-type data and computational biology/bioinformatics in breast cancer are explored. Ultimately, there are several promising areas to investigate such as the prediction of neoantigens and the use of multi-omics data to direct research, with noted appropriate in clinical trial design in terms of end points

Mitochondrial abnormalities and low grade inflammation are present in the skeletal muscle of a minority of patients with amyotrophic lateral sclerosis; an observational myopathology study

BACKGROUND Amyotrophic lateral sclerosis (ALS) is a primary progressive neurodegenerative disease characterised by neuronal loss of lower motor neurons (in the spinal cord and brainstem) and/or upper motor neurons (in the motor cortex) and subsequent denervation atrophy of skeletal muscle. AIM A comprehensive examination of muscle pathology from a cohort of clinically confirmed ALS patients, including an investigation of inflammation, complement activation, and deposition of abnormal proteins in order to compare them with findings from an age-matched, control group. MATERIAL AND METHODS 31 muscle biopsies from clinically confirmed ALS patients and 20 normal controls underwent a comprehensive protocol of histochemical and immunohistochemical stains, including HLA-ABC, C5b-9, p62, and TDP-43. RESULTS Neurogenic changes were confirmed in 30/31 ALS cases. In one case, no neurogenic changes could be detected. Muscle fibre necrosis was seen in 5/31 cases and chronic mononuclear inflammatory cell infiltration in 5/31 (2 of them overlapped with those showing muscle necrosis). In four biopsies there was an increase in the proportion of cytochrome oxidase (COX) negative fibres (2-3%). p62 faintly stained cytoplasmic bodies in eight cases and none were immunoreactive to TDP-43. CONCLUSION This large series of muscle biopsies from patients with ALS demonstrates neurogenic atrophy is a nearly uniform finding and that mild mitochondrial abnormalities and low-grade inflammation can be seen and do not rule out the diagnosis of ALS. These findings could lend support to the notion that ALS is a complex and heterogeneous disorder

Indicators of river system hydromorphological character and dynamics: understanding current conditions and guiding sustainable river management

The work leading to this paper received funding from the EU’s FP7 programme under Grant Agreement No. 282656 (REFORM). The Indicators were developed within the context of REFORM deliverable D2.1, therefore all partners involved in this deliverable contributed to some extent to their discussion and development

Development of paediatric non-stage prognosticator guidelines for population-based cancer registries and updates to the 2014 Toronto Paediatric Cancer Stage Guidelines

Population-based cancer registries (PBCRs) generate measures of cancer incidence and survival that are essential for cancer surveillance, research, and cancer control strategies. In 2014, the Toronto Paediatric Cancer Stage Guidelines were developed to standardise how PBCRs collect data on the stage at diagnosis for childhood cancer cases. These guidelines have been implemented in multiple jurisdictions worldwide to facilitate international comparative studies of incidence and outcome. Robust stratification by risk also requires data on key non-stage prognosticators (NSPs). Key experts and stakeholders used a modified Delphi approach to establish principles guiding paediatric cancer NSP data collection. With the use of these principles, recommendations were made on which NSPs should be collected for the major malignancies in children. The 2014 Toronto Stage Guidelines were also reviewed and updated where necessary. Wide adoption of the resultant Paediatric NSP Guidelines and updated Toronto Stage Guidelines will enhance the harmonisation and use of childhood cancer data provided by PBCRs

Chromothripsis orchestrates leukemic transformation in blast phase MPN through targetable amplification of DYRK1A

Chromothripsis, the process of catastrophic shattering and haphazard repair of chromosomes, is a common event in cancer. Whether chromothripsis might constitute an actionable molecular event amenable to therapeutic targeting remains an open question. We describe recurrent chromothripsis of chromosome 21 in a subset of patients in blast phase of a myeloproliferative neoplasm (BP-MPN), which alongside other structural variants leads to amplification of a region of chromosome 21 in ∼25% of patients (‘chr21amp’). We report that chr21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. The chr21amp event is highly clonal and present throughout the hematopoietic hierarchy. DYRK1A, a serine threonine kinase and transcription factor, is the only gene in the 2.7Mb minimally amplified region which showed both increased expression and chromatin accessibility compared to non-chr21amp BP-MPN controls. We demonstrate that DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development, including DNA repair, STAT signalling and BCL2 overexpression. DYRK1A is essential for BP-MPN cell proliferation in vitro and in vivo, and DYRK1A inhibition synergises with BCL2 targeting to induce BP-MPN cell apoptosis. Collectively, these findings define the chr21amp event as a prognostic biomarker in BP-MPN and link chromothripsis to a druggable target

Climate model forecast biases assessed with a perturbed physics ensemble

Perturbed physics ensembles have often been used to analyse long-timescale climate model behaviour, but have been used less often to study model processes on shorter timescales. We combine a transient perturbed physics ensemble with a set of initialised forecasts to deduce regional process errors present in the standard HadCM3 model, which cause the model to drift in the early stages of the forecast. First, it is shown that the transient drifts in the perturbed physics ensembles can be used to recover quantitatively the parameters that were perturbed. The parameters which exert most influence on the drifts vary regionally, but upper ocean mixing and atmospheric convective processes are particularly important on the 1-month timescale. Drifts in the initialised forecasts are then used to recover the ‘equivalent parameter perturbations’, which allow identification of the physical processes that may be at fault in the HadCM3 representation of the real world. Most parameters show positive and negative adjustments in different regions, indicating that standard HadCM3 values represent a global compromise. The method is verified by correcting an unusually widespread positive bias in the strength of wind-driven ocean mixing, with forecast drifts reduced in a large number of areas as a result. This method could therefore be used to improve the skill of initialised climate model forecasts by reducing model biases through regional adjustments to physical processes, either by tuning or targeted parametrisation refinement. Further, such regionally tuned models might also significantly outperform standard climate models, with global parameter configurations, in longer-term climate studies

Ontogeny of the circadian system during embryogenesis in rainbow trout (Oncorhynchus mykiss) and the effect of prolonged exposure to continuous illumination on daily rhythms of per1, clock, and aanat2 expression

It is widely held that the development of the circadian system during embryogenesis is important for future survival of an organism. Work in teleosts has been, to date, limited to zebrafish, which provides little insight into the diversity of this system within such a large vertebrate class. In this study, we analyzed the diel expression of per1, clock, and aanat2 in unfertilized rainbow trout oocytes and embryos maintained under either a 12:12 light:dark (LD) cycle or continuous illumination (LL) from fertilization. 24-h profiles in expression were measured at fertilization as well as 8, 21 42, and 57 days postfertilization (dpf). Both per1 and clock were expressed in unfertilized oocytes and all embryonic stages, while aanat2 expression was only measureable from 8 dpf. A reduction in both per1 and clock mean expression level between unfertilized oocytes/0-1dpf embryos and 8-9dpf embryos was suggestive of a transition from maternal RNA to endogenous mRNA expression. While aanat2 expression was not clearly associated with photic conditions, photoperiod treatment did alter the expression of per1 and clock expression/rhythmicity from as early as 8 dpf (per1), which could suggest the presence and functionality of an as yet unidentified “photoreceptor”. As a whole, this work demonstrates that clock systems are present and functional during embryonic development in rainbow trout. Further studies of their expression and regulation will help understand how the environment interacts with embryonic development in the species

Hodgkin's disease and birth outcome: a Danish nationwide cohort study

In a Danish nationwide cohort study of 292 births from 1973 to 2002 in women with Hodgkin's disease (HD), we compared birth outcome with 14 042 births from a cohort of mothers without cancer. We found no substantially increased risk of preterm birth, low birth weight at term, or stillbirth and no difference in proportion of male newborns for 192 children of women with HD before pregnancy. The prevalence odds ratio (POR) for congenital abnormalities was 1.7 (95% confidence interval (CI): 0.9–3.1). Among 15 newborns of mothers diagnosed during pregnancy, the POR of preterm birth was 26.6 (95% CI: 8.5–83.0), but five out of the eight preterm deliveries among these women were elective. We found no substantially increased risk of adverse birth outcome among 85 newborns of women diagnosed within 2 years postpartum, though effect estimates were imprecise. The overall findings are reassuring, they cannot exclude the possibility of an increased risk of congenital abnormalities for newborns of women diagnosed with HD before pregnancy

Experimental evidence for splicing of intron-containing transcripts of plant LTR retrotransposon Ogre

Ogre elements are a distinct group of plant Ty3/gypsy-like retrotransposons characterized by several specific features, one of which is a separation of the gag-pol region into two non-overlapping open reading frames: ORF2 coding for Gag-Pro, and ORF3 coding for RT/RH-INT proteins. Previous characterization of Ogre elements from several plant species revealed that part of their transcripts lacks the region between ORF2 and ORF3, carrying one uninterrupted ORF instead. In this work, we investigated a hypothesis that this region represents an intron that is spliced out from part of the Ogre transcripts as a means for preferential production of ORF2-encoded proteins over those encoded by the complete ORF2–ORF3 region. The experiments involved analysis of transcription patterns of well-defined Ogre populations in a model plant Medicago truncatula and examination of transcripts carrying dissected pea Ogre intron expressed within a coding sequence of chimeric reporter gene. Both experimental approaches proved that the region between ORF2 and ORF3 is spliced from Ogre transcripts and showed that this process is only partial, probably due to weak splice signals. This is one of very few known cases of spliced LTR retrotransposons and the only one where splicing does not involve parts of the element’s coding sequences, thus resembling intron splicing found in most cellular genes