Beneficial Effects of GLP-1 Agonist in a Male With Compulsive Food-Related Behavior Associated With Autism

Individuals with autism spectrum disorder (ASD) frequently display intensely repetitive, restricted thoughts, and behaviors. These behaviors have similarities to compulsions and/ or obsessions in obsessive compulsive disorder (OCD) and are primarily treated with behaviourally-based interventions and serotonin uptake inhibitors (SSRIs). Due to the lack of treatment responses in many cases, however, new treatments are being sought. Here we report beneficial effects of treatment with liraglutide, a glucagon-like peptide-1 (GLP-1) analog, on severe obsessive food craving, binge eating, weight gain, and behavioral problems in an adolescent male with infantile autism and moderate intellectual impairment. Liraglutide treatment reduced weight and unwanted behavior seemingly by preventing food-related repetitive thoughts and compulsions. Our report provides clinical evidence that GLP-1 signaling pathway may represent a novel target for treating food-related behavioral problems and aggressive behavior in ASD.Peer reviewe

Purification of Highly Active Alphavirus Replication Complexes Demonstrates Altered Fractionation of Multiple Cellular Membranes

Positive-strand RNA viruses replicate their genomes in membrane-associated structures; alphaviruses and many other groups induce membrane invaginations called spherules. Here, we established a protocol to purify these membranous replication complexes (RCs) from cells infected with Semliki Forest virus (SFV). We isolated SFV spherules located on the plasma membrane and further purified them using two consecutive density gradients. This revealed that SFV infection strongly modifies cellular membranes. We removed soluble proteins, the Golgi membranes, and most of the mitochondria, but plasma membrane, endoplasmic reticulum (ER), and late endosome markers were retained in the membrane fraction that contained viral RNA synthesizing activity, replicase proteins, and minus-and plus-strand RNA. Electron microscopy revealed that the purified membranes displayed spherule-like structures with a narrow neck. This membrane enrichment was specific to viral replication, as such a distribution of membrane markers was only observed after infection. Besides the plasma membrane, SFV infection remodeled the ER, and the cofractionation of the RC-carrying plasma membrane and ER suggests that SFV recruits ER proteins or membrane to the site of replication. The purified RCs were highly active in synthesizing both genomic and subgenomic RNA. Detergent solubilization destroyed the replication activity, demonstrating that the membrane association of the complex is essential. Most of the newly made RNA was in double-stranded replicative molecules, but the purified complexes also produced single-stranded RNA as well as released newly made RNA. This indicates that the purification established here maintained the functionality of RCs and thus enables further structural and functional studies of active RCs. IMPORTANCE Similar to all positive-strand RNA viruses, the arthropod-borne alpha-viruses induce membranous genome factories, but little is known about the arrangement of viral replicase proteins and the presence of host proteins in these replication complexes. To improve our knowledge of alphavirus RNA-synthesizing complexes, we isolated and purified them from infected mammalian cells. Detection of viral RNA and in vitro replication assays revealed that these complexes are abundant and highly active when located on the plasma membrane. After multiple purification steps, they remain functional in synthesizing and releasing viral RNA. Besides the plasma membrane, markers for the endoplasmic reticulum and late endosomes were enriched with the replication complexes, demonstrating that alphavirus infection modified cellular membranes beyond inducing replication spherules on the plasma membrane. We have developed here a gentle purification method to obtain large quantities of highly active replication complexes, and similar methods can be applied to other positive-strand RNA viruses.Peer reviewe

Aesthetics as metaphysical meaning-making in the face of death

In my ethnographic research on death and dying in contemporary Finland, I explore how Finns facing end of life due to a long-term illness or other terminal condition seek to orient themselves and make meaning with cultural tools such as imagery, language, and metaphysical thinking. My primary research material is based on extensive fieldwork at Terhokoti Hospice and in the cancer clinic of Helsinki University Hospital, where I have had numerous conversations with terminally ill patients. This paper seeks to explore the way in which metaphysical aesthetics is assuming the role that religious thinking has traditionally played. When the role of institutional religion is diminishing, it becomes important to understand how emotional and spiritual resolution can be arrived at by means of aesthetics

The RNA Capping Enzyme Domain in Protein A is Essential for Flock House Virus Replication

The nodavirus flock house virus (FHV) and the alphavirus Semliki Forest virus (SFV) show evolutionarily intriguing similarities in their replication complexes and RNA capping enzymes. In this study, we first established an efficient FHV trans-replication system in mammalian cells, which disjoins protein expression from viral RNA synthesis. Following transfection, FHV replicase protein A was associated with mitochondria, whose outer surface displayed pouch-like invaginations with a ‘neck’ structure opening towards the cytoplasm. In mitochondrial pellets from transfected cells, high-level synthesis of both genomic and subgenomic RNA was detected in vitro and the newly synthesized RNA was of positive polarity. Secondly, we initiated the study of the putative RNA capping enzyme domain in protein A by mutating the conserved amino acids H93, R100, D141, and W215. RNA replication was abolished for all mutants inside cells and in vitro except for W215A, which showed reduced replication. Transfection of capped RNA template did not rescue the replication activity of the mutants. Comparing the efficiency of SFV and FHV trans-replication systems, the FHV system appeared to produce more RNA. Using fluorescent marker proteins, we demonstrated that both systems could replicate in the same cell. This work may facilitate the comparative analysis of FHV and SFV replication.The nodavirus flock house virus (FHV) and the alphavirus Semliki Forest virus (SFV) show evolutionarily intriguing similarities in their replication complexes and RNA capping enzymes. In this study, we first established an efficient FHV trans-replication system in mammalian cells, which disjoins protein expression from viral RNA synthesis. Following transfection, FHV replicase protein A was associated with mitochondria, whose outer surface displayed pouch-like invaginations with a 'neck' structure opening towards the cytoplasm. In mitochondrial pellets from transfected cells, high-level synthesis of both genomic and subgenomic RNA was detected in vitro and the newly synthesized RNA was of positive polarity. Secondly, we initiated the study of the putative RNA capping enzyme domain in protein A by mutating the conserved amino acids H93, R100, D141, and W215. RNA replication was abolished for all mutants inside cells and in vitro except for W215A, which showed reduced replication. Transfection of capped RNA template did not rescue the replication activity of the mutants. Comparing the efficiency of SFV and FHV trans-replication systems, the FHV system appeared to produce more RNA. Using fluorescent marker proteins, we demonstrated that both systems could replicate in the same cell. This work may facilitate the comparative analysis of FHV and SFV replication.Peer reviewe

Joint management of marine mammals and a fish species : The case of cod and grey seals in the Nordic-Baltic Sea countries

In this paper, we present a simple theoretical, steady-state equilibrium, predator-prey model for the joint management of marine mammals and a fish species. As an empirical case, we choose cod and grey seals in the Nordic-Baltic Sea countries, and several benefits and costs related to the latter are considered. We show that the optimal grey seal population is much lower than the actual population, and this result is robust to variations in relevant parameter values. This result can be explained by the fact that the profit from harvesting cod is much higher than the net benefits from grey seals.Peer reviewe

Joint management of marine mammals and a fish species : The case of cod and grey seals in the Nordic-Baltic Sea countries

In this paper, we present a simple theoretical, steady-state equilibrium, predator-prey model for the joint management of marine mammals and a fish species. As an empirical case, we choose cod and grey seals in the Nordic-Baltic Sea countries, and several benefits and costs related to the latter are considered. We show that the optimal grey seal population is much lower than the actual population, and this result is robust to variations in relevant parameter values. This result can be explained by the fact that the profit from harvesting cod is much higher than the net benefits from grey seals.Peer reviewe

Combined threats of climate change and land use to boreal protected areas with red-listed forest species in Finland

Peer reviewe

Cellular state landscape and herpes simplex virus type 1 infection progression are connected

Prediction, prevention and treatment of virus infections require understanding of cell-to-cell variability that leads to heterogenous disease outcomes, but the source of this heterogeneity has yet to be clarified. To study the multimodal response of single human cells to herpes simplex virus type 1 (HSV-1) infection, we mapped high-dimensional viral and cellular state spaces throughout the infection using multiplexed imaging and quantitative single-cell measurements of viral and cellular mRNAs and proteins. Here we show that the high-dimensional cellular state scape can predict heterogenous infections, and cells move through the cellular state landscape according to infection progression. Spatial information reveals that infection changes the cellular state of both infected cells and of their neighbors. The multiplexed imaging of HSV-1-induced cellular modifications links infection progression to changes in signaling responses, transcriptional activity, and processing bodies. Our data show that multiplexed quantification of responses at the single-cell level, across thousands of cells helps predict infections and identify new targets for antivirals

Pathogenic Variant Spectrum in Breast Cancer Risk Genes in Finnish Patients

Recurrent pathogenic variants have been detected in several breast and ovarian cancer (BC/OC) risk genes in the Finnish population. We conducted a gene-panel sequencing and copy number variant (CNV) analysis to define a more comprehensive spectrum of pathogenic variants in BRCA1, BRCA2, PALB2, CHEK2, ATM, BARD1, RAD51C, RAD51D, BRIP1, and FANCM genes in Finnish BC patients. The combined frequency of pathogenic variants in the BRCA1/2 genes was 1.8% in 1356 unselected patients, whereas variants in the other genes were detected altogether in 8.3% of 1356 unselected patients and in 12.9% of 699 familial patients. CNVs were detected in 0.3% of both 1137 unselected and 612 familial patients. A few variants covered most of the pathogenic burden in the studied genes. Of the BRCA1/2 carriers, 70.8% had 1 of 10 recurrent variants. In the other genes combined, 92.1% of the carrier patients had at least 1 of 11 recurrent variants. In particular, PALB2 c.1592delT and CHEK2 c.1100delC accounted for 88.9% and 82.9%, respectively, of the pathogenic variation in each gene. Our results highlight the importance of founder variants in the BC risk genes in the Finnish population and could be used in the designing of population screening for the risk variants