Human ANK2 (ankyrin-B) loss-of-function variants are directly linked with arrhythmia phenotypes. However, in atypical non-ion channel arrhythmia genes such as ANK2 that lack the same degree of robust ...structure/function and clinical data, it may be more difficult to assign variant disease risk based simply on variant location, minor allele frequency, and/or predictive structural algorithms. The human ankyrin-B p.L1622I variant found in arrhythmia probands displays significant diversity in minor allele frequency across populations.
The objective of this study was to directly test the in vivo impact of ankyrin-B p.L1622I on cardiac electrical phenotypes and arrhythmia risk using a new animal model.
We tested arrhythmia phenotypes in a new "knock-in" animal model harboring the human ankyrin-B p.L1622I variant.
Ankyrin-B p.L1622I displays reduced posttranslational expression in vivo, resulting in reduced cardiac ankyrin-B expression and reduced association with binding-partner Na/Ca exchanger. Ankyrin-B(L1622I/L1622I) mice display changes in heart rate, atrioventricular and intraventricular conduction, and alterations in repolarization. Furthermore, ankyrin-B(L1622I/L1622I) mice display catecholamine-dependent arrhythmias. At the cellular level, ankyrin-B(L1622I/L1622I) myocytes display increased action potential duration and severe arrhythmogenic afterdepolarizations that provide a mechanistic rationale for the arrhythmias.
Our findings support in vivo arrhythmogenic phenotypes of an ANK2 variant with unusual frequency in select populations. On the basis of our findings and current clinical data, we support classification of p.L1622I as a "mild" loss-of-function variant that may confer arrhythmia susceptibility in the context of secondary risk factors including environment, medication, and/or additional genetic variation.
Zonula occludens-1 (ZO-1) is an intracellular scaffolding protein that orchestrates the anchoring of membrane proteins to the cytoskeleton in epithelial and specialized tissue including the heart. ...There is clear evidence to support the central role of intracellular auxiliary proteins in arrhythmogenesis and previous studies have found altered ZO-1 expression associated with atrioventricular conduction abnormalities. Here, using human cardiac tissues, we identified all three isoforms of ZO-1, canonical (Transcript Variant 1,
), CRA_e (Transcript Variant 4,
), and an additionally expressed (Transcript Variant 3,
) in non-failing myocardium. To investigate the role of ZO-1 on ventricular arrhythmogenesis, we generated a haploinsufficient ZO-1 mouse model (ZO-1
). ZO-1
mice exhibited dysregulated connexin-43 protein expression and localization at the intercalated disc. While ZO-1
mice did not display abnormal cardiac function at baseline, adrenergic challenge resulted in rhythm abnormalities, including premature ventricular contractions and bigeminy. At baseline, ventricular myocytes from the ZO-1
mice displayed prolonged action potential duration and spontaneous depolarizations, with ZO-1
cells displaying frequent unsolicited (non-paced) diastolic depolarizations leading to spontaneous activity with multiple early afterdepolarizations (EADs). Mechanistically, ZO-1 deficient myocytes displayed a reduction in sodium current density (
) and an increased sensitivity to isoproterenol stimulation. Further, ZO-1 deficient myocytes displayed remodeling in
current, likely a compensatory change. Taken together, our data suggest that ZO-1 deficiency results in myocardial substrate susceptible to triggered arrhythmias.
Miners are exposed to silica-bearing dust which can lead to silicosis, a potentially fatal lung disease. Currently, airborne silica is measured by collecting filter samples and sending them to a ...laboratory for analysis. Since this may take weeks, a field method is needed to inform decisions aimed at reducing exposures. This study investigates a field-portable Fourier transform infrared (FTIR) method for end-of-shift (EOS) measurement of silica on filter samples. Since the method entails localized analyses, spatial uniformity of dust deposition can affect accuracy and repeatability. The study, therefore, assesses the influence of radial deposition uniformity on the accuracy of the method. Using laboratory-generated Minusil and coal dusts and three different types of sampling systems, multiple sets of filter samples were prepared. All samples were collected in pairs to create parallel sets for training and validation. Silica was measured by FTIR at nine locations across the face of each filter and the data analyzed using a multiple regression analysis technique that compared various models for predicting silica mass on the filters using different numbers of "analysis shots." It was shown that deposition uniformity is independent of particle type (kaolin vs. silica), which suggests the role of aerodynamic separation is negligible. Results also reflected the correlation between the location and number of shots versus the predictive accuracy of the models. The coefficient of variation (CV) for the models when predicting mass of validation samples was 4%-51% depending on the number of points analyzed and the type of sampler used, which affected the uniformity of radial deposition on the filters. It was shown that using a single shot at the center of the filter yielded predictivity adequate for a field method, (93% return, CV approximately 15%) for samples collected with 3-piece cassettes.
Copyright 2013 American Association for Aerosol Research
The inhalation of toxic substances is a major threat to the health of miners, and dust containing respirable crystalline silica (α-quartz) is of particular concern, due to the recent rise in cases of ...coal workers' pneumoconiosis and silicosis in some US mining regions. Currently, there is no field-portable instrument that can measure airborne α-quartz and give miners timely feedback on their exposure. The US National Institute for Occupational Safety & Health is therefore conducting studies to investigate technologies capable of end-of-shift or real-time measurement of airborne quartz. The present study focuses on the potential application of Fourier transform infrared (FT-IR) spectrometry conducted in the diffuse reflection (DR) mode as a technique for measuring α-quartz in respirable mine dust. It was concluded that, while the DR/FT-IR method is potentially useful for on-filter measurement of quartz in dust samples, the use of PVC filters produced the most accurate results.
The inhalation of toxic substances is a major threat to the health of miners, and dust containing respirable crystalline silica (α-quartz) is of particular concern, due to the recent rise in cases of ...coal workers' pneumoconiosis and silicosis in some U.S. mining regions. Currently, there is no field-portable instrument that can measure airborne α-quartz and give miners timely feedback on their exposure. The U.S. National Institute for Occupational Safety and Health (NIOSH) is therefore conducting studies to investigate technologies capable of end-of-shift or real-time measurement of airborne quartz. The present study focuses on the potential application of Fourier transform infrared (FT-IR) spectrometry conducted in the diffuse reflection (DR) mode as a technique for measuring α-quartz in respirable mine dust. A DR accessory was used to analyze lab-generated respirable samples of Min-U-Sil 5 (which contains more than 90% α-quartz) and coal dust, at mass loadings in the ranges of 100-600 μg and 600-5300 μg, respectively. The dust samples were deposited onto three different types of filters, borosilicate fiberglass, nylon, and polyvinyl chloride (PVC). The reflectance, R, was calculated by the ratio of a blank filter and a filter with deposited mine dust. Results suggest that for coal and pure quartz dusts deposited on 37 mm PVC filters, measurements of -log R correlate linearly with known amounts of quartz on filters, with R
2
values of approximately 0.99 and 0.94, respectively, for samples loaded up to ∼4000 μg. Additional tests were conducted to measure quartz in coal dusts deposited onto the borosilicate fiberglass and nylon filter media used in the NIOSH-developed Personal Dust Monitor (PDM). The nylon filter was shown to be amenable to DR analysis, but quantification of quartz is more accurate when the filter is "free," as opposed to being mounted in the PDM filter holder. The borosilicate fiberglass filters were shown to produce excessive interference, making quartz quantification impossible. It was concluded that, while the DR/FT-IR method is potentially useful for on-filter measurement of quartz in dust samples, the use of PVC filters produced the most accurate results.
Thermophysical properties of the Isidis basin, Mars Murphy, Nathaniel W.; Jakosky, Bruce M.; Rafkin, Scot C. ...
Journal of Geophysical Research - Planets,
20/May , Letnik:
112, Številka:
E5
Journal Article
Recenzirano
Odprti dostop
We investigated the thermal properties of the Isidis basin in order to understand the high values (>450 J m−2 K−1 s−1/2) located in the southern region of the basin. Thermal inertia data were ...compared to a variety of complementary data sets, including radar, visible, and results from mesoscale atmospheric simulations. We considered four mechanisms for creating the high thermal inertia, including (1) the thinning of a dust mantle, (2) the presence of unconsolidated, coarse‐grained material, (3) high rock abundance, and (4) a high degree of induration. Induration is the scenario most consistent with the data, although we cannot rule out unconsolidated materials and it is likely that rocks contribute to values of thermal inertia to a lesser degree. We also investigated three mechanisms for controlling the geographical distribution of the high thermal inertia values, including (1) the influence of topography, (2) the role of surface morphology, and (3) present aeolian processes. Topography plays a significant role along the southern boundary of the basin but not within the basin itself. THEMIS data show a complex relationship between the thermal inertia and morphology. The wind patterns modeled by the Mars Regional Atmospheric Modeling System (MRAMS) are not fully consistent with the wind directions implied by streaks in the thermal data but are consistent with a second group of streaks observed in the visible data. This suggests that small‐scale (tens of kilometers) streaks observed in the thermal data did not form under present‐day, nominal winds.
Abstract
Pneumonia in ICU patients carries a bleak prognosis with high risk for cardiac dysfunction, largely due to cardiac inflammation with subsequent tissue remodeling and fibrosis. Growing ...evidence indicates that resident macrophages are important regulators of cardiac electrical activity and damage following myocardial infarction. After tissue injury, inflammatory monocytes are recruited to the heart and differentiate into macrophages, which contribute to cardiac dysfunction. MicroRNAs have a key role in the regulation and maintenance of macrophage function and cardiac inflammation. However, it is unclear if microRNAs regulate immune cell recruitment or the function of cardiac resident macrophages. To investigate how bacterial pneumonia promotes cardiac dysfunction, we used P. aeruginosa infection in a murine pulmonary model of infection. Our results show an aberrant cardiac electrical activity, and compromised pump function in P. aeruginosa infected animals. Notably, we found increased cardiac fibrosis mainly due to the accumulation of inflammatory macrophages in the heart. Additionally, we found that miR-155 deficiency reversed the P. aeruginosa mediated cardiac dysfunction by limiting the immune cell migration in to the heart. These findings demonstrate that P. aeruginosa infection induces miR-155 dependent immune cell recruitment to the heart, which changes the phenotype and function of resident macrophages, resulting in elevated cardiac fibrosis and heart function.
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