Environmental Scan: Metro Regional Report

In 2010, the Extension Center for Family Development of the University of Minnesota launched a project to learn more about the current and future issues affecting families in Minnesota. During this environmental scan project, community-level interviews were conducted in 11 different regions of the state. This report summarizes the community-level interviews conducted in metro Minnesota. University of Minnesota Extension Center for Family Development staff members — Ali Shurilla, Mary Marczak, Jon Fu, and Heather Lee — assisted in the development of this report.This archival publication may not reflect current scientific knowledge or recommendations. Current information available from the University of Minnesota Extension: https://www.extension.umn.edu

Active Methodologies in Higher Education: Perception and Opinion as Evaluated by Professors and Their Students in the Teaching-Learning Process

The goal of this study is both to determine the opinion that professors and students at the university have of active methodologies and to describe the perception and opinion of the modes of organization, methodological focuses, and evaluation systems that define the teaching-learning process. On surveying the professors and the students in their classes, we found significant differences in 32 of the 92 variables in common. The content of these results shows that professors and students are believe they are making progress toward a learning-centered model, that implementation of active methodologies implies new functions in their teaching practice

Critical Role of Constitutive Type I Interferon Response in Bronchial Epithelial Cell to Influenza Infection

Innate antiviral responses in bronchial epithelial cells (BECs) provide the first line of defense against respiratory viral infection and the effectiveness of this response is critically dependent on the type I interferons (IFNs). However the importance of the antiviral responses in BECs during influenza infection is not well understood. We profiled the innate immune response to infection with H3N2 and H5N1 virus using Calu-3 cells and primary BECs to model proximal airway cells. The susceptibility of BECs to influenza infection was not solely dependent on the sialic acid-bearing glycoprotein, and antiviral responses that occurred after viral endocytosis was more important in limiting viral replication. The early antiviral response and apoptosis correlated with the ability to limit viral replication. Both viruses reduced RIG-I associated antiviral responses and subsequent induction of IFN-β. However it was found that there was constitutive release of IFN-β by BECs and this was critical in inducing late antiviral signaling via type I IFN receptors, and was crucial in limiting viral infection. This study characterizes anti-influenza virus responses in airway epithelial cells and shows that constitutive IFN-β release plays a more important role in initiating protective late IFN-stimulated responses during human influenza infection in bronchial epithelial cells

Interdisciplinary-driven hypotheses on spatial associations of mixtures of industrial air pollutants with adverse birth outcomes

Background: Adverse birth outcomes (ABO) such as prematurity and small for gestational age confer a high risk of mortality and morbidity. ABO have been linked to air pollution; however, relationships with mixtures of industrial emissions are poorly understood. The exploration of relationships between ABO and mixtures is complex when hundreds of chemicals are analyzed simultaneously, requiring the use of novel approaches. Objective: We aimed to generate robust hypotheses spatially linking mixtures and the occurrence of ABO using a spatial data mining algorithm and subsequent geographical and statistical analysis. The spatial data mining approach aimed to reduce data dimensionality and efficiently identify spatial associations between multiple chemicals and ABO. Methods: We discovered co-location patterns of mixtures and ABO in Alberta, Canada (2006–2012). An ad-hoc spatial data mining algorithm allowed the extraction of primary co-location patterns of 136 chemicals released into the air by 6279 industrial facilities (National Pollutant Release Inventory), wind-patterns from 182 stations, and 333,247 singleton live births at the maternal postal code at delivery (Alberta Perinatal Health Program), from which we identified cases of preterm birth, small for gestational age, and low birth weight at term. We selected secondary patterns using a lift ratio metric from ABO and non-ABO impacted by the same mixture. The relevance of the secondary patterns was estimated using logistic models (adjusted by socioeconomic status and ABO-related maternal factors) and a geographic-based assignment of maternal exposure to the mixtures as calculated by kernel density. Results: From 136 chemicals and three ABO, spatial data mining identified 1700 primary patterns from which five secondary patterns of three-chemical mixtures, including particulate matter, methyl-ethyl-ketone, xylene, carbon monoxide, 2-butoxyethanol, and n-butyl alcohol, were subsequently analyzed. The significance of the associations (odds ratio > 1) between the five mixtures and ABO provided statistical support for a new set of hypotheses. Conclusion: This study demonstrated that, in complex research settings, spatial data mining followed by pattern selection and geographic and statistical analyses can catalyze future research on associations between air pollutant mixtures and adverse birth outcomes

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Shared heritability and functional enrichment across six solid cancers

Correction: Nature Communications 10 (2019): art. 4386 DOI: 10.1038/s41467-019-12095-8Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.Peer reviewe

Shared heritability and functional enrichment across six solid cancers

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities