APP processing and synaptic function

A large body of evidence has implicated Abeta peptides and other derivatives of the amyloid precursor protein (APP) as central to the pathogenesis of Alzheimer's disease (AD). However, the functional relationship of APP and its proteolytic derivatives to neuronal electrophysiology is not known. Here, we show that neuronal activity modulates the formation and secretion of Abeta peptides in hippocampal slice neurons that overexpress APP. In turn, Abeta selectively depresses excitatory synaptic transmission onto neurons that overexpress APP, as well as nearby neurons that do not. This depression depends on NMDA-R activity and can be reversed by blockade of neuronal activity. Synaptic depression from excessive Abeta could contribute to cognitive decline during early AD. In addition, we propose that activity-dependent modulation of endogenous Abeta production may normally participate in a negative feedback that could keep neuronal hyperactivity in check. Disruption of this feedback system could contribute to disease progression in AD.     

Integrin αvβ3-Targeted Dynamic Contrast-Enhanced Magnetic Resonance Imaging Using a Gadolinium-Loaded Polyethylene Gycol-Dendrimer-Cyclic RGD Conjugate to Evaluate Tumor Angiogenesis and to Assess Early Antiangiogenic Treatment Response in a Mouse Xenograft Tumor Model

AbstractThe purpose of this study was to validate an integrin αvβ3-targeted magnetic resonance contrast agent, PEG-G3-(Gd-DTPA)6-(cRGD-DTPA)2, for its ability to detect tumor angiogenesis and assess early response to antiangiogenic therapy using dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). Integrin αvβ3-positive U87 cells and control groups were incubated with fluorescein-labeled cRGD-conjugated dendrimer, and the cellular attachment of the dendrimer was observed. DCE MRI was performed on mice bearing KB xenograft tumors using either PEG-G3-(Gd-DTPA)6-(cRGD-DTPA)2 or PEG-G3-(Gd-DTPA)6-(cRAD-DTPA)2. DCE MRI was also performed 2 hours after anti-integrin αvβ3 monoclonal antibody treatment and after bevacizumab treatment on days 3 and 6t. Using DCE MRI, the 30-minute contrast washout percentage was significantly lower in the cRGD-conjugate injection groups. The enhancement patterns were different between the two contrast injection groups. In the antiangiogenic therapy groups, a rapid increase in 30-minute contrast washout percentage was observed in both the LM609 and bevacizumab treatment groups, and this occurred before there was an observable decrease in tumor size. The integrin αvβ3 targeting ability of PEG-G3-(Gd-DTPA)6-(cRGD-DTPA)2 in vitro and in vivo was demonstrated. The 30-minute contrast washout percentage is a useful parameter for examining tumor angiogenesis and for the early assessment of antiangiogenic treatment response.     

Single Nucleotide Polymorphism Array Lesions, TET2, DNMT3A, ASXL1 and CBL Mutations Are Present in Systemic Mastocytosis

We hypothesized that analysis of single nucleotide polymorphism arrays (SNP-A) and new molecular defects may provide new insight in the pathogenesis of systemic mastocytosis (SM). SNP-A karyotyping was applied to identify recurrent areas of loss of heterozygosity and bidirectional sequencing was performed to evaluate the mutational status of TET2, DNMT3A, ASXL1, EZH2, IDH1/IDH2 and the CBL gene family. Overall survival (OS) was analyzed using the Kaplan-Meier method. We studied a total of 26 patients with SM. In 67% of SM patients, SNP-A karyotyping showed new chromosomal abnormalities including uniparental disomy of 4q and 2p spanning TET2/KIT and DNMT3A. Mutations in TET2, DNMT3A, ASXL1 and CBL were found in 23%, 12%, 12%, and 4% of SM patients, respectively. No mutations were observed in EZH2 and IDH1/IDH2. Significant differences in OS were observed for SM mutated patients grouped based on the presence of combined TET2/DNMT3A/ASXL1 mutations independent of KIT (P = 0.04) and sole TET2 mutations (P<0.001). In conclusion, TET2, DNMT3A and ASXL1 mutations are also present in mastocytosis and these mutations may affect prognosis, as demonstrated by worse OS in mutated patients.     

Sexual compatibility among different host-originated isolates of Aphelenchoides besseyi and the inheritance of the parasitism

Nine isolates of Aphelenchoides besseyi from two different hosts were studied. The isolates were identified at the species level according to morphometrics and fine structures observed under a scanning electron microscope. Two fern-originated isolates, Fu, and Fm, one rice-originated isolate, Rl, were not able to reproduce from a single juvenile, based on at least 50 replicates. The other six isolates were able to develop into a small population when inoculated with a single juvenile, demonstrating parthenogenesis. Crosses between isolates were conducted. In a compatibility cross experiment, three fern-originated isolates were selfed and crossed reciprocally, and all nine crossings had viable offspring. When fern isolates were used as paternal lines, the only two successful crosses were with the Rd line, and as maternal lines, only the Ff x Re and Fu x Rn crosses had viable offspring. Rl was used as the maternal line and Fm as the paternal line to study the inheritance of the bird's-nest fern parasitism. Twenty of the 80 attempted crosses resulted in viable offspring and among these; six lines had the ability to parasitize on the bird's-nest fern. When the F(1) lines were back-crossed to the Rl maternal line, 20 viable offspring lines were obtained and among them 4 were able to parasitize bird's-nest fern. These results indicate that bird's-nest fern parasitism can be transferred to new generations by cross fertilization.     

Extracting Multiscale Pattern Information of fMRI Based Functional Brain Connectivity with Application on Classification of Autism Spectrum Disorders

We employed a multi-scale clustering methodology known as “data cloud geometry” to extract functional connectivity patterns derived from functional magnetic resonance imaging (fMRI) protocol. The method was applied to correlation matrices of 106 regions of interest (ROIs) in 29 individuals with autism spectrum disorders (ASD), and 29 individuals with typical development (TD) while they completed a cognitive control task. Connectivity clustering geometry was examined at both “fine” and “coarse” scales. At the coarse scale, the connectivity clustering geometry produced 10 valid clusters with a coherent relationship to neural anatomy. A supervised learning algorithm employed fine scale information about clustering motif configurations and prevalence, and coarse scale information about intra- and inter-regional connectivity; the algorithm correctly classified ASD and TD participants with sensitivity of and specificity of . Most of the predictive power of the logistic regression model resided at the level of the fine-scale clustering geometry, suggesting that cellular versus systems level disturbances are more prominent in individuals with ASD. This article provides validation for this multi-scale geometric approach to extracting brain functional connectivity pattern information and for its use in classification of ASD.     

A Study on the Dose Distributions in Various Materials from an Ir-192 HDR Brachytherapy Source

Dose distributions of (192)Ir HDR brachytherapy in phantoms simulating water, bone, lung tissue, water-lung and bone-lung interfaces using the Monte Carlo codes EGS4, FLUKA and MCNP4C are reported. Experiments were designed to gather point dose measurements to verify the Monte Carlo results using Gafchromic film, radiophotoluminescent glass dosimeter, solid water, bone, and lung phantom. The results for radial dose functions and anisotropy functions in solid water phantom were consistent with previously reported data (Williamson and Li). The radial dose functions in bone were affected more by depth than those in water. Dose differences between homogeneous solid water phantoms and solid water-lung interfaces ranged from 0.6% to 14.4%. The range between homogeneous bone phantoms and bone-lung interfaces was 4.1% to 15.7%. These results support the understanding in dose distribution differences in water, bone, lung, and their interfaces. Our conclusion is that clinical parameters did not provide dose calculation accuracy for different materials, thus suggesting that dose calculation of HDR treatment planning systems should take into account material density to improve overall treatment quality.     

Evaluation of multi-scale climate effects on annual recruitment levels of the Japanese eel, Anguilla japonica, to Taiwan

Long-term (1967–2008) glass eel catches were used to investigate climatic effects on the annual recruitment of Japanese eel to Taiwan. Specifically, three prevailing hypotheses that potentially explain the annual recruitment were evaluated. Hypothesis 1: high precipitation shifts the salinity front northward, resulting in favorable spawning locations. Hypothesis 2: a southward shift of the position of the North Equatorial Current (NEC) bifurcation provides a favorable larval transport route. Hypothesis 3: ocean conditions (eddy activities and productivity) along the larval migration route influence larval survival. Results of time series regression and wavelet analyses suggest that Hypothesis 1 is not supported, as the glass eel catches exhibited a negative relationship with precipitation. Hypothesis 2 is plausible. However, the catches are correlated with the NEC bifurcation with a one-year lag. Considering the time needed for larval transport (only four to six months), the one-year lag correlation does not support the direct transport hypothesis. Hypothesis 3 is supported indirectly by the results. Significant correlations were found between catches and climate indices that affect ocean productivity and eddy activities, such as the Quasi Biennial Oscillation (QBO), North Pacific Gyre Oscillation (NPGO), Pacific Decadal Oscillation (PDO), and Western Pacific Oscillation (WPO). Wavelet analysis reveals three periodicities of eel catches: 2.7, 5.4, and 10.3 years. The interannual coherence with QBO and the Niño 3.4 region suggests that the shorter-term climate variability is modulated zonally by equatorial dynamics. The low-frequency coherence with WPO, PDO, and NPGO demonstrates the decadal modulation of meridional teleconnection via ocean–atmosphere interactions. Furthermore, WPO and QBO are linked to solar activities. These results imply that the Japanese eel recruitment may be influenced by multi-timescale climate variability. Our findings call for investigation of extra-tropical ocean dynamics that affect survival of eels during transport, in addition to the existing efforts to study the equatorial system.