Cholesterol is the major component of native lipoproteins activating the p38 mitogen-activated protein kinases

Elevated low-density lipoprotein (LDL) levels induce activation of the p38 mitogen-activated protein kinase (MAPK), a stress-activated protein kinase potentially participating in the development of atherosclerosis. The nature of the lipoprotein components inducing p38 MAPK activation has remained unclear however. We show here that both LDLs and high-density lipoproteins (HDLs) have the ability to stimulate the p38 MAPKs with potencies that correlate with their cholesterol content. Cholesterol solubilized in methyl-β-cyclodextrin was sufficient to activate the p38 MAPK pathway. Liposomes made of phosphatidylcholine (PC) or sphingomyelin, the two main phospholipids found in lipoproteins, were unable to stimulate the p38 MAPKs. In contrast, PC liposomes loaded with cholesterol potently activated this pathway. Reducing the cholesterol content of LDL particles lowered their ability to activate the p38 MAPKs. Cell lines representative of the three main cell types found in blood vessels (endothelial cells, smooth muscle cells and fibroblasts) all activated their p38 MAPK pathway in response to LDLs or cholesterol-loaded PC liposomes. These results indicate that elevated cholesterol content in lipoproteins, as seen in hypercholesterolemia, favors the activation of the stress-activated p38 MAPK pathway in cells from the vessel wall, an event that might contribute to the development of atherosclerosi

Learning Design through the Lens of Service: A Qualitative Study

Twenty-four senior-level capstone engineering design projects were completed at a large, public, primarily undergraduate university involving 85 students (70 male and 15 female). All projects involved the design of equipment to facilitate physical activity for people with disabilities. The effects on: i) learning design, ii) attitude towards people with disabilities, iii) motivation to complete team design projects and iv) interdisciplinary collaboration were analyzed through 24 one-hour focus groups. We explored the student experience using a constructivist approach and grounded theory. Four major themes (with associated sub-themes) emerged from our data analysis: learning design (project management, iterative design process, and user-centered design), motivation to complete design (engineering, disabilities, user), perceptions of people with disabilities (previous experience, changed attitudes and beliefs), and multidisciplinary collaboration (etiquette presentation, communication between disciplines, defining roles and expectations). Students completing these projects were shown to appreciate user-centered design, exhibit greater motivation when able to meet and develop a relationship with their client in person, discuss altruistic factors regarding their capstone experience, and were able to develop strong multidisciplinary skills

Studying Underlying Characteristics of Computing and Engineering Student Success (SUCCESS) Survey

This survey was developed to measure underlying factors that may influence student success including personality, community, grit, thriving, identity, mindset, motivation, perceptions of faculty caring, stress, gratitude, self-control, mindfulness, and belongingness. We measure these underlying factors because each engineering and computing student admitted to a university has clear potential for academic and personal success in their undergraduate curriculum based upon admissions criteria. However, while some thrive academically, others struggle in a variety of ways. In our NSF-funded project (1626287/1626185/1626148), we posit that some collection of characteristics—apparently not visible on their admission applications and perhaps not related to their talent or intelligence—is an important piece of the student performance puzzle. We developed a survey to measure various non-cognitive and affective factors that we believe are important for student achievement, academically, personally, and professionally. These non-cognitive and affective factors are representative of multifaceted aspects of undergraduate student success in prior literature. Each of the constructs we chose had validity evidence from prior studies, some within an engineering population. An exploratory and confirmatory factor analysis have been conducted on the original list of items to develop this finalized survey (Scheidt et al., 2018). The survey takes approximately 30 minutes for students to complete. Scheidt, M., & Godwin, A., & Senkpeil, R. R., & Ge, J. S., & Chen, J., & Self, B. P., & Widmann, J. M., & Berger, E. J. (2018, June), Validity Evidence for the SUCCESS Survey: Measuring Non-Cognitive and Affective Traits of Engineering and Computing Students. Paper presented at 2018 ASEE Annual Conference & Exposition, Salt Lake City, Utah. https://peer.asee.org/3122

Origins of the Highly Ionized Gas along the Line of Sight towards HD 116852

We present Hubble Space Telescope Imaging Spectrograph (HST/STIS) and Far Ultraviolet Spectroscopic Explorer (FUSE) observations of high ion interstellar absorption along the sight line to HD 116852. At a distance of 4.8 kpc, HD 116852 is an O9 III star lying in the low Galactic halo, -1.3 kpc from the plane of the Galaxy in the direction l = 304.9, b = -16.1. The STIS E140H grating observations provide high-resolution (FWHM = 2.7 km/s) spectra of the resonance doublets of Si IV, C IV, and N V. These data are complemented by medium-resolution (FWHM = 20 km/s) FUSE spectra of O VI. We find evidence for three distinct types of highly ionized gas present in the data. First, two narrow absorption components are resolved in the Si IV and C IV profiles, at approximate LSR velocities of -36 and -10 km/s. These narrow components appear to be produced in gas associated with the Norma and Sagittarius spiral arms, at approximate z-distances of -1.0 and -0.5 kpc, respectively. Second, we detect an intermediate-width component in C IV and Si IV, at 17 km/s, which we propose could arise at the conductive interface at the boundary between a low column density neutral or weakly ionized cloud and the surrounding hot medium. Finally, a broad collisionally ionized component of gas responsible for producing the smooth N V and O VI profiles is observed; such absorption is also present to a lesser degree in the profiles of Si IV and C IV. The broad O VI absorption is observed at a velocity displaced from the broad C IV component by almost 20 km/s, an amount large enough to suggest that the two ions may not co-exist in the same physical location.Comment: 39 pages, 6 figures; accepted for publication in January 10, 2003 edition of The Astrophysical Journa

Elecsys CSF biomarker immunoassays demonstrate concordance with amyloid-PET imaging

Background: β-amyloid (Aβ) positron emission tomography (PET) imaging is currently the only Food and Drug Administration-approved method to support clinical diagnosis of Alzheimer\u27s disease (AD). However, numerous research studies support the use of cerebrospinal fluid (CSF) biomarkers, as a cost-efficient, quick and equally valid method to define AD pathology. Methods: Using automated Elecsys® assays (Roche Diagnostics) for Aβ (1-42) (Aβ42), Aβ (1-40) (Aβ40), total tau (tTau) and phosphorylated tau (181P) (pTau), we examined CSF samples from 202 participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing cohort, to demonstrate the concordance with pathological AD via PET imaging. Results: Ratios Aβ42/Aβ40, tTau/Aβ42 and pTau/Aβ42 had higher receiver operator characteristic - area under the curve (all 0.94), and greater concordance with Aβ-PET (overall percentage agreement ~ 90%), compared with individual biomarkers. Conclusion: Strong concordance between CSF biomarkers and Aβ-PET status was observed overall, including for cognitively normal participants, further strengthening the association between these markers of AD neuropathological burden for both developmental research studies and for use in clinical trials. © 2020 The Author(s)

Efficient large-scale protein sequence comparison and gene matching to identify orthologs and co-orthologs

Broadly, computational approaches for ortholog assignment is a three steps process: (i) identify all putative homologs between the genomes, (ii) identify gene anchors and (iii) link anchors to identify best gene matches given their order and context. In this article, we engineer two methods to improve two important aspects of this pipeline [specifically steps (ii) and (iii)]. First, computing sequence similarity data [step (i)] is a computationally intensive task for large sequence sets, creating a bottleneck in the ortholog assignment pipeline. We have designed a fast and highly scalable sort-join method (afree) based on k-mer counts to rapidly compare all pairs of sequences in a large protein sequence set to identify putative homologs. Second, availability of complex genomes containing large gene families with prevalence of complex evolutionary events, such as duplications, has made the task of assigning orthologs and co-orthologs difficult. Here, we have developed an iterative graph matching strategy where at each iteration the best gene assignments are identified resulting in a set of orthologs and co-orthologs. We find that the afree algorithm is faster than existing methods and maintains high accuracy in identifying similar genes. The iterative graph matching strategy also showed high accuracy in identifying complex gene relationships. Standalone afree available from http://vbc.med.monash.edu.au/∼kmahmood/afree. EGM2, complete ortholog assignment pipeline (including afree and the iterative graph matching method) available from http://vbc.med.monash.edu.au/∼kmahmood/EGM2

Dynamically and Statistically Downscaled Seasonal Simulations of Maximum Surface Air Temperature Over the Southeastern United States

Coarsely resolved surface air temperature (2 m height) seasonal integrations from the Florida State University/Center for Ocean-Atmospheric Prediction Studies Global Spectral Model (FSU/COAPS GSM) (~1.8º lon.-lat. (T63)) for the period of 1994 to 2002 (March through September each year) are downscaled to a fine spatial scale of ~20 km. Dynamical and statistical downscaling methods are applied for the southeastern United States region, covering Florida, Georgia, and Alabama. Dynamical downscaling is conducted by running the FSU/COAPS Nested Regional Spectral Model (NRSM), which is nested into the domain of the FSU/COAPS GSM. We additionally present a new statistical downscaling method. The rationale for the statistical approach is that clearer separation of prominent climate signals (e.g., seasonal cycle, intraseasonal, or interannual oscillations) in observation and GSM, respectively, over the training period can facilitate the identification of the statistical relationship in climate variability between two data sets. Cyclostationary Empirical Orthogonal Function (CSEOF) analysis and multiple regressions are trained with those data sets to extract their statistical relationship, which eventually leads to better prediction of regional climate from the large-scale simulations. Downscaled temperatures are compared with the FSU/COAPS GSM fields and observations. Downscaled seasonal anomalies exhibit strong agreement with observations and a reduction in bias relative to the direct GSM simulations. Interannual temperature change is also reasonably simulated at local grid points. A series of evaluations including mean absolute errors, anomaly correlations, frequency of extreme events, and categorical predictability reveal that both downscaling techniques can be reliably used for numerous seasonal climate applications

Rib Cage Deformities Alter Respiratory Muscle Action and Chest Wall Function in Patients with Severe Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is an inherited connective tissue disorder characterized by bone fragility, multiple fractures and significant chest wall deformities. Cardiopulmonary insufficiency is the leading cause of death in these patients.Seven patients with severe OI type III, 15 with moderate OI type IV and 26 healthy subjects were studied. In addition to standard spirometry, rib cage geometry, breathing pattern and regional chest wall volume changes at rest in seated and supine position were assessed by opto-electronic plethysmography to investigate if structural modifications of the rib cage in OI have consequences on ventilatory pattern. One-way or two-way analysis of variance was performed to compare the results between the three groups and the two postures. compared to predicted values, on condition that updated reference equations are considered. In both positions, ventilation was lower in OI patients than control because of lower tidal volume (p<0.01). In contrast to OI type IV patients, whose chest wall geometry and function was normal, OI type III patients were characterized by reduced (p<0.01) angle at the sternum (pectus carinatum), paradoxical inspiratory inward motion of the pulmonary rib cage, significant thoraco-abdominal asynchronies and rib cage distortions in supine position (p<0.001).In conclusion, the restrictive respiratory pattern of Osteogenesis Imperfecta is closely related to the severity of the disease and to the sternal deformities. Pectus carinatum characterizes OI type III patients and alters respiratory muscles coordination, leading to chest wall and rib cage distortions and an inefficient ventilator pattern. OI type IV is characterized by lower alterations in the respiratory function. These findings suggest that functional assessment and treatment of OI should be differentiated in these two forms of the disease

Induction of Central Host Signaling Kinases during Pneumococcal Infection of Human THP-1 Cells

Streptococcus pneumoniae is a widespread colonizer of the mucosal epithelia of the upper respiratory tract of human. However, pneumococci are also responsible for numerous local as well as severe systemic infections, especially in children under the age of five and the elderly. Under certain conditions, pneumococci are able to conquer the epithelial barrier, which can lead to a dissemination of the bacteria into underlying tissues and the bloodstream. Here, specialized macrophages represent an essential part of the innate immune system against bacterial intruders. Recognition of the bacteria through different receptors on the surface of macrophages leads thereby to an uptake and elimination of bacteria. Accompanied cytokine release triggers the migration of leukocytes from peripheral blood to the site of infection, where monocytes differentiate into mature macrophages. The rearrangement of the actin cytoskeleton during phagocytosis, resulting in the engulfment of bacteria, is thereby tightly regulated by receptor-mediated phosphorylation cascades of different protein kinases. The molecular cellular processes including the modulation of central protein kinases are only partially solved. In this study, the human monocytic THP-1 cell line was used as a model system to examine the activation of Fcγ and complement receptor-independent signal cascades during infection with S. pneumoniae. Pneumococci cultured either in chemically defined or complex medium showed no significant differences in pneumococcal phagocytosis by phorbol 12-myristate 13-acetate (PMA) differentiated THP-1 cells. Double immuno-fluorescence microscopy and antibiotic protection assays demonstrated a time-dependent uptake and killing of S. pneumoniae 35A inside of macrophages. Infections of THP-1 cells in the presence of specific pharmacological inhibitors revealed a crucial role of actin polymerization and importance of the phosphoinositide 3-kinase (PI3K) and Protein kinase B (Akt) as well during bacterial uptake. The participation of essential host cell signaling kinases in pneumococcal phagocytosis was deciphered for the kinase Akt, ERK1/2, and p38 and phosphoimmunoblots showed an increased phosphorylation and thus activation upon infection with pneumococci. Taken together, this study deciphers host cell kinases in innate immune cells that are induced upon infection with pneumococci and interfere with bacterial clearance after phagocytosis