Adenovirus-Mediated Transfer of the CFTR Gene to Lung of Nonhuman Primates: Biological Efficacy Study

Overview summary Recombinant adenoviruses hold tremendous promise for gene therapies of lung disease in cystic fibrosis (CF). An evaluation of the feasibility and safety of this technology in nonhuman primates is critical in the design of clinical protocols. In a series of two papers, Wilson and colleagues describe an extensive study in baboons designed to evaluate the feasibility and safety of direct instillation of CF transmembrane conductance regulator (CFTR)-expressing adenoviruses into the airway. This paper by Engelhardt et al., addresses the biological efficacy of E1-deleted adenoviruses for gene therapy of CF lung disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63146/1/hum.1993.4.6-759.pd

Status, trends, and population demographics of selected sportfish species in the La Grange Reach of the Illinois River

Sportfish species, specifically Yellow Bass Morone mississippiensis, White Bass Morone chrysops, Largemouth Bass Micropterus salmoides, Bluegill Lepomis macrochirus, Black Crappie Pomoxis nigromaculatus, and White Crappie P. annularis, often drive economically valuable fisheries in large river systems, including the Upper Mississippi River System (UMRS). Within the Illinois River, part of the UMRS, these species are routinely sampled by an ongoing long-term fisheries monitoring program. Through this program, we investigated long-term trends (1993-2017) in catch rates and relative weights and quantified demographic rates from 2012-2016. We found all six species, with the exception of Yellow Bass, to have declining catch rates with this decline being most stark in larger, older fishes. Population demographics for Yellow Bass, White Bass, Bluegill, and Black Crappie suggest populations are dominated by younger individuals, with only Black Crappie regularly living to age 3 and older, which may be driving population declines. There are many environmental stressors acting on the Illinois River that could be contributing to the lack of older and larger fishes, including, but not limited to, navigation efforts, altered hydrology, pollution, sedimentation, lack of overwintering habitat, and introduction of invasive species. Results of this study demonstrate that additional research to understand mechanisms driving reduced abundance and stunted age structure are needed to identify effective management actions that would benefit populations of recreationally valuable sportfish species.is peer reviewedOpe

Estimating population size of largemouth bass and black crappie at The Nature Conservancy's Emiquon Preserve prior to reconnection to the Illinois River

Prior to completion of the water control structure at The Nature Conservancy’s Emiquon Nature Preserve (Emiquon), a mark-recapture study was conducted on largemouth bass Micropterus salmoides and black crappie Pomoxis nigromaculatus to estimate the populations of both species. Largemouth bass > 150 mm and black crappie > 100 mm were captured using pulsed-DC electrofishing, fyke nets, and tandem fyke nets and double tagged using T-bar style clear tags. Results of this study show very large populations of both species, with populations of largemouth bass estimated at 21,090 (17,110-27,484) and black crappie estimated at 205,042 (91,198-490,563). Information gained in this study will allow Nature Conservancy managers to make informed decisions on future management actions and allow for potential evaluation of those management actions on two major components of the recreational fishery at Emiquon.Ope

“There was something very peculiar about Doc…”: Deciphering Queer Intimacy in Representations of Doc Holliday

This is an Accepted Manuscript of an article published by Taylor & Francis in American Nineteenth-Century History on 8-12-14, available online: http://dx.doi.org/10.1080/14664658.2014.971481This essay discusses representations of male intimacy in life-writing about consumptive gunfighter John Henry “Doc” Holliday (1851-1887). I argue that twentieth-century commentators rarely appreciated the historical specificity of Holliday’s friendships in a frontier culture that not only normalized but actively celebrated same-sex intimacy. Indeed, Holliday lived on the frayed edges of known nineteenth-century socio-sexual norms, and his interactions with other men were further complicated by his vicious reputation and his disability. His short life and eventful afterlife exposes the gaps in available evidence – and the flaws in our ability to interpret it. Yet something may still be gleaned from the early newspaper accounts of Holliday. Having argued that there is insufficient evidence to justify positioning him within modern categories of hetero/homosexuality, I analyze the language used in pre-1900 descriptions of first-hand encounters with Holliday to illuminate the consumptive gunfighter’s experience of intimacy, if not its meaning

Back to the Shop Floor: Behavioural Insights From Workplace Sociology

This article compares insights into decision-making and behaviour developed by Kahneman and Tversky in behavioural economics with the main findings from studies of pay incentives in workplace sociology in the middle decades of the 20th century. The article shows how many of the insights offered by behavioural economists, such as loss aversion, were anticipated and considered by the workplace sociologists. It is argued that the sociological studies offer deeper and more convincing accounts of worker behaviour through a better understanding of the role of social structure, context, and social processes in framing and influencing action

A multi-targeted approach to suppress tumor-promoting inflammation

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes

Molecular biology of breast cancer metastasis Molecular expression of vascular markers by aggressive breast cancer cells

During embryogenesis, the formation of primary vascular networks occurs via the processes of vasculogenesis and angiogenesis. In uveal melanoma, vasculogenic mimicry describes the 'embryonic-like' ability of aggressive, but not nonaggressive, tumor cells to form networks surrounding spheroids of tumor cells in three-dimensional culture; these recapitulate the patterned networks seen in patients' aggressive tumors and correlates with poor prognosis. The molecular profile of these aggressive tumor cells suggests that they have a deregulated genotype, capable of expressing vascular phenotypes. Similarly, the embryonic-like phenotype expressed by the aggressive human breast cancer cells is associated with their ability to express a variety of vascular markers. These studies may offer new insights for consideration in breast cancer diagnosis and therapeutic intervention strategies

Identification of novel conserved peptide uORF homology groups in Arabidopsis and rice reveals ancient eukaryotic origin of select groups and preferential association with transcription factor-encoding genes

Abstract Background Upstream open reading frames (uORFs) can mediate translational control over the largest, or major ORF (mORF) in response to starvation, polyamine concentrations, and sucrose concentrations. One plant uORF with conserved peptide sequences has been shown to exert this control in an amino acid sequence-dependent manner but generally it is not clear what kinds of genes are regulated, or how extensively this mechanism is invoked in a given genome. Results By comparing full-length cDNA sequences from Arabidopsis and rice we identified 26 distinct homology groups of conserved peptide uORFs, only three of which have been reported previously. Pairwise Ka/Ks analysis showed that purifying selection had acted on nearly all conserved peptide uORFs and their associated mORFs. Functions of predicted mORF proteins could be inferred for 16 homology groups and many of these proteins appear to have a regulatory function, including 6 transcription factors, 5 signal transduction factors, 3 developmental signal molecules, a homolog of translation initiation factor eIF5, and a RING finger protein. Transcription factors are clearly overrepresented in this data set when compared to the frequency calculated for the entire genome (p = 1.2 × 10-7). Duplicate gene pairs arising from a whole genome duplication (ohnologs) with a conserved uORF are much more likely to have been retained in Arabidopsis (Arabidopsis thaliana) than are ohnologs of other genes (39% vs 14% of ancestral genes, p = 5 × 10-3). Two uORF groups were found in animals, indicating an ancient origin of these putative regulatory elements. Conclusion Conservation of uORF amino acid sequence, association with homologous mORFs over long evolutionary time periods, preferential retention after whole genome duplications, and preferential association with mORFs coding for transcription factors suggest that the conserved peptide uORFs identified in this study are strong candidates for translational controllers of regulatory genes.</p

Pleiotropic meta-analysis of cognition, education, and schizophrenia differentiates roles of early neurodevelopmental and adult synaptic pathways

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected (“concordant”) direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive (“discordant”) relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10−8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms—early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways—that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.Peer reviewe