Modeling all alternative solutions for highly renewable energy systems

As the world is transitioning towards highly renewable energy systems, advanced tools are needed to analyze such complex networks. Energy system design is, however, challenged by real-world objective functions consisting of a blurry mix of technical and socioeconomic agendas, with limitations that cannot always be clearly stated. As a result, it is highly likely that solutions which are techno-economically suboptimal will be preferable. Here, we present a method capable of determining the continuum containing all techno-economically near-optimal solutions, moving the field of energy system modeling from discrete solutions to a new era where continuous solution ranges are available. The presented method is applied to study a range of technical and socioeconomic metrics on a model of the European electricity system. The near-optimal region is found to be relatively flat allowing for solutions that are slightly more expensive than the optimum but better in terms of equality, land use, and implementation time.Comment: 25 pages, 7 figures, also available as preprint at: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=368204

Targeting transferrin receptors at the blood-brain barrier improves the uptake of immunoliposomes and subsequent cargo transport into the brain parenchyma

Abstract Drug delivery to the brain is hampered by the presence of the blood-brain barrier, which excludes most molecules from freely diffusing into the brain, and tightly regulates the active transport mechanisms that ensure sufficient delivery of nutrients to the brain parenchyma. Harnessing the possibility of delivering neuroactive drugs by way of receptors already present on the brain endothelium has been of interest for many years. The transferrin receptor is of special interest since its expression is limited to the endothelium of the brain as opposed to peripheral endothelium. Here, we investigate the possibility of delivering immunoliposomes and their encapsulated cargo to the brain via targeting of the transferrin receptor. We find that transferrin receptor-targeting increases the association between the immunoliposomes and primary endothelial cells in vitro, but that this does not correlate with increased cargo transcytosis. Furthermore, we show that the transferrin receptor-targeted immunoliposomes accumulate along the microvessels of the brains of rats, but find no evidence for transcytosis of the immunoliposome. Conversely, the increased accumulation correlated both with increased cargo uptake in the brain endothelium and subsequent cargo transport into the brain. These findings suggest that transferrin receptor-targeting is a relevant strategy of increasing drug exposure to the brain

Influenza A virus H10N7 detected in dead harbor seals (Phoca vitulina) at several locations in Denmark 2014.

Influenza A virus (IAV) affects a wide range of species, though waterfowl is regarded the natural host for most IAV subtypes. Avian influenza (AI) viruses replicate in the intestinal tract of birds and are mainly transmitted by the fecal-oral route. Pinnipeds share the same shoreline habitats as many waterfowl species and are therefore potentially exposed to AIV. Outbreaks of AI in seals have been described in North America and Asia but prior to 2014 never in Europe. In 2014 massive deaths of harbor seals (Phoca vitulina) were reported in Northern Europe. In Denmark, harbor seals were initially found dead on the Danish island Anholt in Kattegat, which is the sea surrounded by Denmark, Norway and Sweden. Between June and August, 152 harbor seals were found dead. Four seals were submitted to the National Veterinary Institute in Dennmark and diagnosed with severe pneumonia. Influenza A virus of the subtype H10N7 was detected in two out of four seals. Subsequently IAV was detected in dead harbor seals at several locations in Denmark. The IAV outbreak appeared to move with time to the west through the Limfjord to the North Sea and further down south along the west coast of Jutland to the Wadden Sea. Outbreaks were subsequently reported from Germany and The Netherlands. The aim of this study was to characterize the viruses detected at the several locations by molecular and phylogenetic analysis. All viruses were subtyped as H10N7 with genes of avian origin. The HA and NA genes of the viruses were highly similar to H10N7 IAV detected in harbor seals in Sweden in the spring of 2014 and in Germany in the autumn of 2014, suggesting that the same strain of virus had spread from Sweden to Denmark and further on to Germany

Mannose 6-Phosphate Receptor Is Reduced in -Synuclein Overexpressing Models of Parkinsons Disease

Increasing evidence points to defects in autophagy as a common denominator in most neurodegenerative conditions. Progressive functional decline in the autophagy-lysosomal pathway (ALP) occurs with age, and the consequent impairment in protein processing capacity has been associated with a higher risk of neurodegeneration. Defects in cathepsin D (CD) processing and α-synuclein degradation causing its accumulation in lysosomes are particularly relevant for the development of Parkinson's disease (PD). However, the mechanism by which alterations in CD maturation and α-synuclein degradation leads to autophagy defects in PD neurons is still uncertain. Here we demonstrate that MPR300 shuttling between endosomes and the trans Golgi network is altered in α-synuclein overexpressing neurons. Consequently, CD is not correctly trafficked to lysosomes and cannot be processed to generate its mature active form, leading to a reduced CD-mediated α-synuclein degradation and α-synuclein accumulation in neurons. MPR300 is downregulated in brain from α-synuclein overexpressing animal models and in PD patients with early diagnosis. These data indicate MPR300 as crucial player in the autophagy-lysosomal dysfunctions reported in PD and pinpoint MRP300 as a potential biomarker for PD

Diabetic retinopathy as a potential marker of Parkinson's disease:a register-based cohort study

Neurodegeneration is an early event in the pathogenesis of diabetic retinopathy, and an association between diabetic retinopathy and Parkinson’s disease has been proposed. In this nationwide register-based cohort study, we investigated the prevalence and incidence of Parkinson’s disease among patients screened for diabetic retinopathy in a Danish population-based cohort. Cases (n = 173 568) above 50 years of age with diabetes included in the Danish Registry of Diabetic Retinopathy between 2013 and 2018 were matched 1:5 by gender and birth year with a control population without diabetes (n = 843 781). At index date, the prevalence of Parkinson’s disease was compared between cases and controls. To assess the longitudinal relationship between diabetic retinopathy and Parkinson’s disease, a multivariable Cox proportional hazard model was estimated. The prevalence of Parkinson’s disease was 0.28% and 0.44% among cases and controls, respectively. While diabetic retinopathy was not associated with present (adjusted odds ratio 0.93, 95% confidence interval 0.72–1.21) or incident Parkinson’s disease (adjusted hazard ratio 0.77, 95% confidence interval 0.56–1.05), cases with diabetes were in general less likely to have or to develop Parkinson’s disease compared to controls without diabetes (adjusted odds ratio 0.79, 95% confidence interval 0.71–0.87 and adjusted hazard ratio 0.88, 95% confidence interval 0.78–1.00). In a national cohort of more than 1 million persons, patients with diabetes were 21% and 12% were less likely to have prevalent and develop incident Parkinson’s disease, respectively, compared to an age- and gender-matched control population without diabetes. We found no indication for diabetic retinopathy as an independent risk factor for incident Parkinson’s disease

The Splicing Efficiency of Activating HRAS Mutations Can Determine Costello Syndrome Phenotype and Frequency in Cancer

Costello syndrome (CS) may be caused by activating mutations in codon 12/13 of the HRAS proto-oncogene. HRAS p.Gly12Val mutations have the highest transforming activity, are very frequent in cancers, but very rare in CS, where they are reported to cause a severe, early lethal, phenotype. We identified an unusual, new germline p.Gly12Val mutation, c.35_36GC>TG, in a 12-year-old boy with attenuated CS. Analysis of his HRAS cDNA showed high levels of exon 2 skipping. Using wild type and mutant HRAS minigenes, we confirmed that c.35_36GC>TG results in exon 2 skipping by simultaneously disrupting the function of a critical Exonic Splicing Enhancer (ESE) and creation of an Exonic Splicing Silencer (ESS). We show that this vulnerability of HRAS exon 2 is caused by a weak 3' splice site, which makes exon 2 inclusion dependent on binding of splicing stimulatory proteins, like SRSF2, to the critical ESE. Because the majority of cancer- and CS- causing mutations are located here, they affect splicing differently. Therefore, our results also demonstrate that the phenotype in CS and somatic cancers is not only determined by the different transforming potentials of mutant HRAS proteins, but also by the efficiency of exon 2 inclusion resulting from the different HRAS mutations. Finally, we show that a splice switching oligonucleotide (SSO) that blocks access to the critical ESE causes exon 2 skipping and halts proliferation of cancer cells. This unravels a potential for development of new anti-cancer therapies based on SSO-mediated HRAS exon 2 skipping