Exploration of Pluto: Search for Applicable Small Satellite Technology

Pluto is the last known planet in our Solar System awaiting spacecraft reconnaissance. In its eccentric orbit taking it 50 AU from the Sun, Pluto presently has a thin atmosphere containing methane, which is projected to collapse back to the icy planet\u27s surface in about three decades, following Pluto\u27s 1989 perihelion pass at 30 AU. Based on ground and Earth-orbit-based observing capabilities limited by Pluto\u27s small size and extreme distance, present top-priority scientific questions for the first mission concern Pluto and Charon\u27s surface geology, morphology and composition, and Pluto\u27s neutral atmosphere composition. Budgetary realities preclude a large, many-instrument flyby spacecraft, while distance and launch energy requirements preclude any but the smallest orbiter using presently available launch vehicles and propulsion techniques. A NASA sponsored Pluto Mission Development activity began this year at the Jet Propulsion Laboratory. The Pluto Fast Flyby (PFF) tentative mission baseline utilizes two 125-160 kg spacecraft launched in 1998-99 aboard Titan IV(SRMU)/Centaurs or Protons on 7-10 year direct trajectories to Pluto. Instruments are likely to include a CCO imaging camera combined with an infrared spectrometer, plus an ultraviolet spectrometer. An ultra-stable oscillator is to be added to the telecommunications subsystem for radio occultation measurements. Solid state memory stores data during the brief encounter. to be played back over several months. Cost is the primary design driver with major tradeoffs between spacecraft development, launch services, radioisotope thermoelectric generator procurement and launch approval, and mission operations. Significant benefits are apparent from incorporating small satellite technologies from Earth orbiters, with a primary challenge to upgrade component lifetimes consistent with mission duration. The Pluto Team is presently identifying hardware, software and experience from the small satellite community and elsewhere which will be helpful in implementing the Pluto Fast Flyby mission within stringent cost, lifetime and performance constraints. The desired technology flight qualification date is 1994

Novel Magnetic Resonance Imaging strategy targeting Neurotensin Receptors in detection of Prostate Cancer [preprint]

Prostate cancer is the second leading cause of all male cancer deaths. One of the factors present in malignant prostate cells and shown to support its metastatic growth is the neuropeptide neurotensin (NT). The primary goal of the present study was to establish the feasibility of using a newly developed paramagnetic receptor ligand for NT and non-invasive ultrahigh-field magnetic resonance (MR) imaging to visualize prostate cancer in rodents. Orthotropic xenografts were initiated in six-week old male BALB/c nu/nu athymic mice (n = 28) by intra-prostatic (ventral lobe) inoculation of human prostate cancer cells (10 μL of PC3 cells (10^6/100 μL)). Palpable tumors developed within 30-60 days. A micro-imager utilized in these studies was an actively shielded 9.4T, 89 mm bore, Oxford superconducting magnet with a 100 gauss/cm gradient system. Prior to contrast injection, T2 weighted anatomy scans were done to localize the tumor with a spin-echo multi-slice sequence with TR: 2000 TE: 40 and NEX: 1 in both coronal and axial planes. The paramagnetic ligand data sets were collected with a spin-echo, T1 weighted pulse sequence (MSME): TR 300 msec; TE 5 msec; NEX 4 in both axial and coronal planes. The data sets were taken initially at 5-min intervals post contrast injection for the first half hour and then at 15 min intervals for the next 1.5-2 hours for a time series analyses. The temporal distribution of MR signal intensity in various regions were determined in the absence and presence of NT. Our results confirm that the novel NT molecule was protected from enzymatic degradation and capable of forming a high-affinity paramagnetic NT ligand with an extended half-life. During the imaging studies, the signal intensity increased by 200% in the region of the tumor. This increase in signal intensity approached maximum binding within 30 minutes and remained visible for 1-hour post-injection of the contrast agent. Taken together, these findings suggest that it is feasible to detect and image prostate cancer using a paramagnetic NT ligand and the emergence of the NT receptor ligand that may be used as a diagnostic marker for prostate cancer in humans

Multiobjective, preference-based search in acyclic OR-graphs

We consider the problem of determining a most preferred path from a start node to a goal node set in an acyclic OR-graph, given a multiattribute preference function, a multiobjective reward structure, and heuristic information about this reward structure. We present an algorithm which is shown to terminate with a most preferred path, given an admissible heuristic set. The algorithm illustrates how Artificial Intelligence techniques can be productively employed to solve multiobjective problems.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30207/1/0000597.pd

The membrane mucin MUC4 is elevated in breast tumor lymph node metastases relative to matched primary tumors and confers aggressive properties to breast cancer cells

Abstract Introduction Previous studies indicate that overexpression of the membrane-associated mucin MUC4 is potently anti-adhesive to cultured tumor cells, and suppresses cellular apoptotic response to a variety of insults. Such observations raise the possibility that MUC4 expression could contribute to tumor progression or metastasis, but the potential involvement of MUC4 in breast cancer has not been rigorously assessed. The present study aimed to investigate the expression of the membrane mucin MUC4 in normal breast tissue, primary breast tumors and lymph node metastases, and to evaluate the role of MUC4 in promoting the malignant properties of breast tumor cells. Methods MUC4 expression levels in patient-matched normal and tumor breast tissue was initially examined by immunoblotting lysates of fresh frozen tissue samples with a highly specific preparation of anti-MUC4 monoclonal antibody 1G8. Immunohistochemical analysis was then carried out using tissue microarrays encompassing patient-matched normal breast tissue and primary tumors, and patient-matched lymph node metastases and primary tumors. Finally, shRNA-mediated knockdown was employed to assess the contribution of MUC4 to the cellular growth and malignancy properties of JIMT-1 breast cancer cells. Results Immunoblotting and immunohistochemistry revealed that MUC4 levels are suppressed in the majority (58%, p < 0.001) of primary tumors relative to patient-matched normal tissue. On the other hand, lymph node metastatic lesions from 37% (p < 0.05) of patients expressed higher MUC4 protein levels than patient-matched primary tumors. MUC4-positive tumor emboli were often found in lymphovascular spaces of lymph node metastatic lesions. shRNA-mediated MUC4 knockdown compromised the migration, proliferation and anoikis resistance of JIMT-1 cells, strongly suggesting that MUC4 expression actively contributes to cellular properties associated with breast tumor metastasis. Conclusions Our observations suggest that after an initial loss of MUC4 levels during the transition of normal breast tissue to primary tumor, the re-establishment of elevated MUC4 levels confers an advantage to metastasizing breast tumor cells by promoting the acquisition of cellular properties associated with malignancy

Ozone exposure is associated with acute changes in inflammation, fibrinolysis, and endothelial cell function in coronary artery disease patients

Air pollution is a major risk factor for cardiovascular disease, of which ozone is a major contributor. Several studies have found associations between ozone and cardiovascular morbidity, but the results have been inconclusive. We investigated associations between ozone and changes across biological pathways associated with cardiovascular disease

CAG expansion affects the expression of mutant huntingtin in the Huntington's disease brain

AbstractA trinucleotide repeat (CAG) expansion in the huntingtin gene causes Huntington's disease (HD). In brain tissue from HD heterozygotes with adult onset and more clinically severe juvenile onset, where the largest expansions occur, a mutant protein of equivalent intensity to wild-type huntingtin was detected in cortical synaptosomes, indicating that a mutant species is synthesized and transported with the normal protein to nerve endings. The increased size of mutant huntingtin relative to the wild type was highly correlated with CAG repeat expansion, thereby linking an altered electrophoretic mobility of the mutant protein to its abnormal function. Mutant huntingtin appeared in gray and white matter with no difference in expression in affected regions. The mutant protein was broader than the wild type and in 6 of 11 juvenile cases resolved as a complex of bands, consistent with evidence at the DNA level for somatic mosaicism. Thus, HD pathogenesis results from a gain of function by an aberrant protein that is widely expressed in brain and is harmful only to some neurons

Peat Bog Wildfire Smoke Exposure in Rural North Carolina Is Associated with Cardiopulmonary Emergency Department Visits Assessed through Syndromic Surveillance

Background: In June 2008, burning peat deposits produced haze and air pollution far in excess of National Ambient Air Quality Standards, encroaching on rural communities of eastern North Carolina. Although the association of mortality and morbidity with exposure to urban air pollution is well established, the health effects associated with exposure to wildfire emissions are less well understood. Objective: We investigated the effects of exposure on cardiorespiratory outcomes in the population affected by the fire. Methods: We performed a population-based study using emergency department (ED) visits reported through the syndromic surveillance program NC DETECT (North Carolina Disease Event Tracking and Epidemiologic Collection Tool). We used aerosol optical depth measured by a satellite to determine a high-exposure window and distinguish counties most impacted by the dense smoke plume from surrounding referent counties. Poisson log-linear regression with a 5-day distributed lag was used to estimate changes in the cumulative relative risk (RR). Results: In the exposed counties, significant increases in cumulative RR for asthma [1.65 (95% confidence interval, 1.25–2.1)], chronic obstructive pulmonary disease [1.73 (1.06–2.83)], and pneumonia and acute bronchitis [1.59 (1.07–2.34)] were observed. ED visits associated with cardiopulmonary symptoms [1.23 (1.06–1.43)] and heart failure [1.37 (1.01–1.85)] were also significantly increased. Conclusions: Satellite data and syndromic surveillance were combined to assess the health impacts of wildfire smoke in rural counties with sparse air-quality monitoring. This is the first study to demonstrate both respiratory and cardiac effects after brief exposure to peat wildfire smoke

Progress in Assessing Air Pollutant Risks from In Vitro Exposures: Matching Ozone Dose and Effect in Human Airway Cells

In vitro exposures to air pollutants could, in theory, facilitate a rapid and detailed assessment of molecular mechanisms of toxicity. However, it is difficult to ensure that the dose of a gaseous pollutant to cells in tissue culture is similar to that of the same cells during in vivo exposure of a living person. The goal of the present study was to compare the dose and effect of O3 in airway cells of humans exposed in vivo to that of human cells exposed in vitro. Ten subjects breathed labeled O3 (18O3, 0.3 ppm, 2 h) while exercising intermittently. Bronchial brush biopsies and lung lavage fluids were collected 1 h post exposure for in vivo data whereas in vitro data were obtained from primary cultures of human bronchial epithelial cells exposed to 0.25–1.0 ppm 18O3 for 2 h. The O3 dose to the cells was defined as the level of 18O incorporation and the O3 effect as the fold increase in expression of inflammatory marker genes (IL-8 and COX-2). Dose and effect in cells removed from in vivo exposed subjects were lower than in cells exposed to the same 18O3 concentration in vitro suggesting upper airway O3 scrubbing in vivo. Cells collected by lavage as well as previous studies in monkeys show that cells deeper in the lung receive a higher O3 dose than cells in the bronchus. We conclude that the methods used herein show promise for replicating and comparing the in vivo dose and effect of O3 in an in vitro system

Dissection of the Inflammatory Bowel Disease Transcriptome Using Genome-Wide cDNA Microarrays

BACKGROUND: The differential pathophysiologic mechanisms that trigger and maintain the two forms of inflammatory bowel disease (IBD), Crohn disease (CD), and ulcerative colitis (UC) are only partially understood. cDNA microarrays can be used to decipher gene regulation events at a genome-wide level and to identify novel unknown genes that might be involved in perpetuating inflammatory disease progression. METHODS AND FINDINGS: High-density cDNA microarrays representing 33,792 UniGene clusters were prepared. Biopsies were taken from the sigmoid colon of normal controls (n = 11), CD patients (n = 10) and UC patients (n = 10). (33)P-radiolabeled cDNA from purified poly(A)(+) RNA extracted from biopsies (unpooled) was hybridized to the arrays. We identified 500 and 272 transcripts differentially regulated in CD and UC, respectively. Interesting hits were independently verified by real-time PCR in a second sample of 100 individuals, and immunohistochemistry was used for exemplary localization. The main findings point to novel molecules important in abnormal immune regulation and the highly disturbed cell biology of colonic epithelial cells in IBD pathogenesis, e.g., CYLD (cylindromatosis, turban tumor syndrome) and CDH11 (cadherin 11, type 2). By the nature of the array setup, many of the genes identified were to our knowledge previously uncharacterized, and prediction of the putative function of a subsection of these genes indicate that some could be involved in early events in disease pathophysiology. CONCLUSION: A comprehensive set of candidate genes not previously associated with IBD was revealed, which underlines the polygenic and complex nature of the disease. It points out substantial differences in pathophysiology between CD and UC. The multiple unknown genes identified may stimulate new research in the fields of barrier mechanisms and cell signalling in the context of IBD, and ultimately new therapeutic approaches

Inhibition of Progenitor Dendritic Cell Maturation by Plasma from Patients with Peripartum Cardiomyopathy: Role in Pregnancy-associated Heart Disease

Dendritic cells (DCs) play dual roles in innate and adaptive immunity based on their functional maturity, and both innate and adaptive immune responses have been implicated in myocardial tissue remodeling associated with cardiomyopathies. Peripartum cardiomyopathy (PPCM) is a rare disorder which affects women within one month antepartum to five months postpartum. A high occurrence of PPCM in central Haiti (1 in 300 live births) provided the unique opportunity to study the relationship of immune activation and DC maturation to the etiology of this disorder. Plasma samples from two groups (n = 12) of age- and parity-matched Haitian women with or without evidence of PPCM were tested for levels of biomarkers of cardiac tissue remodeling and immune activation. Significantly elevated levels of GM-CSF, endothelin-1, proBNP and CRP and decreased levels of TGF- were measured in PPCM subjects relative to controls. Yet despite these findings, in vitro maturation of normal human cord blood derived progenitor dendritic cells (CBDCs) was significantly reduced (p < 0.001) in the presence of plasma from PPCM patients relative to plasma from post-partum control subjects as determined by expression of CD80, CD86, CD83, CCR7, MHC class II and the ability of these matured CBDCs to induce allo-responses in PBMCs. These results represent the first findings linking inhibition of DC maturation to the dysregulation of normal physiologic cardiac tissue remodeling during pregnancy and the pathogenesis of PPCM