Schizophrenia: Genome, Interrupted

Structural chromosomal variation is increasingly recognized as an important contributor to human diseases, particularly those of neurodevelopment, such as autism. A current paper makes a significant advance to schizophrenia genetics by establishing an association with rare copy number variants (CNV), which are over-represented in neurodevelopmental genes

Replication of linkage at chromosome 20p13 and identification of suggestive sex-differential risk loci for autism spectrum disorder.

BackgroundAutism spectrum disorders (ASDs) are male-biased and genetically heterogeneous. While sequencing of sporadic cases has identified de novo risk variants, the heritable genetic contribution and mechanisms driving the male bias are less understood. Here, we aimed to identify familial and sex-differential risk loci in the largest available, uniformly ascertained, densely genotyped sample of multiplex ASD families from the Autism Genetics Resource Exchange (AGRE), and to compare results with earlier findings from AGRE.MethodsFrom a total sample of 1,008 multiplex families, we performed genome-wide, non-parametric linkage analysis in a discovery sample of 847 families, and separately on subsets of families with only male, affected children (male-only, MO) or with at least one female, affected child (female-containing, FC). Loci showing evidence for suggestive linkage (logarithm of odds ≥2.2) in this discovery sample, or in previous AGRE samples, were re-evaluated in an extension study utilizing all 1,008 available families. For regions with genome-wide significant linkage signal in the discovery stage, those families not included in the corresponding discovery sample were then evaluated for independent replication of linkage. Association testing of common single nucleotide polymorphisms (SNPs) was also performed within suggestive linkage regions.ResultsWe observed an independent replication of previously observed linkage at chromosome 20p13 (P < 0.01), while loci at 6q27 and 8q13.2 showed suggestive linkage in our extended sample. Suggestive sex-differential linkage was observed at 1p31.3 (MO), 8p21.2 (FC), and 8p12 (FC) in our discovery sample, and the MO signal at 1p31.3 was supported in our expanded sample. No sex-differential signals met replication criteria, and no common SNPs were significantly associated with ASD within any identified linkage regions.ConclusionsWith few exceptions, analyses of subsets of families from the AGRE cohort identify different risk loci, consistent with extreme locus heterogeneity in ASD. Large samples appear to yield more consistent results, and sex-stratified analyses facilitate the identification of sex-differential risk loci, suggesting that linkage analyses in large cohorts are useful for identifying heritable risk loci. Additional work, such as targeted re-sequencing, is needed to identify the specific variants within these loci that are responsible for increasing ASD risk

Enhanced Integrin α4β1-Mediated Adhesion Contributes to a Mobilization Defect of Endothelial Progenitor Cells in Diabetes.

Diabetes is associated with a deficit of circulating endothelial progenitor cells (EPCs), which has been attributed to their defective mobilization from the bone marrow. The basis for this mobilization defect is not completely understood, and we sought to determine if hyperglycemic conditions enhanced EPC adhesion. We found that culturing EPCs in high glucose media increased adhesion to bone marrow stromal cells. This enhanced adhesion was associated with decreased expression of protein kinase A regulatory subunit 1β (PRKAR1β), activation of protein kinase A (PKA), and phosphorylation of α4-integrin on serine 988. This potentiated adhesion was reversed by treatment with a PKA inhibitor, overexpression of PRKAR1β, or expression of a phosphorylation-defective α4-integrin variant (α4[S988A]). Using a model of type 1 diabetes, we showed that α4(S988A)-expressing mice have more circulating EPCs than their wild-type counterparts. Moreover, diabetic α4(S988A) mice demonstrate enhanced revascularization after hind limb ischemia. Thus, we have identified a novel signaling mechanism activating PKA in diabetes (downregulation of an inhibitory regulatory subunit) that leads to deficits of circulating EPCs and impaired vascular repair, which could be reversed by α4-integrin mutation

Epidemiology of Gastrointestinal Nematodes in Grazing Yearling Beef Cattle in Saskatchewan

Gastrointestinal nematodes (GIN) in beef cattle can be a concern for cattle producers due to loss in profit associated with anthelmintic treatment costs and reduced production performance. There is limited current information regarding the epidemiology of GIN in grazing yearling beef cattle in western Canada. Hence, the objectives of this research were to: 1) describe the epidemiology of GIN and assess their impact on weight gain (Chapter 2), and 2) conduct a nemabiome study to determine the diversity and abundance of nematode species within Saskatchewan pastured beef cattle (Chapter 3). Seventeen cohorts of pastured yearling beef cattle were processed in the spring and fall of 2019. Animals were individually weighed, and rectal fecal samples obtained for pooled fecal egg count (FEC). A subset of calves (n = 25) in each herd was administered oral fenbendazole (Safeguard®, Merck, Canada) and a parenterally administered extended-release eprinomectin (LongRange®, Boehringer Ingelheim, Canada), while the remaining cohort was left untreated. Eggs per gram of feces (EPG) were determined in pooled fecal samples using the Modified Wisconsin Sugar Flotation Technique, and deep amplicon nemabiome sequencing of the ITS-2 DNA locus was used to describe nematode species diversity and abundance. Across all cattle (n = 867), there were differences between treatment and control groups regarding FEC (p < 0.01). In the generalized estimating equations (GEE) model, FEC decreased by 44 times over the grazing season, and FEC were 1.8 times greater on pastures located in black/gray soil versus dark brown soil zones. Areas with higher precipitation also had higher FEC. There was no significant difference (p = 0.41) in the ADG across all cattle, but differences were found in the ADG between treated and control cattle in five cohorts. Haemonchus placei was found in all spring cohorts, accounting for 30% of the L3 species composition. Hence, it was one of the dominant species together with Ostertagia ostertagi (40%) and Cooperia oncophora (26.2%). Ostertagia ostertagi (47.5%) and C. oncophora (42.0%) were the most common species recovered at the time of fall sampling. Haemonchus placei represented 5.2% of the species diversity at the time of fall sampling, which is higher than previously reported in western Canada. The lack of correlation between FEC and ADG is likely due to differences in farm-specific environmental conditions (rain, temperature), soil type and husbandry factors

Transcriptomic analysis of autistic brain reveals convergent molecular pathology.

Autism spectrum disorder (ASD) is a common, highly heritable neurodevelopmental condition characterized by marked genetic heterogeneity. Thus, a fundamental question is whether autism represents an aetiologically heterogeneous disorder in which the myriad genetic or environmental risk factors perturb common underlying molecular pathways in the brain. Here, we demonstrate consistent differences in transcriptome organization between autistic and normal brain by gene co-expression network analysis. Remarkably, regional patterns of gene expression that typically distinguish frontal and temporal cortex are significantly attenuated in the ASD brain, suggesting abnormalities in cortical patterning. We further identify discrete modules of co-expressed genes associated with autism: a neuronal module enriched for known autism susceptibility genes, including the neuronal specific splicing factor A2BP1 (also known as FOX1), and a module enriched for immune genes and glial markers. Using high-throughput RNA sequencing we demonstrate dysregulated splicing of A2BP1-dependent alternative exons in the ASD brain. Moreover, using a published autism genome-wide association study (GWAS) data set, we show that the neuronal module is enriched for genetically associated variants, providing independent support for the causal involvement of these genes in autism. In contrast, the immune-glial module showed no enrichment for autism GWAS signals, indicating a non-genetic aetiology for this process. Collectively, our results provide strong evidence for convergent molecular abnormalities in ASD, and implicate transcriptional and splicing dysregulation as underlying mechanisms of neuronal dysfunction in this disorder

Magnetic field dependence of the internal quality factor and noise performance of lumped-element kinetic inductance detectors

We present a technique for increasing the internal quality factor of kinetic inductance detectors (KIDs) by nulling ambient magnetic fields with a properly applied magnetic field. The KIDs used in this study are made from thin-film aluminum, they are mounted inside a light-tight package made from bulk aluminum, and they are operated near $150 \, \mathrm{mK}$. Since the thin-film aluminum has a slightly elevated critical temperature ($T_\mathrm{c} = 1.4 \, \mathrm{K}$), it therefore transitions before the package ($T_\mathrm{c} = 1.2 \, \mathrm{K}$), which also serves as a magnetic shield. On cooldown, ambient magnetic fields as small as approximately $30 \, \mathrm{\mu T}$ can produce vortices in the thin-film aluminum as it transitions because the bulk aluminum package has not yet transitioned and therefore is not yet shielding. These vortices become trapped inside the aluminum package below $1.2 \, \mathrm{K}$ and ultimately produce low internal quality factors in the thin-film superconducting resonators. We show that by controlling the strength of the magnetic field present when the thin film transitions, we can control the internal quality factor of the resonators. We also compare the noise performance with and without vortices present, and find no evidence for excess noise beyond the increase in amplifier noise, which is expected with increasing loss.Comment: 5 pages, 4 figure

Long-term efficacy of endoscopic cyclophotocoagulation in the management of glaucoma following cataract surgery in children

Purpose To report the long-term efficacy of endoscopic cyclophotocoagulation (ECP) in pediatric glaucoma following cataract surgery (GFCS). Methods ECP was performed on 35 eyes of 25 patients 24 mm Hg, alternative glaucoma procedure following ECP, or occurrence of visually significant complications. Analysis was performed to estimate risk factors for failure. Results A total of 27 aphakic and 8 pseudophakic eyes were included. Pretreatment IOP averaged 33.9 ± 7.9 mm Hg. Final IOP after a mean follow-up period of 7.2 years was 18.9 ± 8.8 mm Hg (P < 0.001). The success rate was 54% (19/35 eyes). The failure rate was not increased in pseudophakic patients relative to aphakic patients. Patients with single ECP demonstrated preserved visual acuity from baseline to final follow-up. Conclusions In this patient cohort, with average follow-up period of 7.2 years, ECP was useful in the treatment of pediatric GFCS

Estandarización de la Cría Masiva de Apanteles gelechiidivoris Marsh (Hymenoptera: Braconidae) para el Control de Tuta Absoluta Meyrick (Lepidoptera: Gelechiidae)

Tuta absoluta Meyrick (Lepidoptera: Gelechiidae) is a limitin pest of tomato corps which can reduces production up to 90%. For T. absoluta the parasitic action of Apanteles gelechiidivoris on third instar larvae have been documented, being responsible of around 80% mortality larvae in crops where the parasitoid is released. With the purpose of make periodic releases in the field, in the Military University Nueva Granada efforts are being made to design and implement a massive rearing system that allows obtain the parasitoid in the needed quantities with a suitable quality. To initiate this process was necessary to determine the maximum density of T. absoluta supported by tomato plants in order to ensure a host supply for (Apanteles gelechiidivoris). In this study seven infestation densities with T. absoluta on tomato plants were evaluated: 0, 4, 8, 12, 16, 20 y 24 females/ plant. The highest densities (20 and 24 females/plant) affected negatively the plant and did not allow to T. absoluta complete its development. The best results were obtained with 12 females/plant, which provides a high production of females and third instar larvae susceptible to parasitization. Subsequently, densities of 4, 8, 12, 16 y 20 females/plant were evaluated to determine its effect on longevity, percentage parasitism and sex ratio. The quality variables were not negatively affected when 8 females/plant were used. Finally a comparison between productions systems with and without implementing the results obtained was made. The quantity of adults and female (for the pest and the parasitoid respectively) obtained was registered and a evaluation of costs was made. The production of phytophagous and parasitoid females increased between 50-70% in the system implemented with the recommendations of this research, leading to reduction in the production costs around 73.6%.Tuta absoluta Meyrick (Lepidoptera: Gelechiidae) es una plaga limitante de la producción de tomate hasta de un 90%. En el caso de T. absoluta se reconoce la acción parasítica de Apanteles gelechiidivoris sobre larvas de tercer instar siendo responsable de hasta un 80% de la mortalidad de larvas en cultivos de tomate. Con el objetivo de realizar liberaciones periódicas de parasitoides en campo, en la Facultad de Ciencias de la Universidad Militar Nueva Granada se busca diseñar e implementar un proceso de cría masiva de parasitoides, que permita obtener cantidad constante y de buena calidad. Para iniciar este proceso fue necesario identificar la densidad óptima de la infestación de T. absoluta en las plantas de tomate y la densidad óptima de liberación del parasitoide (Apanteles gelechiidivoris) para producir hembras que cumplan con los parámetros de calidad. El estudio incluyó siete densidades de infestación de Tuta absoluta 0, 4, 8, 12, 16, 20 y 24 hembras / planta. . Se encontró que las densidades de 20 y 24 hembras/planta afectan negativamente las variables de la planta y no permiten el desarrollo completo de Tuta absoluta. La densidad de 12 hembrasdel fitófago/planta aunque tuvo un efecto en las variables de crecimiento y desarrollo de la planta, permitió una mayor producción no solo de hembras de Tuta absoluta, sino larvas de tercer instar susceptibles a parasitación. Posteriormente se evaluaron 4, 8, 12, 16 y 20 hembras del parasitoide/planta y se registró la longevidad, porcentaje de parasitismo y proporción sexual. Se encontró que la densidad 8 hembras/plantano afecta los parámetros de calidad evaluados. Finalmente se realizó una comparación entre un sistema con la implementación de los resultados obtenidos y otro sin la implementación. Se registró cantidad de adultos y hembras (plaga y parasitoide) obtenidos en ambos sistemas y se calculó el costo. Se obtuvoun aumento de un 50% al 70% en la producción tanto del fitófago como del parasitoide en el sistema de cría implementado y una disminución en el costo por avispa del 73.6%