Ribosome profiling-guided depletion of an mRNA increases cell growth rate and protein secretion

Recombinant protein production coopts the host cell machinery to provide high protein yields of industrial enzymes or biotherapeutics. However, since protein translation is energetically expensive and tightly controlled, it is unclear if highly expressed recombinant genes are translated as efficiently as host genes. Furthermore, it is unclear how the high expression impacts global translation. Here, we present the first genome-wide view of protein translation in an IgG-producing CHO cell line, measured with ribosome profiling. Through this we found that our recombinant mRNAs were translated as efficiently as the host cell transcriptome, and sequestered up to 15% of the total ribosome occupancy. During cell culture, changes in recombinant mRNA translation were consistent with changes in transcription, demonstrating that transcript levels influence specific productivity. Using this information, we identified the unnecessary resistance marker NeoR to be a highly transcribed and translated gene. Through siRNA knock-down of NeoR, we improved the production- and growth capacity of the host cell. Thus, ribosomal profiling provides valuable insights into translation in CHO cells and can guide efforts to enhance protein production

Carbon bioavailability in a high Arctic fjord influenced by glacial meltwater, NE Greenland

The land-to-ocean flux of organic carbon is increasing in glacierized regions in response to increasing temperatures in the Arctic (Hood et al., 2015). In order to understand the response of the coastal ecosystem metabolism to the organic carbon input it is essential to determine the bioavailability of the different carbon sources in the system.We quantified the bacterial turnover of organic carbon in a high Arctic fjord system (Young Sound, NE Greenland) during the ice-free period (July-October 2014) and assessed the quality and quantity of the 3 major organic carbon sources; (1) local phytoplankton production (2) runoff from land-terminating glaciers and a lowland river and (3) inflow from the ocean shelf. We found that despite relatively low concentrations of DOC in the rivers, the bioavailability of the river–DOC was significantly higher than in the fjord, and characterized by high cell-specific bacterial production and low C:N ratios. In contrast, the DOC source entering via inflow of coastal shelf waters had high DOC concentrations with high C:N and low specific bacterial production. The phytoplankton production in the fjord could not sustain the bacterial carbon demand, but was still the major source of organic carbon for bacterial growth. We assessed the bacterial community composition and found that communities were specific for the different water types i.e., the bacterial community of the coastal inflow water could be traced mainly in the subsurface water, while the glacial river community strongly dominated the surface water in the fjord

Drivers of Change in Arctic Fjord Socio-ecological Systems: Examples from the European Arctic

Fjord systems are transition zones between land and sea, resulting in complex and dynamic environments. They are of particular interest in the Arctic as they harbour ecosystems inhabited by a rich range of species and provide many societal benefits. The key drivers of change in the European Arctic (i.e., Greenland, Svalbard, and Northern Norway) fjord socio-ecological systems are reviewed here, structured into five categories: cryosphere (sea ice, glacier mass balance, and glacial and riverine discharge), physics (seawater temperature, salinity, and light), chemistry (carbonate system, nutrients), biology (primary production, biomass, and species richness), and social (governance, tourism, and fisheries). The data available for the past and present state of these drivers, as well as future model projections, are analysed in a companion paper. Changes to the two drivers at the base of most interactions within fjords, seawater temperature and glacier mass balance, will have the most significant and profound consequences on the future of European Arctic fjords. This is because even though governance may be effective at mitigating/adapting to local disruptions caused by the changing climate, there is possibly nothing that can be done to halt the melting of glaciers, the warming of fjord waters, and all of the downstream consequences that these two changes will have. This review provides the first transdisciplinary synthesis of the interactions between the drivers of change within Arctic fjord socio-ecological systems. Knowledge of what these drivers of change are, and how they interact with one another, should provide more expedient focus for future research on the needs of adapting to the changing Arctic

The Third International Symposium on Fungal Stress – ISFUS

Stress is a normal part of life for fungi, which can survive in environments considered inhospitable or hostile for other organisms. Due to the ability of fungi to respond to, survive in, and transform the environment, even under severe stresses, many researchers are exploring the mechanisms that enable fungi to adapt to stress. The International Symposium on Fungal Stress (ISFUS) brings together leading scientists from around the world who research fungal stress. This article discusses presentations given at the third ISFUS, held in São José dos Campos, São Paulo, Brazil in 2019, thereby summarizing the state-of-the-art knowledge on fungal stress, a field that includes microbiology, agriculture, environmental science, ecology, biotechnology, medicine, and astrobiology

Generic pregabalin : current situation and implications for health authorities, generics and biosimilars manufacturers in the future

The manufacturer of pregabalin has a second use patent covering prescribing for neuropathic pain: its principal indication. The manufacturer has threatened legal action in the UK if generic pregabalin rather than Lyrica is prescribed for this indication. No problems exist for practitioners who prescribe pregabalin for epilepsy or generalized anxiety disorder. This has serious implications for health authorities. In Germany, however, generics could be legally prescribed for any approved indication once one indication loses its patent. We aim to establish the current situation with pregabalin among principally European countries. Personnel from 33 regional and national health authorities mainly from Europe, and nine from universities across Europe working as advisers to health authorities or with insight into their activities, were surveyed regarding four specific questions via email to shed light on the current situation with Lyrica and pregabalin in their country. The information collated from each country was subsequently checked for accuracy with each co-author by email and face-to-face contact and collated into five tables. The scenarios ranged from extending the patent life of Lyrica (e.g. France), endorsing the prescribing of Lyrica for neuropathic pain (e.g. Catalonia and South Korea), and current prescribing of pregabablin for all indications (e.g. Serbia and Germany). Little activity has taken place in European countries in which generic pregabalin is not yet reimbursed. The availability of generic pregabalin has prompted a number of different activities to be undertaken among the 33 countries and regions surveyed. The situation in Serbia and the historic situation in Germany provide examples of ways to maximize savings once a product loses its patent for at least one indication

Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia

We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10-9). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD's polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology

15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2) : prolonged remissions without survival plateau

In recent decades, the prognosis of Mantle Cell Lymphoma (MCL) has been significantly improved by intensified first-line regimens containing cytarabine, rituximab and consolidation with high-dose-therapy and autologous stem cell transplantation. One such strategy is the Nordic MCL2 regimen, developed by the Nordic Lymphoma Group. We here present the 15-year updated results of the Nordic MCL2 study after a median follow-up of 114years: For all patients on an intent-to-treat basis, the median overall and progression-free survival was 127 and 85years, respectively. The MCL International Prognostic Index (MIPI), biological MIPI, including Ki67 expression (MIPI-B) and the MIPI-B including mIR-18b expression (MIPI-B-miR), in particular, significantly divided patients into distinct risk groups. Despite very long response durations of the low and intermediate risk groups, we observed a continuous pattern of relapse and the survival curves never reached a plateau. In conclusion, despite half of the patients being still alive and 40% in first remission after more than 12years, we still see an excess disease-related mortality, even among patients experiencing long remissions. Even though we consider the Nordic regimen as a very good choice of regimen, we recommend inclusion in prospective studies to explore the benefit of novel agents in the frontline treatment of MCL.Peer reviewe