Genes and Gene Ontologies Common to Airflow Obstruction and Emphysema in the Lungs of Patients with COPD

Chronic obstructive pulmonary disease (COPD) is a major public health problem with increasing prevalence worldwide. The primary aim of this study was to identify genes and gene ontologies associated with COPD severity. Gene expression profiling was performed on total RNA extracted from lung tissue of 18 former smokers with COPD. Class comparison analysis on mild (n = 9, FEV1 80–110% predicted) and moderate (n = 9, FEV1 50–60% predicted) COPD patients identified 46 differentially expressed genes (p<0.01), of which 14 genes were technically confirmed by quantitative real-time-PCR. Biological replication in an independent test set of 58 lung samples confirmed the altered expression of ten genes with increasing COPD severity, with eight of these genes (NNMT, THBS1, HLA-DPB1, IGHD, ETS2, ELF1, PTGDS and CYRBD1) being differentially expressed by greater than 1.8 fold between mild and moderate COPD, identifying these as candidate determinants of COPD severity. These genes belonged to ontologies potentially implicated in COPD including angiogenesis, cell migration, proliferation and apoptosis. Our secondary aim was to identify gene ontologies common to airway obstruction, indicated by impaired FEV1 and KCO. Using gene ontology enrichment analysis we have identified relevant biological and molecular processes including regulation of cell-matrix adhesion, leukocyte activation, cell and substrate adhesion, cell adhesion, angiogenesis, cell activation that are enriched among genes involved in airflow obstruction. Exploring the functional significance of these genes and their gene ontologies will provide clues to molecular changes involved in severity of COPD, which could be developed as targets for therapy or biomarkers for early diagnosis

Sex stereotypes influence adults' perception of babies' cries

Background: Despite widespread evidence that gender stereotypes influence human parental behavior, their potential effects on adults’ perception of babies’ cries have been overlooked. In particular, whether adult listeners overgeneralize the sex dimorphism that characterizes the voice of adult speakers (men are lower-pitched than women) to their perception of babies’ cries has not been investigated. Methods: We used playback experiments combining natural and re-synthesised cries of 3 month-old babies to investigate whether the interindividual variation in the fundamental frequency (pitch) of cries affected adult listeners’ identification of the baby’s sex, their perception the baby’s femininity and masculinity, and whether these biases interacted with their perception of the level of discomfort expressed by the cry. Results: We show that low-pitched cries are more likely to be attributed to boys and high-pitched cries to girls, despite the absence of sex differences in pitch. Moreover, low-pitched boys are perceived as more masculine and high-pitched girls are perceived as more feminine. Finally, adult men rate relatively low-pitched cries as expressing more discomfort when presented as belonging to boys than to girls. Conclusion: Such biases in caregivers’ responses to babies’ cries may have implications on children’s immediate welfare and on the development of their gender identity

Gestational Valproate Alters BOLD Activation in Response to Complex Social and Primary Sensory Stimuli

Valproic acid (VPA) has been used clinically as an anticonvulsant medication during pregnancy; however, it poses a neurodevelopmental risk due to its high teratogenicity. We hypothesized that midgestational (GD) exposure to VPA will lead to lasting deficits in social behavior and the processing of social stimuli. To test this, animals were given a single IP injection of 600 mg/kg of VPA on GD 12.5. Starting on postnatal day 2 (PND2), animals were examined for physical and behavior abnormalities. Functional MRI studies were carried out after PND60. VPA and control animals were given vehicle or a central infusion of a V1a antagonist 90 minutes before imaging. During imaging sessions, rats were presented with a juvenile test male followed by a primary visual stimulus (2 Hz pulsed light) to examine the effects of prenatal VPA on neural processing. VPA rats showed greater increases in BOLD signal response to the social stimulus compared to controls in the temporal cortex, thalamus, midbrain and the hypothalamus. Blocking the V1a receptor reduced the BOLD response in VPA animals only. Neural responses to the visual stimulus, however, were lower in VPA animals. Blockade with the V1a antagonist did not revert this latter effect. Our data suggest that prenatal VPA affects the processing of social stimuli and perhaps social memory, partly through a mechanism that may involve vasopressin V1a neurotransmission

Using Molecular Mechanics to Predict Bulk Material Properties of Fibronectin Fibers

The structural proteins of the extracellular matrix (ECM) form fibers with finely tuned mechanical properties matched to the time scales of cell traction forces. Several proteins such as fibronectin (Fn) and fibrin undergo molecular conformational changes that extend the proteins and are believed to be a major contributor to the extensibility of bulk fibers. The dynamics of these conformational changes have been thoroughly explored since the advent of single molecule force spectroscopy and molecular dynamics simulations but remarkably, these data have not been rigorously applied to the understanding of the time dependent mechanics of bulk ECM fibers. Using measurements of protein density within fibers, we have examined the influence of dynamic molecular conformational changes and the intermolecular arrangement of Fn within fibers on the bulk mechanical properties of Fn fibers. Fibers were simulated as molecular strands with architectures that promote either equal or disparate molecular loading under conditions of constant extension rate. Measurements of protein concentration within micron scale fibers using deep ultraviolet transmission microscopy allowed the simulations to be scaled appropriately for comparison to in vitro measurements of fiber mechanics as well as providing estimates of fiber porosity and water content, suggesting Fn fibers are approximately 75% solute. Comparing the properties predicted by single molecule measurements to in vitro measurements of Fn fibers showed that domain unfolding is sufficient to predict the high extensibility and nonlinear stiffness of Fn fibers with surprising accuracy, with disparately loaded fibers providing the best fit to experiment. This work shows the promise of this microstructural modeling approach for understanding Fn fiber properties, which is generally applicable to other ECM fibers, and could be further expanded to tissue scale by incorporating these simulated fibers into three dimensional network models

Computational On-Chip Imaging of Nanoparticles and Biomolecules using Ultraviolet Light

Significant progress in characterization of nanoparticles and biomolecules was enabled by the development of advanced imaging equipment with extreme spatial-resolution and sensitivity. To perform some of these analyses outside of well-resourced laboratories, it is necessary to create robust and cost-effective alternatives to existing high-end laboratory-bound imaging and sensing equipment. Towards this aim, we have designed a holographic on-chip microscope operating at an ultraviolet illumination wavelength (UV) of 266 nm. The increased forward scattering from nanoscale objects at this short wavelength has enabled us to detect individual sub-30 nm nanoparticles over a large field-of- view of > 16 mm(2) using an on-chip imaging platform, where the sample is placed at <= 0.5 mm away from the active area of an opto-electronic sensor-array, without any lenses in between. The strong absorption of this UV wavelength by biomolecules including nucleic acids and proteins has further enabled high-contrast imaging of nanoscopic aggregates of biomolecules, e.g., of enzyme Cu/Zn-superoxide dismutase, abnormal aggregation of which is linked to amyotrophic lateral sclerosis (ALS)-a fatal neurodegenerative disease. This UV-based wide-field computational imaging platform could be valuable for numerous applications in biomedical sciences and environmental monitoring, including disease diagnostics, viral load measurements as well as air-and water-quality assessment.Army Research Office (ARO) [W911NF-13-1-0419, W911NF-13-1-0197]; ARO Life Sciences Division; National Science Foundation (NSF) CBET Division Biophotonics Program; NSF Emerging Frontiers in Research and Innovation (EFRI) Award; NSF EAGER Award; NSF INSPIRE Award; NSF Partnerships for Innovation; Building Innovation Capacity (PFI: BIC) Program; Office of Naval Research (ONR); National Institutes of Health (NIH); Howard Hughes Medical Institute (HHMI); Vodafone Americas Foundation; Vodafone Americas Foundation, the Mary Kay Foundation; Steven & Alexandra Cohen Foundation; KAUST; RGK Foundation [20143057]; National Science Foundation [0963183]; American Recovery and Reinvestment Act of 2009 (ARRA)This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Maternal fluoxetine infusion does not alter fetal endocrine and biophysical circadian rhythms in pregnant sheep

ObjectiveDepression during pregnancy is frequently treated with the selective serotonin reuptake inhibitor (SSRI), fluoxetine (FX), commonly known as Prozac (Eli Lilly & Co, Indianapolis, IN). FX potentiates serotoninergic neurotransmission and serotonin has been implicated in the regulation of circadian rhythms. We have therefore investigated the effect of chronic administration of FX on maternal and fetal circadian rhythms in sheep.MethodsFollowing an initial bolus dose of 70 mg FX, an 8-day continuous infusion of FX (n = 11, 98.5 microg/kg x d) was performed. Controls (n = 13) were treated with sterile water vehicle only. Maternal and fetal plasma melatonin and prolactin concentrations were determined every 3 hours for 24 hours and then every 6 hours for 24 hours beginning on the fourth day of infusion.ResultsFX treatment did not alter either the basal or circadian rhythms of either maternal or fetal plasma melatonin and prolactin concentrations. Fetal cardiovascular and behavioral state parameters were measured continuously. While the incidence of low-voltage (LV) electrocortical (ECOG) activity was significantly reduced in fetuses in the FX group, there was no effect of FX on the diurnal rhythms in fetal arterial pressure, heart rate, breathing movements, or behavioral state.ConclusionThese results show that maternal FX treatment does not result in significant alterations in maternal and fetal hormonal and behavioral circadian rhythms.Janna L. Morrison, Dan W. Rurak, Caly Chien, David J. Kennaway, Nancy Gruber, I. Caroline McMillen, and K. Wayne Rigg