A SEL1L mutation links a canine progressive early-onset cerebellar ataxia to the endoplasmic reticulum-associated protein degradation (ERAD) machinery

Inherited ataxias are characterized by degeneration of the cerebellar structures, which results in progressive motor incoordination. Hereditary ataxias occur in many species, including humans and dogs. Several mutations have been found in humans, but the genetic background has remained elusive in dogs. The Finnish Hound suffers from an early-onset progressive cerebellar ataxia. We have performed clinical, pathological, and genetic studies to describe the disease phenotype and to identify its genetic cause. Neurological examinations on ten affected dogs revealed rapidly progressing generalized cerebellar ataxia, tremors, and failure to thrive. Clinical signs were present by the age of 3 months, and cerebellar shrinkage was detectable through MRI. Pathological and histological examinations indicated cerebellum-restricted neurodegeneration. Marked loss of Purkinje cells was detected in the cerebellar cortex with secondary changes in other cortical layers. A genome-wide association study in a cohort of 31 dogs mapped the ataxia gene to a 1.5 Mb locus on canine chromosome 8 (p_raw = 1.1×10⁻⁷, p_genome = 7.5×10⁻⁴). Sequencing of a functional candidate gene, sel-1 suppressor of lin-12-like (SEL1L), revealed a homozygous missense mutation, c.1972T>C; p.Ser658Pro, in a highly conserved protein domain. The mutation segregated fully in the recessive pedigree, and a 10% carrier frequency was indicated in a population cohort. SEL1L is a component of the endoplasmic reticulum (ER)–associated protein degradation (ERAD) machinery and has not been previously associated to inherited ataxias. Dysfunctional protein degradation is known to cause ER stress, and we found a significant increase in expression of nine ER stress responsive genes in the cerebellar cortex of affected dogs, supporting the pathogenicity of the mutation. Our study describes the first early-onset neurodegenerative ataxia mutation in dogs, establishes an ERAD–mediated neurodegenerative disease model, and proposes SEL1L as a new candidate gene in progressive childhood ataxias. Furthermore, our results have enabled the development of a genetic test for breeders.     

The genetic liability to disability retirement: a 30-year follow-up study of 24,000 Finnish twins

Background

No previous studies on the effect of genetic factors on the liability to disability retirement have been carried out. The main aim of this study was to investigate the contribution of genetic factors on disability retirement due to the most common medical causes, including depressive disorders.

Methods

The study sample consisted of 24 043 participants (49.7% women) consisting of 11 186 complete same-sex twin pairs including 3519 monozygotic (MZ) and 7667dizygotic (DZ) pairs. Information on retirement events during 1.1.1975–31.12.2004, including disability pensions (DPs) with diagnoses, was obtained from the Finnish nationwide official pension registers. Correlations in liability for MZ and DZ twins and discrete time correlated frailty model were used to investigate the genetic liability to age at disability retirement.

Results

The 30 year cumulative incidence of disability retirement was 20%. Under the best fitting genetic models, the heritability estimate for DPs due to any medical cause was 0.36 (95% CI 0.32–0.40), due to musculoskeletal disorders 0.37 (0.30–0.43), cardiovascular diseases 0.48 (0.39–0.57), mental disorders 0.42 (0.35–0.49) and all other reasons 0.24 (0.17–0.31). The effect of genetic factors decreased with increasing age of retirement. For DP due to depressive disorders, 28% of the variance was explained by environmental factors shared by family members (95% CI 21–36) and 58% of the variance by the age interval specific environmental factors (95% CI 44–71).

Conclusions

A moderate genetic contribution to the variation of disability retirement due to any medical cause was found. The genetic effects appeared to be stronger at younger ages of disability retirement suggesting the increasing influence of environmental factors not shared with family members with increasing age. Familial aggregation in DPs due to depressive disorders was best explained by the common environmental factors and genetic factors were not needed to account for the pattern of familial aggregation.     

Pathology of Puumala hantavirus infection in macaques

Hantaviruses are globally important human pathogens that cause hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Capillary leakage is central to hantaviral diseases, but how it develops, has remained unknown. It has been hypothesized that the pathogenesis of hantavirus infection would be a complex interplay between direct viral effects and immunopathological mechanisms. Both of these were studied in the so far best model of mild hemorrhagic fever with renal syndrome, i.e. cynomolgus macaques infected with wild-type Puumala hantavirus. Viral RNA detected by in situ hybridization and nucleocapsid protein detected by immunohistochemical staining were observed in kidney, spleen and liver tissues. Inflammatory cell infiltrations and tubular damage were found in the kidneys, and these infiltrations contained mainly CD8-type T-cells. Importantly, these results are consistent with those obtained from patients with hantaviral disease, thus showing that the macaque model of hantavirus infection mimics human infection also on the tissue level. Furthermore, both the markers of viral replication and the T-cells appeared to co-localize in the kidneys to the sites of tissue damage, suggesting that these two together might be responsible for the pathogenesis of hantavirus infection.     

The effect of cosolvents on the formulation of nanoparticles from low-molecular-weight poly(I)lactide

The aim of this study was to formulate nanoparticles from poly(I)lactide by a modified nanoprecipitation method. The main focus was to study the effect of cosolvent selection on the shape, size, formation efficiency, degree of crystallinity, x-ray diffraction (XRD) reflection pattern, and zeta potential value of the particles. Low-molecular-weight (2000 g/mol) poly(I)lactide was used as a polymer, and sodium cromoglycate was used as a drug. Acetone, ethanol, and methanol were selected as cosolvents. Optimal nanoparticles were achieved with ethanol as a cosolvent, and the formation efficiency of the particles was also higher with ethanol as compared with acetone or methanol. The particles formulated by ethanol and acetone appeared round and smooth, while with methanol they were slightly angular. When the volume of the inner phase was decreased during the nanoprecipitation process, the mean particle size was also decreased with all the solvents, but the particles were more prone to aggregate. The XRD reflection pattern and the degree of crystallinity were more dependent were more prone to aggregate. The XRD reflection pattern and the degree of crystallinity were more dependent on the amount of the solvents in the inner phase than on the properties of the individual cosolvents. The zeta potential values of all the particle batches were slightly negative, which partially explains the increased tendency toward particle aggregation.     

What Data to Use for Forest Conservation Planning? A Comparison of Coarse Open and Detailed Proprietary Forest Inventory Data in Finland

The boreal region is facing intensifying resource extraction pressure, but the lack of comprehensive biodiversity data makes operative forest conservation planning difficult. Many countries have implemented forest inventory schemes and are making extensive and up-to-date forest databases increasingly available. Some of the more detailed inventory databases, however, remain proprietary and unavailable for conservation planning. Here, we investigate how well different open and proprietary forest inventory data sets suit the purpose of conservation prioritization in Finland. We also explore how much priorities are affected by using the less accurate but open data. First, we construct a set of indices for forest conservation value based on quantitative information commonly found in forest inventories. These include the maturity of the trees, tree species composition, and site fertility. Secondly, using these data and accounting for connectivity between forest types, we investigate the patterns in conservation priority. For prioritization, we use Zonation, a method and software for spatial conservation prioritization. We then validate the prioritizations by comparing them to known areas of high conservation value. We show that the overall priority patterns are relatively consistent across different data sources and analysis options. However, the coarse data cannot be used to accurately identify the high-priority areas as it misses much of the fine-scale variation in forest structures. We conclude that, while inventory data collected for forestry purposes may be useful for forest conservation purposes, it needs to be detailed enough to be able to account for more fine-scaled features of high conservation value. These results underline the importance of making detailed inventory data publicly available. Finally, we discuss how the prioritization methodology we used could be integrated into operative forest management, especially in countries in the boreal zone.     

Early Life Stage Mortality Syndrome in Fishes of the Great Lakes and Baltic Sea (American Fisheries Society Symposium 21). Edited by Gordon McDonald,John D. Fitzsimons and Dale C. Honeyfield

Reviews in Fish Biology and Fisheries -     

Ornithine Decarboxylase Activity in Brain Regulated by a Specific Macromolecul, the Antizyme

Mouse brain ornithine decarboxylase activity is about 70-fold higher at the time of birth compared with that of adult mice. Enzyme activity declines rapidly after birth and reaches the adult level by 3 weeks. Immunoreactive enzyme concentration parallels very closely the decrease of enzyme activity during the first postnatal week, remaining constant thereafter. The content of brain antizyme, the macromolecular inhibitor to ornithine decarboxylase, in turn is very low during the first 7 days and starts then to increase and at the age of 3 weeks it is about six times the level of that in newborn mice. This may explain the decrease in enzyme activity during brain maturation, and suggests the regulation of polyamine biosynthesis by an antizyme-mediated mechanism in adult brain.     

Mobile Phone Call Data as a Regional Socio-Economic Proxy Indicator

The advent of publishing anonymized call detail records opens the door for temporal and spatial human dynamics studies. Such studies, besides being useful for creating universal models for mobility patterns, could be also used for creating new socio-economic proxy indicators that will not rely only on the local or state institutions. In this paper, from the frequency of calls at different times of the day, in different small regional units (sub-prefectures) in Côte d''Ivoire, we infer users'' home and work sub-prefectures. This division of users enables us to analyze different mobility and calling patterns for the different regions. We then compare how those patterns correlate to the data from other sources, such as: news for particular events in the given period, census data, economic activity, poverty index, power plants and energy grid data. Our results show high correlation in many of the cases revealing the diversity of socio-economic insights that can be inferred using only mobile phone call data. The methods and the results may be particularly relevant to policy-makers engaged in poverty reduction initiatives as they can provide an affordable tool in the context of resource-constrained developing economies, such as Côte d''Ivoire''s.     

Leaching losses of nitrogen from a clay soil under grass and cereal crops in Finland

Summary A 16-plot experimental field was established in 1975 on a clay soil in Jokioinen, Finland. The water discharge through tile drains was measured and its ammonium and nitrate N contents determined for each plot separately. The surface runoff was also measured and analysed. The annual runoff and the N leached from the surface of moderately fertilized (100 kg/ha/y N) cereal plots varied during 1976–1982 from 21 to 301 mm and from 2 to 7 kg/ha, respectively. The discharge of water and leaching of N through subdrains varied from 65 to 225 mm and from 1 to 38 kg/ha, respectively. The highest leaching was probably caused by a previous fallow. The annual N uptake by the crop varied between 41 and 122 kg/ha.Of the fertilizer-N used for cereals, 20% of that applied in the autumn was lost, but only 1 to 4 per cent was lost when applied in the spring. There was much less N leaching from ley than from barley plots, although the former was given twice as much N. The rate of N fertilization had only a very slight effect on N leaching from both ley and barley plots.The results were compared with those obtained in lysimeters filled with clay, silt, sand and peat soils. No definite conclusions can be drawn because the lysimeter experimental data are only for the first year.