Expression of a1-Adrenergic receptors on immune cells during inflammation

The immune system is a complex network of interacting cells and proteins that are constantly protecting the host from pathogens. Lymphoid and myeloid cells are the cellular mediators of the immune system, and the functions of these cells are partly controlled by the nervous system, however the mechanisms are not understood. The sympathetic nervous system may play a role through a family of receptors called adrenergic receptors (AR). Adrenergic receptors are G-protein coupled receptors that mediate the actions of adrenaline and noradrenaline. These receptors are spilt into the a- and b- subtypes, which can be further divided into subtypes. While b-ARs have been well-studied, less is known about a-ARs and their roles in immune regulation. The a-ARs can be divided into the a1- and a2 - subtypes: this project focussed on the a1-ARs as there is evidence to suggest that they play a role in inflammatory diseases. However, relatively little is known about which immune cell types express a1-ARs, and how they vary during inflammation. The major Aim of this project was to examine the expression of a1-ARs on lymphoid and myeloid cells in mouse spleen and establish whether simulating an acute inflammatory response (bacterial lipopolysaccharide: LPS) in splenocytes would alter the protein expression of a1-ARs. Protocols were optimised for the multi-parameter labelling and analysis of mouse spleen lymphoid and myeloid cells by flow cytometry, and the optimisation of specific a1-AR surface protein staining using BODIPY-prazosin. Normal mouse lymphoid and myeloid populations were found to express varying levels of -ARs, and that all except plasmacytoid dendritic cells (pDC) showed an unexpected reduction in a1-AR protein expression after exposure to LPS in vitro. The results of this project provide preliminary evidence that except for pDC, lymphoid and myeloid cell populations within the spleen undergo downregulation of a1 -ARs during an acute inflammatory response

Switching adaptive control of a bioassistive exoskeleton

The effectiveness of existing control designs for bioassistive, exoskeletal devices, especially in highly uncertain working environments, depends on the degree of certainty associated with the overall system model. Of particular concern is the robustness of a control design to large-bandwidth exogenous disturbances, time delays in the sensor and actuator loops, and kinematic and inertial variability across the population of likely users. In this study, we propose an adaptive control framework for robotic exoskeletons that uses a low-pass filter structure in the feedback channel to decouple the estimation loop from the control loop. The design facilitates a significant increase in the rate of estimation and adaptation, without a corresponding loss of robustness. In particular, the control implementation is tolerant of time delays in the control loop and maintains clean control channels even in the presence of measurement noise. Tuning of the filter also allows for shaping the nominal response and enhancing the time-delay margin. Importantly, the proposed formulation is independent of detailed model information. The performance of the proposed architecture is demonstrated in simulation for two basic control scenarios, namely, (i) static positioning, for which the predefined desired joint motions are constant; and (ii) command following, where the desired motions are not known a priori and instead inferred using interaction measurements. We consider, in addition, an operating modality in which the control scheme switches between static positioning and command following to facilitate flexible integration of a human operator in the loop. Here, the transition from static positioning to command following is triggered when either the human–machine interaction force at the wrist or the end-effector velocity exceeds the corresponding critical value. The controller switches from command following back to static positioning when both the interaction force and the velocity fall below the corresponding thresholds. This strategy allows for smooth transition between two phases of operation and provides an alternative to an implementation relying on wearable electromyographic sensors

Needs Assessment of Barriers to Cervical Cancer Screening in Vietnamese American Health Care Providers

Vietnamese women living in the United States have a cervical cancer incidence rate that is five times that of White women. The low rate of cervical cancer screening among this high-risk population contributes to this disparity. In 2004, the National Cancer Institute collaborated with the Vietnamese American Medical Association to conduct a short needs assessment questionnaire (Pap Test Barriers Questionnaire for Health Care Providers) among its members to assess provider views about cervical cancer, barriers to Pap testing among Vietnamese women living in the United States, and types of patient education materials needed to help motivate Vietnamese women to receive a Pap test. Information from the questionnaire was used to inform development of a brochure and identify additional strategies to enhance outreach to Vietnamese women and providers. Almost all of the respondents (95%) thought that Pap tests were “very important” in the early detection of cervical cancer in Vietnamese women. In addition, knowledge about the importance of Pap tests was identified as the most influential factor for Vietnamese women not seeking a Pap test. Print materials that included both English and Vietnamese translations in the same publication were cited as a preferred communication tool. Further, health education through Vietnamese media was recommended as a primary strategy for reaching women with educational messages. Findings from this needs assessment contributes to a larger formative research effort to build NCI’s cervical cancer education program within its Office of Education and Special Initiatives

Does it match? Analyzing self-reported online dermatology match data to Charting Outcomes in the Match

Dermatology is arguably the most competitive residency (81.6% match rate for United States allopathic seniors) with significantly more applicants than available positions. To objectify this process, the National Residency Match Program (NRMP) has produced bi-annual Charting Outcomes in Match (COM) datasets, which aggregate data from the prior two application cycles and tabulate statistics to aid applicants. In parallel, online forums provide medical trainees with vast amounts of information, including residency application insights. Reddit medical school subforum compiles annual spreadsheets of anonymous, individualized applicant data to aid future applicants. We compared this data to NRMP data to show that although the data means are similar (e.g. Step 1), the Reddit dermatology spreadsheet collects more data and the individualized nature aids applicants in a personalized way unlike the mean aggregate data in NRMP. Under univariate analysis, Alpha Omega Alpha status, overall publications, and dermatology-specific publications are associated with interview invitation rates. Although limitations of the study include small data size and reporting bias, this is the first of its kind to our knowledge to compare these two often-used tools to aid dermatology applicants. Future endeavors should expand anonymous data reporting and use the data to carry out more extensive studies to investigate factors influencing the application process

Effects of installation sequence of concrete rigid inclusions by ground-displacement piling method on previously installed columns

University of Technology Sydney. Faculty of Engineering and Information Technology.Ground improvement techniques using concrete injected column (CIC) or controlled modulus column (CMC) have been widely used since 1980s. However, impacts of ground displacement induced by the techniques have not been studied adequately. This project advances both experimental and numerical bases for assessing effects of installing CICs or CMCs on the surrounding soils and previously installed columns, with interests given to installation sequence and behaviour of concrete inclusion at early age. Three-dimensional numerical modelling was conducted to investigate how groups of columns installed in different sequences could affect previously installed columns. The assessment included coupled consolidation analyses in large strain mode, considering soil-column interaction. CMC installation was modelled numerically with the combined use of cylindrical and spherical cavity expansion theories. Where possible, the results were compared with analytical solutions and published field cases. The study revealed that the use of different installation sequences resulted in noticeable differences in the soil responses near existing CMCs as well as the difference in the bending moments generated in the previously installed columns. A soil-displacement piling rig and a fully instrumented soil tank were also designed and built in the laboratory to simulate column installations and to study the soil behaviour and the responses of previously built columns to nearby installations. A group of concrete columns were cast in-situ in soft soil using low strength concrete. The installation effects in terms of soil behaviours and structural responses of the columns were well captured by 3D laser scanning, soil miniature instrumentation, and a customised strain gauge system installed in CMCs. Test results revealed complex interactions between the soil and the columns, which are otherwise often difficult to observe in the field

Evaluation of the Terminal Area Precision Scheduling and Spacing System for Performance-Based Navigation Arrivals

The growth of global demand for air transportation has put increasing strain on the nation's air traffic management system. To relieve this strain, the International Civil Aviation Organization has urged all nations to adopt Performance-Based Navigation (PBN), which can help to reduce air traffic congestion, decrease aviation fuel consumption, and protect the environment. NASA has developed a Terminal Area Precision Scheduling and Spacing (TAPSS) system that can support increased use of PBN during periods of high traffic, while supporting fuel-efficient, continuous descent approaches. In the original development of this system, arrival aircraft are assigned fuel-efficient Area Navigation (RNAV) Standard Terminal Arrival Routes before their initial descent from cruise, with routing defined to a specific runway. The system also determines precise schedules for these aircraft that facilitate continuous descent through the assigned routes. To meet these schedules, controllers are given a set of advisory tools to precisely control aircraft. The TAPSS system has been evaluated in a series of human-in-the-loop (HITL) air traffic simulations during 2010 and 2011. Results indicated increased airport arrival throughput up to 10 over current operations, and maintained fuel-efficient aircraft decent profiles from the initial descent to landing with reduced controller workload. This paper focuses on results from a joint NASA and FAA HITL simulation conducted in 2012. Due to the FAA rollout of the advance terminal area PBN procedures at mid-sized airports first, the TAPSS system was modified to manage arrival aircraft as they entered Terminal Radar Approach Control (TRACON). Dallas-Love Field airport (DAL) was selected by the FAA as a representative mid-sized airport within a constrained TRACON airspace due to the close proximity of a major airport, in this case Dallas-Ft Worth International Airport, one of the busiest in the world. To address this constraint, RNAV routes and Required Navigation Performance with the particular capability known as Radius-to-Fix (RNP-RF) approaches to a short final were used. The purpose of this simulation was to get feedback on how current operations could benefit with the TAPSS system and also to evaluate the efficacy of the advisory tools to support the broader use of PBN in the US National Airspace System. For this NASA-FAA joint experiment, an Air Traffic Control laboratory at NASA Ames was arranged to simulate arrivals into DAL in Instrument Meteorological Conditions utilizing parallel dependent approaches, with two feeder positions that handed off traffic to one final position. Four FAA controllers participated, alternately covering these three positions. All participants were Full-Performance Level terminal controllers and members of the National Air Traffic Controllers Association. During the simulation, PBN arrival operations were compared and contrasted in three conditions. They were the Baseline, where none of the TAPSS systems TRACON controller decision support advisories were provided, the Limited Advisories, reflecting the existing but dormant capabilities of the current terminal automation equipment with providing a subset of the TAPSS systems advisories; numerical delay, landing sequence, and runway assignment information, and the Full Advisories, with providing the following in addition to the ones in the Limited condition; trajectory slot markers, timelines of estimated times of arrivals and sche

Evaluation of the Terminal Sequencing and Spacing System for Performance Based Navigation Arrivals

NASA has developed the Terminal Sequencing and Spacing (TSS) system, a suite of advanced arrival management technologies combining timebased scheduling and controller precision spacing tools. TSS is a ground-based controller automation tool that facilitates sequencing and merging arrivals that have both current standard ATC routes and terminal Performance-Based Navigation (PBN) routes, especially during highly congested demand periods. In collaboration with the FAA and MITRE's Center for Advanced Aviation System Development (CAASD), TSS system performance was evaluated in human-in-the-loop (HITL) simulations with currently active controllers as participants. Traffic scenarios had mixed Area Navigation (RNAV) and Required Navigation Performance (RNP) equipage, where the more advanced RNP-equipped aircraft had preferential treatment with a shorter approach option. Simulation results indicate the TSS system achieved benefits by enabling PBN, while maintaining high throughput rates-10% above baseline demand levels. Flight path predictability improved, where path deviation was reduced by 2 NM on average and variance in the downwind leg length was 75% less. Arrivals flew more fuel-efficient descents for longer, spending an average of 39 seconds less in step-down level altitude segments. Self-reported controller workload was reduced, with statistically significant differences at the p less than 0.01 level. The RNP-equipped arrivals were also able to more frequently capitalize on the benefits of being "Best-Equipped, Best- Served" (BEBS), where less vectoring was needed and nearly all RNP approaches were conducted without interruption

Fighting Oxidative Stress with Sulfur:Hydrogen Sulfide in the Renal and Cardiovascular Systems

Hydrogen sulfide (H2S) is an essential gaseous signaling molecule. Research on its role in physiological and pathophysiological processes has greatly expanded. Endogenous enzymatic production through the transsulfuration and cysteine catabolism pathways can occur in the kidneys and blood vessels. Furthermore, non-enzymatic pathways are present throughout the body. In the renal and cardiovascular system, H2S plays an important role in maintaining the redox status at safe levels by promoting scavenging of reactive oxygen species (ROS). H2S also modifies cysteine residues on key signaling molecules such as keap1/Nrf2, NF kappa B, and HIF-1 alpha, thereby promoting anti-oxidant mechanisms. Depletion of H2S is implicated in many age-related and cardiorenal diseases, all having oxidative stress as a major contributor. Current research suggests potential for H2S-based therapies, however, therapeutic interventions have been limited to studies in animal models. Beyond H2S use as direct treatment, it could improve procedures such as transplantation, stem cell therapy, and the safety and efficacy of drugs including NSAIDs and ACE inhibitors. All in all, H2S is a prime subject for further research with potential for clinical use

Mice with an induced mutation in collagen 8A2 develop larger eyes and are resistant to retinal ganglion cell damage in an experimental glaucoma model

PURPOSE: To study susceptibility to glaucoma injury as it may be affected by mutations in ocular connective tissue components. METHODS: Mice homozygous for an N-ethyl-N-nitrosourea induced G257D exchange (Gly to Asp) missense mutation (Aca23) in their collagen 8A2 gene were studied to measure intraocular pressure (IOP), axial length and width, number of retinal ganglion cells (RGC), and inflation responses. Three month old homozygous Aca23 mutant and wild type (WT) mice had 6 weeks exposure to elevated IOP induced by polystyrene microbead injection. Additional Aca23 and matched controls were studied at ages of 10 and 18 months. RESULTS: Aca23 mice had no significant difference from WT in IOP level, and in both strains IOP rose with age. In multivariable models, axial length and width were significantly larger in Aca23 than WT, became larger with age, and were larger after exposure to glaucoma (n=227 mice). From inflation test data, the estimates of scleral stress resultants in Aca23 mice were similar to age-matched and younger WT C57BL/6 (B6) mice, while the strain estimates for Aca23 were significantly less than those for either WT group in the mid-sclera and in some of the more anterior scleral measures (p<0.001; n=29, 22, 20 eyes in Aca23, older WT, younger WT, respectively). With chronic IOP elevation, Aca23 eyes increased 9% in length and 7% in width, compared to untreated fellow eyes (p<0.05, <0.01). With similar elevated IOP exposure, WT eyes enlarged proportionately twice as much as Aca23, increasing in length by 18% and in nasal-temporal width by 13% (both p<0.001, Mann-Whitney test). In 4 month old control optic nerves, mean RGC axon number was not different in Aca23 and WT (46,905±7,592, 43,628±11,162, respectively; p=0.43, Mann-Whitney test, n=37 and 29). With chronic glaucoma, Aca23 mice had a mean axon loss of only 0.57±17%, while WT mice lost 21±31% (median loss: 1% versus 10%, n=37, 29, respectively; p=0.001; multivariable model adjusting for positive integral IOP exposure). CONCLUSIONS: The Aca23 mutation in collagen 8α2 is the first gene defect found to alter susceptibility to experimental glaucoma, reducing RGC loss possibly due to differences in mechanical behavior of the sclera. Detailed study of the specific changes in scleral connective tissue composition and responses to chronic IOP elevation in this strain could produce new therapeutic targets for RGC neuroprotection

Probing Heme Coordination States of Inducible Nitric Oxide Synthase with a Re(I)(imidazole-alkyl-nitroarginine) Sensitizer-Wire

Mammalian inducible nitric oxide synthase (iNOS) catalyzes the production of L-citrulline and nitric oxide (NO) from L-arginine and O_2. The Soret peak in the spectrum of the iNOS heme domain (iNOS_(oxy)) shifts from 423 to 390 nm upon addition of a sensitizer-wire, [Re^I-imidazole-(CH_2)_8-nitroarginine]^+, or [ReC_8argNO_2]^+, owing to partial displacement of the water ligand in the active site. From analysis of competitive binding experiments with imidazole, the dissociation constant (K_d) for [ReC_8argNO_2]^+−iNOS_(oxy) was determined to be 3.0 ± 0.1 μM, confirming that the sensitizer-wire binds with higher affinity than both L-arginine (K_d = 22 ± 5 μM) and imidazole (K_d = 14 ± 3 μM). Laser excitation (355 nm) of [ReC_8argNO_2]^+−iNOS_(oxy) triggers electron transfer to the active site of the enzyme, producing a ferroheme in less than ∼1 μs