Abstract
In Alzheimer’s disease (AD), neurodegenerative processes are ongoing for years prior to the time that cortical atrophy can be reliably detected using conventional neuroimaging techniques. ...Recent advances in diffusion-weighted imaging have provided new techniques to study neural microstructure, which may provide additional information regarding neurodegeneration. In this study, we used neurite orientation dispersion and density imaging (NODDI), a multi-compartment diffusion model, in order to investigate cortical microstructure along the clinical continuum of mild cognitive impairment (MCI) and AD dementia. Using gray matter-based spatial statistics (GBSS), we demonstrated that neurite density index (NDI) was significantly lower throughout temporal and parietal cortical regions in MCI, while both NDI and orientation dispersion index (ODI) were lower throughout parietal, temporal, and frontal regions in AD dementia. In follow-up ROI analyses comparing microstructure and cortical thickness (derived from T1-weighted MRI) within the same brain regions, differences in NODDI metrics remained, even after controlling for cortical thickness. Moreover, for participants with MCI, gray matter NDI—but not cortical thickness—was lower in temporal, parietal, and posterior cingulate regions. Taken together, our results highlight the utility of NODDI metrics in detecting cortical microstructural degeneration that occurs prior to measurable macrostructural changes and overt clinical dementia.
Collocated global atmospheric temperature, humidity, and refractivity profiles from radiosondes and from Constellation Observing System for Meteorology, Ionosphere, and Climate (COSMIC) radio ...occultation data for April 2008 to October 2009 are compared for two purposes. The first is to quantify the error characteristics of 12 radiosonde types flown in the global operational network, as a function of height and for both day and nighttime observations, for each of the three variables. The second is to determine the effects of imperfect temporal and spatial collocation on the radiosonde‐COSMIC differences, for application to the general problem of satellite calibration and validation using in situ sounding data. Statistical analyses of the comparisons reveal differences among radiosonde types in refractivity, relative humidity, and radiation‐corrected temperature data. Most of the radiosonde types show a dry bias, particularly in the upper troposphere, with the bias in daytime drier than in nighttime. Weather‐scale variability, introduced by collocation time and distance mismatch, affects the comparison of radiosonde and COSMIC data by increasing the standard deviation errors, which are generally proportional to the size of the time and distance mismatch within the collocation window of 6 h and 250 km considered. Globally, in the troposphere (850–200 hPa), the collocation mismatch impacts on the comparison standard deviation errors for temperature are 0.35 K per 3 h and 0.42 K per 100 km and, for relative humidity, are 3.3% per 3 h and 3.1% per 100 km, indicating an approximate equivalence of 3 h to 100 km in terms of mismatch impact.
Introduction
Neurite orientation dispersion and density imaging (NODDI), a multi‐compartment diffusion‐weighted imaging (DWI) model, may be useful for detecting early cortical microstructural ...alterations in Alzheimer's disease prior to cognitive impairment.
Methods
Using neuroimaging (NODDI and T1‐weighted magnetic resonance imaging MRI) and cerebrospinal fluid (CSF) biomarker data (measured using Elecsys® CSF immunoassays) from 219 cognitively unimpaired participants, we tested the main and interactive effects of CSF amyloid beta (Aβ)42/Aβ40 and phosphorylated tau (p‐tau) on cortical NODDI metrics and cortical thickness, controlling for age, sex, and apolipoprotein E ε4.
Results
We observed a significant CSF Aβ42/Aβ40 × p‐tau interaction on cortical neurite density index (NDI), but not orientation dispersion index or cortical thickness. The directionality of these interactive effects indicated: (1) among individuals with lower CSF p‐tau, greater amyloid burden was associated with higher cortical NDI; and (2) individuals with greater amyloid and p‐tau burden had lower cortical NDI, consistent with cortical neurodegenerative changes.
Discussion
NDI is a particularly sensitive marker for early cortical changes that occur prior to gross atrophy or development of cognitive impairment.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
This paper describes, along with some validation results, the one-dimensional variational method (1D-Var) that is in use at the University Corporation for Atmospheric Research (UCAR) to retrieve ...atmospheric profiles of temperature, pressure, and humidity from the observation of the Global Navigation Satellite System (GNSS) radio occultation (RO). The retrieved profiles are physically consistent among the variables and statistically optimal as regards to a priori error statistics. Tests with idealized data demonstrate that the 1D-Var is highly effective in spreading the observational information and confirm that the method works as designed and expected, provided that correct input data are given. Tests for real-world data sets show that the retrieved profiles agree remarkably well with global weather analyses and collocated high vertical resolution radiosonde observations, and that the 1D-Var can produce value-added retrievals with respect to a priori profiles. We also find that the retrieved profiles are of exceptional long-term stability, suggesting that the 1D-Var can provide an excellent climate data record.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
This paper investigates the global ionospheric response during the January 2009 stratospheric sudden warming (SSW) event by using electron density profiles derived from GPS radio occultation ...measurements of the COSMIC satellites. The peak density (NmF2), peak height (hmF2), and ionospheric total electron content (ITEC) increase in the morning hours and decrease in the afternoon globally for 75% of the cases, in which electron density profiles during SSW and non‐SSW days are available around the same location and local time bins. NmF2, hmF2, and ITEC during SSW days, on average, increase 19%, 12 km, and 17% in the morning and decrease 23%, 19 km, and 25% in the afternoon, respectively, in comparison with those during non‐SSW days from global COSMIC observations. These results agree well with previous results from total electron content observations in low‐latitude and equatorial regions. Interestingly, the unique COSMIC observations also revealed that during this SSW event the ionosphere responds globally, not only in the equatorial regions but also at the high and middle latitudes. The high‐latitude ionosphere shows increased NmF2 and ITEC and decreased hmF2 in either the morning or afternoon sector. Thus, these results indicate that the ionospheric response in low‐middle latitude and equatorial regions during SSW can be explained by either the modulated vertical drift resulting from the interaction between the planetary waves and tides through E region dynamo or the possible direct propagation of tides from the lower atmosphere, whereas the ionospheric variations at the middle and high latitude during the SSW might be attributed to the neutral background changes due to the direct propagation of tides from the lower atmosphere to the ionospheric F2 region. The competitive effects of different physical processes, such as the electric field, neutral wind, and composition, might cause the complex features of ionospheric variations during this SSW event.
With the increased number of low Earth orbit (LEO) satellites equipped with GPS receivers, LEO based GPS observations play a more important role in space weather research because of better global ...coverage and higher vertical resolution. GPS slant total electron content (TEC) is one of the most important space weather products. In this paper, the LEO based slant TEC derivation method and the main error sources, including the multipath calibration, the leveling of phase to the pseudorange TEC, and the differential code bias (DCB) estimation, are described systematically. It is found that the DCB estimation method based on the spherical symmetry ionosphere assumption can obtain reasonable results by analyzing data from multiple LEO missions. The accuracy of the slant TEC might be enhanced if the temperature dependency of DCB estimation is considered. The calculated slant TEC is validated through comparison with empirical models and analyzing the TEC difference of COSMIC colocated clustered observations during the initial stage. Quantitatively, the accuracy of the LEO slant TEC can be estimated at 1–3 tecu, depending on the mission. Possible use of the LEO GPS data in ionosphere and plasmasphere is discussed.
Key Points
The errors of LEO slant TEC calculation are quantitatively studied
The effect of environment temperature on the DCB estimation is studied
The significance of LEO TEC on space weather is discussed
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Integrated clinical clerkships represent a relatively new and innovative approach to medical education that uses continuity as an organizing principle, thus increasing patient-centeredness and ...learner-centeredness. Medical schools are offering longitudinal integrated clinical clerkships in increasing numbers. This report collates the experiences of medical schools that use longitudinal integrated clerkships for medical student education in order to establish a clearer characterization of these experiences and summarize outcome data, when possible.
The authors sent an e-mail survey with open text responses to 17 medical schools with known longitudinal integrated clerkships.
Sixteen schools in four countries on three continents responded to the survey. Fifteen institutions have active longitudinal integrated clerkships in place. Two programs began before 1995, but the others are newer. More than 2,700 students completed longitudinal integrated clerkships in these schools. The median clerkship length is 40 weeks, and in 15 of the schools, the core clinical content was in medicine, surgery, pediatrics, and obstetrics-gynecology. Eleven schools reported supportive student responses to the programs. No differences were noted in nationally normed exam scores between program participants and those in the traditional clerkships. Limited outcomes data suggest that students who participate in these programs are more likely to enter primary care careers.
This study documents the increasing use of longitudinal integrated clerkships and provides initial insights for institutions that may wish to develop similar clinical programs. Further study will be needed to assess the long-term impact of these programs on medical education and workforce initiatives.
We report preliminary results of a global 3-D ionospheric electron density reanalysis demonstration study during 2002-2011 based on multisource data assimilation. The monthly global ionospheric ...electron density reanalysis has been done by assimilating the quiet days ionospheric data into a data assimilation model constructed using the International Reference Ionosphere (IRI) 2007 model and a Kalman filter technique. These data include global navigation satellite system (GNSS) observations of ionospheric total electron content (TEC) from ground-based stations, ionospheric radio occultations by CHAMP, GRACE, COSMIC, SAC-C, Metop-A, and the TerraSAR-X satellites, and Jason-1 and 2 altimeter TEC measurements. The output of the reanalysis are 3-D gridded ionospheric electron densities with temporal and spatial resolutions of 1 h in universal time, 5deg in latitude, 10deg in longitude, and approx.30 km in altitude. The climatological features of the reanalysis results, such as solar activity dependence, seasonal variations, and the global morphology of the ionosphere, agree well with those in the empirical models and observations. The global electron content derived from the international GNSS service global ionospheric maps, the observed electron density profiles from the Poker Flat Incoherent Scatter Radar during 2007-2010, and foF2 observed by the global ionosonde network during 2002-2011 are used to validate the reanalysis method. All comparisons show that the reanalysis have smaller deviations and biases than the IRI-2007 predictions. Especially after April 2006 when the six COSMIC satellites were launched, the reanalysis shows significant improvement over the IRI predictions. The obvious overestimation of the low-latitude ionospheric F region densities by the IRI model during the 23/24 solar minimum is corrected well by the reanalysis. The potential application and improvements of the reanalysis are also discussed.
Outer membrane protein A (OmpA) is a key outer membrane protein found in Gram‐negative bacteria that contributes to several crucial processes in bacterial virulence. In Porphyromonas gingivalis, OmpA ...is predicted as a heterotrimer of OmpA1 and OmpA2 subunits encoded by adjacent genes. Here we describe the role of OmpA and its individual subunits in the interaction of P. gingivalis with oral cells. Using knockout mutagenesis, we show that OmpA2 plays a significant role in biofilm formation and interaction with human epithelial cells. We used protein structure prediction software to identify extracellular loops of OmpA2, and determined these are involved in interactions with epithelial cells as evidenced by inhibition of adherence and invasion of P. gingivalis by synthetic extracellular loop peptides and the ability of the peptides to mediate interaction of latex beads with human cells. In particular, we observe that OmpA2‐loop 4 plays an important role in the interaction with host cells. These data demonstrate for the first time the important role of P. gingivalis OmpA2 extracellular loops in interaction with epithelial cells, which may help design novel peptide‐based antimicrobial therapies for periodontal disease.
This paper presents evidence that surface exposed loops of the OmpA2 outer membrane protein of the periodontitis causing pathogen Porphyromonas gingivalis directs interaction with oral epithelial cells and inert surfaces during biofilm formation. These data reveal new insight into two processes key to periodontal pathogen virulence and suggest new avenues for antimicrobial strategies for periodontitis.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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