Interstellar Dust Close to the Sun

The low density interstellar medium (ISM) close to the Sun and inside of the heliosphere provides a unique laboratory for studying interstellar dust grains. Grain characteristics in the nearby ISM are obtained from observations of interstellar gas and dust inside of the heliosphere and the interstellar gas towards nearby stars. Comparison between the gas composition and solar abundances suggests that grains are dominated by olivines and possibly some form of iron oxide. Measurements of the interstellar Ne/O ratio by the Interstellar Boundary Explorer spacecraft indicate that a high fraction of interstellar oxygen in the ISM must be depleted onto dust grains. Local interstellar abundances are consistent with grain destruction in ~150 km/s interstellar shocks, provided that the carbonaceous component is hydrogenated amorphous carbon and carbon abundances are correct. Variations in relative abundances of refractories in gas suggest variations in the history of grain destruction in nearby ISM. The large observed grains, > 1 micron, may indicate a nearby reservoir of denser ISM. Theoretical three-dimensional models of the interaction between interstellar dust grains and the solar wind predict that plumes of about 0.18 micron dust grains form around the heliosphere.Comment: 2011 AGOS Taiwan meeting; accepted for publication in Earth, Planets and Spac

Further Insight into Mechanisms of Ventricular Tachycardia from the Clinical Electrophysiology Laboratory

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72003/1/j.1540-8167.1991.tb01319.x.pd

Search algorithms as a framework for the optimization of drug combinations

Combination therapies are often needed for effective clinical outcomes in the management of complex diseases, but presently they are generally based on empirical clinical experience. Here we suggest a novel application of search algorithms, originally developed for digital communication, modified to optimize combinations of therapeutic interventions. In biological experiments measuring the restoration of the decline with age in heart function and exercise capacity in Drosophila melanogaster, we found that search algorithms correctly identified optimal combinations of four drugs with only one third of the tests performed in a fully factorial search. In experiments identifying combinations of three doses of up to six drugs for selective killing of human cancer cells, search algorithms resulted in a highly significant enrichment of selective combinations compared with random searches. In simulations using a network model of cell death, we found that the search algorithms identified the optimal combinations of 6-9 interventions in 80-90% of tests, compared with 15-30% for an equivalent random search. These findings suggest that modified search algorithms from information theory have the potential to enhance the discovery of novel therapeutic drug combinations. This report also helps to frame a biomedical problem that will benefit from an interdisciplinary effort and suggests a general strategy for its solution.Comment: 36 pages, 10 figures, revised versio

Blocking TLR7- and TLR9-mediated IFN-α Production by Plasmacytoid Dendritic Cells Does Not Diminish Immune Activation in Early SIV Infection

Persistent production of type I interferon (IFN) by activated plasmacytoid dendritic cells (pDC) is a leading model to explain chronic immune activation in human immunodeficiency virus (HIV) infection but direct evidence for this is lacking. We used a dual antagonist of Toll-like receptor (TLR) 7 and TLR9 to selectively inhibit responses of pDC but not other mononuclear phagocytes to viral RNA prior to and for 8 weeks following pathogenic simian immunodeficiency virus (SIV) infection of rhesus macaques. We show that pDC are major but not exclusive producers of IFN-α that rapidly become unresponsive to virus stimulation following SIV infection, whereas myeloid DC gain the capacity to produce IFN-α, albeit at low levels. pDC mediate a marked but transient IFN-α response in lymph nodes during the acute phase that is blocked by administration of TLR7 and TLR9 antagonist without impacting pDC recruitment. TLR7 and TLR9 blockade did not impact virus load or the acute IFN-α response in plasma and had minimal effect on expression of IFN-stimulated genes in both blood and lymph node. TLR7 and TLR9 blockade did not prevent activation of memory CD4+ and CD8+ T cells in blood or lymph node but led to significant increases in proliferation of both subsets in blood following SIV infection. Our findings reveal that virus-mediated activation of pDC through TLR7 and TLR9 contributes to substantial but transient IFN-α production following pathogenic SIV infection. However, the data indicate that pDC activation and IFN-α production are unlikely to be major factors in driving immune activation in early infection. Based on these findings therapeutic strategies aimed at blocking pDC function and IFN-α production may not reduce HIV-associated immunopathology. © 2013 Kader et al

Gene expression and matrix turnover in overused and damaged tendons

Chronic, painful conditions affecting tendons, frequently known as tendinopathy, are very common types of sporting injury. The tendon extracellular matrix is substantially altered in tendinopathy, and these changes are thought to precede and underlie the clinical condition. The tendon cell response to repeated minor injuries or “overuse” is thought to be a major factor in the development of tendinopathy. Changes in matrix turnover may also be effected by the cellular response to physical load, altering the balance of matrix turnover and changing the structure and composition of the tendon. Matrix turnover is relatively high in tendons exposed to high mechanical demands, such as the supraspinatus and Achilles, and this is thought to represent either a repair or tissue maintenance function. Metalloproteinases are a large family of enzymes capable of degrading all of the tendon matrix components, and these are thought to play a major role in the degradation of matrix during development, adaptation and repair. It is proposed that some metalloproteinase enzymes are required for the health of the tendon, and others may be damaging, leading to degeneration of the tissue. Further research is required to investigate how these enzyme activities are regulated in tendon and altered in tendinopathy. A profile of all the metalloproteinases expressed and active in healthy and degenerate tendon is required and may lead to the development of new drug therapies for these common and debilitating sports injuries

Feed intake and production parameters of lactating crossbred cows fed maize-based diets of stover, silage or quality protein silage

Thirty-six Boran × Friesian dairy cows (392 ± 12 kg; mean ± SD) in early parity were used in a randomised complete block design. Cows were blocked by parity into three blocks of 12 animals and offered normal maize (NM) stover (T1), NM silage (T2) or quality protein maize (QPM) silage (T3) basal diets supplemented with a similar concentrate mix. Feed intake, body weight and condition changes and milk yield and composition were assessed. The daily intake of DM, OM, NDF and ADF for cows fed the NM stover-based diet was higher (P < 0.05) than for the cows fed the NM silage and QPM silage-based diets. However, the daily intake of DOM (9.3 kg) and ME (140.8 MJ) for cows on QPM silage-based diet was higher (P < 0.05) than for cows on NM stover-based diet (8.4 kg and 124.2 MJ) and NM silage-based diet (7.9 kg and 119.1 MJ). Body weight of cows was affected (P < 0.05) by the diet, but diet had no effect (P > 0.05) on body condition score, milk yield and milk composition. The digestible organic matter in the NM stover-based diet (724 g/kg DM) was lower (P < 0.05) than that in the NM (770 g/kg DM) and QPM silage-based diet (762 g/kg DM). It was concluded that the performances of the cows on the NM silage and QPM silage diets were similar and were not superior to that of the NM stover-based diet

Revealing the former bed of Thwaites Glacier using sea-floor bathymetry: Implications for warm-water routing and bed controls on ice flow and buttressing

Abstract. The geometry of the sea floor immediately beyond Antarctica's marine-terminating glaciers is a fundamental control on warm-water routing, but it also describes former topographic pinning points that have been important for ice-shelf buttressing. Unfortunately, this information is often lacking due to the inaccessibility of these areas for survey, leading to modelled or interpolated bathymetries being used as boundary conditions in numerical modelling simulations. At Thwaites Glacier (TG) this critical data gap was addressed in 2019 during the first cruise of the International Thwaites Glacier Collaboration (ITGC) project. We present more than 2000 km2 of new multibeam echo-sounder (MBES) data acquired in exceptional sea-ice conditions immediately offshore TG, and we update existing bathymetric compilations. The cross-sectional areas of sea-floor troughs are under-predicted by up to 40 % or are not resolved at all where MBES data are missing, suggesting that calculations of trough capacity, and thus oceanic heat flux, may be significantly underestimated. Spatial variations in the morphology of topographic highs, known to be former pinning points for the floating ice shelf of TG, indicate differences in bed composition that are supported by landform evidence. We discuss links to ice dynamics for an overriding ice mass including a potential positive feedback mechanism where erosion of soft erodible highs may lead to ice-shelf ungrounding even with little or no ice thinning. Analyses of bed roughnesses and basal drag contributions show that the sea-floor bathymetry in front of TG is an analogue for extant bed areas. Ice flow over the sea-floor troughs and ridges would have been affected by similarly high basal drag to that acting at the grounding zone today. We conclude that more can certainly be gleaned from these 3D bathymetric datasets regarding the likely spatial variability of bed roughness and bed composition types underneath TG. This work also addresses the requirements of recent numerical ice-sheet and ocean modelling studies that have recognised the need for accurate and high-resolution bathymetry to determine warm-water routing to the grounding zone and, ultimately, for predicting glacier retreat behaviour. </jats:p

Association of the transthyretin variant V122I with polyneuropathy among individuals of African ancestry

Hereditary transthyretin-mediated (hATTR) amyloidosis is an underdiagnosed, progressively debilitating disease caused by mutations in the transthyretin (TTR) gene. V122I, a common pathogenic TTR mutation, is found in 3-4% of individuals of African ancestry in the United States and has been associated with cardiomyopathy and heart failure. To better understand the phenotypic consequences of carrying V122I, we conducted a phenome-wide association study scanning 427 ICD diagnosis codes in UK Biobank participants of African ancestry (n = 6062). Significant associations were tested for replication in the Penn Medicine Biobank (n = 5737) and the Million Veteran Program (n = 82,382). V122I was significantly associated with polyneuropathy in the UK Biobank (odds ratio [OR] = 6.4, 95% confidence interval [CI] 2.6-15.6, p = 4.2 × 10-5), which was replicated in the Penn Medicine Biobank (OR = 1.6, 95% CI 1.2-2.4, p = 6.0 × 10-3) and Million Veteran Program (OR = 1.5, 95% CI 1.2-1.8, p = 1.8 × 10-4). Polyneuropathy prevalence among V122I carriers was 2.1%, 9.0%, and 4.8% in the UK Biobank, Penn Medicine Biobank, and Million Veteran Program, respectively. The cumulative incidence of common hATTR amyloidosis manifestations (carpal tunnel syndrome, polyneuropathy, cardiomyopathy, heart failure) was significantly enriched in V122I carriers compared with non-carriers (HR = 2.8, 95% CI 1.7-4.5, p = 2.6 × 10-5) in the UK Biobank, with 37.4% of V122I carriers having at least one of these manifestations by age 75. Our findings show that V122I carriers are at increased risk of polyneuropathy. These results also emphasize the underdiagnosis of disease in V122I carriers with a significant proportion of subjects showing phenotypic changes consistent with hATTR amyloidosis. Greater understanding of the manifestations associated with V122I is critical for earlier diagnosis and treatment

Reducing gender disparities in post-total knee arthroplasty expectations through a decision aid

BACKGROUND: Gender disparities in total knee arthroplasty utilization may be due to differences in perceptions and expectations about total knee arthroplasty outcomes. This study evaluates the impact of a decision aid on perceptions about total knee arthroplasty and decision-making parameters among patients with knee osteoarthritis. METHODS: Patients with moderate to severe knee osteoarthritis viewed a video about knee osteoarthritis treatments options, including total knee arthroplasty, and received a personalized arthritis report. An adapted version of the Western Ontario and McMaster Universities Osteoarthritis Index was used to assess pain and physical function expectations following total knee arthroplasty before/after the intervention. These scores were compared to an age- and gender-adjusted means for a cohort of patients who had undergone total knee arthroplasty. Decision readiness and conflict were also measured. RESULTS: At baseline, both men and women had poorer expectations about post-operative pain and physical outcomes compared with observed outcomes of the comparator group. Following the intervention, women’s mean age-adjusted expectations about post- total knee arthroplasty pain outcomes improved (Pre: 27.0; Post: 21.8 [p =0.08; 95% CI −0.7, 11.0]) and were closer to observed post-TKA outcomes; whereas men did not have a significant change in their pain expectations (Pre: 21.3; Post: 19.6 [p = 0.6; 95% CI −5.8, 9.4]). Women also demonstrated a significant improvement in decision readiness; whereas men did not. Both genders had less decision conflict after the intervention. CONCLUSIONS: Both women and men with osteoarthritis had poor estimates of total knee arthroplasty outcomes. Women responded to the intervention with more accurate total knee arthroplasty outcome expectations and greater decision readiness. Improving patient knowledge of total knee arthroplasty through a decision aid may improve medical decision-making and reduce gender disparities in total knee arthroplasty utilization. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12891-015-0473-x) contains supplementary material, which is available to authorized users