716 research outputs found

    Associations between polygenic risk for psychiatric disorders and substance involvement

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    Despite evidence of substantial comorbidity between psychiatric disorders and substance involvement, the extent to which common genetic factors contribute to their co-occurrence remains understudied. In the current study, we tested for associations between polygenic risk for psychiatric disorders and substance involvement (i.e., ranging from ever-use to severe dependence) among 2573 non-Hispanic European-American participants from the Study of Addiction: Genetics and Environment. Polygenic risk scores (PRS) for cross-disorder psychopathology (CROSS) were generated based on the Psychiatric Genomics Consortiumā€™s Cross-Disorder meta-analysis and then tested for associations with a factor representing general liability to alcohol, cannabis, cocaine, nicotine, and opioid involvement (GENSUB). Follow-up analyses evaluated specific associations between each of the 5 psychiatric disorders which comprised CROSSā€”attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (AUT), bipolar disorder (BIP), major depressive disorder (MDD), and schizophrenia (SCZ)ā€”and involvement with each component substance included in GENSUB. CROSS PRS explained 1.10% of variance in GENSUB in our sample (p<0.001). After correction for multiple testing in our follow-up analyses of polygenic risk for each individual disorder predicting involvement with each component substance, associations remained between: A) MDD PRS and non-problem cannabis use, B) MDD PRS and severe cocaine dependence, C) SCZ PRS and non-problem cannabis use and severe cannabis dependence, and D) SCZ PRS and severe cocaine dependence. These results suggest that shared covariance from common genetic variation contributes to psychiatric and substance involvement comorbidity

    CALHM1-Mediated ATP Release and Ciliary Beat Frequency Modulation in Nasal Epithelial Cells

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    Mechanical stimulation of airway epithelial cells causes apical release of ATP, which increases ciliary beat frequency (CBF) and speeds up mucociliary clearance. The mechanisms responsible for this ATP release are poorly understood. CALHM1, a transmembrane protein with shared structural features to connexins and pannexins, has been implicated in ATP release from taste buds, but it has not been evaluated for a functional role in the airway. In the present study, Calhm1 knockout, Panx1 knockout, and wild-type mouse nasal septal epithelial cells were grown at an air-liquid interface (ALI) and subjected to light mechanical stimulation from an air puff. Apical ATP release was attenuated in Calhm1 knockout cultures following mechanical stimulation at a pressure of 55 mmHg for 50 milliseconds (p \u3c 0.05). Addition of carbenoxolone, a PANX1 channel blocker, completely abolished ATP release in Calhm1 knockout cultures but not in wild type or Panx1 knockout cultures. An increase in CBF was observed in wild-type ALIs following mechanical stimulation, and this increase was significantly lower (p \u3c 0.01) in Calhm1 knockout cultures. These results demonstrate that CALHM1 plays a newly defined role, complementary to PANX1, in ATP release and downstream CBF modulation following a mechanical stimulus in airway epithelial cells. Ā© 2017 The Author(s)

    The role of deficient pain modulatory systems in the development of persistent post-traumatic headaches following mild traumatic brain injury: an exploratory longitudinal study

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    Background: Post-traumatic headache (PTH) is one of the most common and long-lasting symptoms following mild traumatic brain injury (TBI). However, the pathological mechanisms underlying the development of persistent PTH remain poorly understood. The primary purpose of this prospective pilot study was to evaluate whether early pain modulatory profiles (sensitization and endogenous pain inhibitory capacity) and psychological factors after mild TBI predict the development of persistent PTH in mild TBI patients. Methods: Adult mild TBI patients recruited from Level I Emergency Department Trauma Centers completed study sessions at 1-2 weeks, 1-month, and 4-months post mild TBI. Participants completed the following outcome measures during each session: conditioned pain modulation to measure endogenous pain inhibitory capacity, temporal summation of pain and pressure pain thresholds of the head to measure sensitization of the head, Pain Catastrophizing Scale, Center for Epidemiological Studies - Depression Scale, and a standardized headache survey. Participants were classified into persistent PTH (PPTH) and no-PPTH groups based on the 4-month data. Results: The results revealed that mild TBI patients developing persistent PTH exhibited significantly diminished pain inhibitory capacity, and greater depression and pain catastrophizing following injury compared to those who do not develop persistent PTH. Furthermore, logistic regression indicated that headache pain intensity at 1-2 weeks and pain inhibitory capacity on the conditioned pain modulation test at 1-2 weeks predicted persistent PTH classification at 4 months post injury. Conclusions: Overall, the results suggested that persistent PTH is characterized by dysfunctional alterations in endogenous pain modulatory function and psychological processes in the early stages following mild TBI, which likely exacerbate risk for the maintenance of PTH

    Loss of CFTR function is associated with reduced bitter taste receptor-stimulated nitric oxide innate immune responses in nasal epithelial cells and macrophages

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    IntroductionBitter taste receptors (T2Rs) are G protein-coupled receptors identified on the tongue but expressed all over the body, including in airway cilia and macrophages, where T2Rs serve an immune role. T2R isoforms detect bitter metabolites (quinolones and acyl-homoserine lactones) secreted by gram negative bacteria, including Pseudomonas aeruginosa, a major pathogen in cystic fibrosis (CF). T2R activation by bitter bacterial products triggers calcium-dependent nitric oxide (NO) production. In airway cells, the NO increases mucociliary clearance and has direct antibacterial properties. In macrophages, the same pathway enhances phagocytosis. Because prior studies linked CF with reduced NO, we hypothesized that CF cells may have reduced T2R/NO responses, possibly contributing to reduced innate immunity in CF.MethodsImmunofluorescence, qPCR, and live cell imaging were used to measure T2R localization, calcium and NO signaling, ciliary beating, and antimicrobial responses in air-liquid interface cultures of primary human nasal epithelial cells and immortalized bronchial cell lines. Immunofluorescence and live cell imaging was used to measure T2R signaling and phagocytosis in primary human monocyte-derived macrophages.ResultsPrimary nasal epithelial cells from both CF and non-CF patients exhibited similar T2R expression, localization, and calcium signals. However, CF cells exhibited reduced NO production also observed in immortalized CFBE41o- CF cells and non-CF 16HBE cells CRISPR modified with CF-causing mutations in the CF transmembrane conductance regulator (CFTR). NO was restored by VX-770/VX-809 corrector/potentiator pre-treatment, suggesting reduced NO in CF cells is due to loss of CFTR function. In nasal cells, reduced NO correlated with reduced ciliary and antibacterial responses. In primary human macrophages, inhibition of CFTR reduced NO production and phagocytosis during T2R stimulation.ConclusionsTogether, these data suggest an intrinsic deficiency in T2R/NO signaling caused by loss of CFTR function that may contribute to intrinsic susceptibilities of CF patients to P. aeruginosa and other gram-negative bacteria that activate T2Rs

    The Grizzly, September 24, 2015

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    CIE Professors Lend a Hand at Columbia U. ā€¢ As Rush Week Ends, Greek Numbers Defy Expectations ā€¢ Getting Back on Track ā€¢ Healthy Addition: HEP Welcomes Rugby Coach to Faculty Lineup ā€¢ Improving the Higher Education Experience ā€¢ UC Student Trains Service Dog on Campus ā€¢ Students Work with College Communications Office ā€¢ Main Street Life: Upperclassmen Debate Housing\u27s Pros and Cons ā€¢ Opinions: The Visit Rates 5 / 10; Extra-curricular Options for Students ā€¢ Going Pro : Symposium on Sports Business and the Entrepreneurial Mindset Comes to Ursinus ā€¢ Looking to Three-peathttps://digitalcommons.ursinus.edu/grizzlynews/1671/thumbnail.jp

    Pharmacokinetics and Efficacy of PEGylated Liposomal Doxorubicin in an Intracranial Model of Breast Cancer

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    Breast cancer brain metastases (BCBM) are a challenging consequence of advanced BC. Nanoparticle agents, including liposomes, have shown enhanced delivery to solid tumors and brain. We compared pharmacokinetics (PK) and efficacy of PEGylated liposomal doxorubicin (PLD) with non-liposomal doxorubicin (NonL-doxo) in an intracranial model of BC

    The prognostic contribution of clinical breast cancer subtype, age, and race among patients with breast cancer brain metastases

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    Brain metastases (BM) arising from Triple-negative breast cancer (TNBC) portend poor prognosis. TNBC is more common in premenopausal and African-American (AA) patients; both also confer poor prognosis. In a single institution cohort study, we sought to determine if inferior outcome of TN BCBM is more reflective of a higher-risk population or subtype itself

    Carbon Dioxide Fluxes Reflect Plant Zonation and Belowground Biomass in a Coastal Marsh

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    Coastal wetlands are major global carbon sinks; however, they are heterogeneous and dynamic ecosystems. To characterize spatial and temporal variability in a New England salt marsh, greenhouse gas (GHG) fluxes were compared among major plant-defined zones during growing seasons. Carbon dioxide (CO2) and methane (CH4) fluxes were compared in two mensurative experiments during summer months (2012ā€“2014) that included low marsh (Spartina alterniflora), high marsh (Distichlis spicata and Juncus gerardiidominated), invasive Phragmites australis zones, and unvegetated ponds. Day- and nighttime fluxes were also contrasted in the native marsh zones. N2O fluxes were measured in parallel with CO2 and CH4 fluxes, but were not found to be significant. To test the relationships of CO2 and CH4 fluxes with several native plant metrics, a multivariate nonlinear model was used. Invasive P. australis zones (āˆ’7 to āˆ’15 Ī¼mol CO2Ā·māˆ’2Ā·sāˆ’1) and S. alterniflora low marsh zones (up to āˆ’14 Ī¼mol CO2Ā·māˆ’2Ā·sāˆ’1) displayed highest average CO2 uptake rates, while those in the native high marsh zone (less than āˆ’2 Ī¼mol CO2Ā·māˆ’2Ā·sāˆ’1) were much lower. Unvegetated ponds were typically small sources of CO2 to the atmosphere (\u3c0.5 Ī¼mol CO2Ā·māˆ’2Ā·sāˆ’1). Nighttime emissions of CO2 averaged only 35% of daytime uptake in the low marsh zone, but they exceeded daytime CO2 uptake by up to threefold in the native high marsh zone. Based on modeling, belowground biomass was the plant metric most strongly correlated with CO2 fluxes in native marsh zones, while none of the plant variables correlated significantly with CH4 fluxes. Methane fluxes did not vary between day and night and did not significantly offset CO2 uptake in any vegetated marsh zones based on sustained global warming potential calculations. These findings suggest that attention to spatial zonation as well as expanded measurements and modeling of GHG emissions across greater temporal scales will help to improve accuracy of carbon accounting in coastal marshe

    Carbon Dioxide Fluxes Reflect Plant Zonation and Belowground Biomass in a Coastal Marsh

    Get PDF
    Coastal wetlands are major global carbon sinks; however, they are heterogeneous and dynamic ecosystems. To characterize spatial and temporal variability in a New England salt marsh, greenhouse gas (GHG) fluxes were compared among major plant-defined zones during growing seasons. Carbon dioxide (CO2) and methane (CH4) fluxes were compared in two mensurative experiments during summer months (2012ā€“2014) that included low marsh (Spartina alterniflora), high marsh (Distichlis spicata and Juncus gerardiidominated), invasive Phragmites australis zones, and unvegetated ponds. Day- and nighttime fluxes were also contrasted in the native marsh zones. N2O fluxes were measured in parallel with CO2 and CH4 fluxes, but were not found to be significant. To test the relationships of CO2 and CH4 fluxes with several native plant metrics, a multivariate nonlinear model was used. Invasive P. australis zones (āˆ’7 to āˆ’15 Ī¼mol CO2Ā·māˆ’2Ā·sāˆ’1) and S. alterniflora low marsh zones (up to āˆ’14 Ī¼mol CO2Ā·māˆ’2Ā·sāˆ’1) displayed highest average CO2 uptake rates, while those in the native high marsh zone (less than āˆ’2 Ī¼mol CO2Ā·māˆ’2Ā·sāˆ’1) were much lower. Unvegetated ponds were typically small sources of CO2 to the atmosphere (\u3c0.5 Ī¼mol CO2Ā·māˆ’2Ā·sāˆ’1). Nighttime emissions of CO2 averaged only 35% of daytime uptake in the low marsh zone, but they exceeded daytime CO2 uptake by up to threefold in the native high marsh zone. Based on modeling, belowground biomass was the plant metric most strongly correlated with CO2 fluxes in native marsh zones, while none of the plant variables correlated significantly with CH4 fluxes. Methane fluxes did not vary between day and night and did not significantly offset CO2 uptake in any vegetated marsh zones based on sustained global warming potential calculations. These findings suggest that attention to spatial zonation as well as expanded measurements and modeling of GHG emissions across greater temporal scales will help to improve accuracy of carbon accounting in coastal marshe
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