Dissociation between Brain Amyloid Deposition and Metabolism in Early Mild Cognitive Impairment

Background

The hypothetical model of dynamic biomarkers for Alzheimer’s disease (AD) describes high amyloid deposition and hypometabolism at the mild cognitive impairment (MCI) stage. However, it remains unknown whether brain amyloidosis and hypometabolism follow the same trajectories in MCI individuals. We used the concept of early MCI (EMCI) and late MCI (LMCI) as defined by the Alzheimer’s disease Neuroimaging Initiative (ADNI)-Go in order to compare the biomarker profile between EMCI and LMCI.

Objectives

To examine the global and voxel-based neocortical amyloid burden and metabolism among individuals who are cognitively normal (CN), as well as those with EMCI, LMCI and mild AD.

Methods

In the present study, 354 participants, including CN (n = 109), EMCI (n = 157), LMCI (n = 39) and AD (n = 49), were enrolled between September 2009 and November 2011 through ADNI-GO and ADNI-2. Brain amyloid load and metabolism were estimated using [¹⁸F]AV45 and [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) PET, respectively. Uptake ratio images of [¹⁸F]AV45 and [¹⁸F]FDG were calculated by dividing the summed PET image by the median counts of the grey matter of the cerebellum and pons, respectively. Group differences of global [¹⁸F]AV45 and [¹⁸F]FDG were analyzed using ANOVA, while the voxel-based group differences were estimated using statistic parametric mapping (SPM).

Results

EMCI patients showed higher global [¹⁸F]AV45 retention compared to CN and lower uptake compared to LMCI. SPM detected higher [¹⁸F]AV45 uptake in EMCI compared to CN in the precuneus, posterior cingulate, medial and dorsal lateral prefrontal cortices, bilaterally. EMCI showed lower [¹⁸F]AV45 retention than LMCI in the superior temporal, inferior parietal, as well as dorsal lateral prefrontal cortices, bilaterally. Regarding to the global [¹⁸F]FDG, EMCI patients showed no significant difference from CN and a higher uptake ratio compared to LMCI. At the voxel level, EMCI showed higher metabolism in precuneus, hippocampus, entorhinal and inferior parietal cortices, as compared to LMCI.

Conclusions

The present results indicate that brain metabolism remains normal despite the presence of significant amyloid accumulation in EMCI. These results suggest a role for anti-amyloid interventions in EMCI aiming to delay or halt the deposition of amyloid and related metabolism impairment.     

Pectinase and cellulase activity in the digestive system of the elm leaf beetle,Xanthogaleruca luteola Muller (Coleoptera: Chrysomelidae)

The elm leaf beetle, Xanthogaleruca luteola, is a serious pest of elm trees in urban areas. Partial biochemical characterization of pectinases and cellulases was conducted using the larval digestive system of the pest. Midgut extracts from larvae showed optimum activity for pectinase and cellulase against pectin and carboxymethyl cellulose, respectively, under acidic conditions (pH 6). Pectinases and cellulases were respectively more stable under acidic conditions (pH 4–7) and slightly acidic conditions (pH 5–7) than under highly acidic and alkaline conditions. However, the enzymes were more stable in slightly acidic conditions (pH 6) when incubation time was increased. Maximum activity for the pectinases and cellulases incubated at different temperatures was observed at 45 and 50 °C, respectively. Mg²⁺ remarkably increased pectinase activity, and cellulase activity increased significantly in the presence of Ca²⁺ and Mg²⁺. Sodium dodecyl sulfate significantly decreased pectinase and cellulase activity. The Michaelis–Menten constant (K_M) and the maximal reaction velocity (V_max) values for pectinase were 2 mg·mL^? 1 and 0.017 mmol·min^? 1·mg^? 1 protein toward pectin, respectively. Zymogram analyses revealed the presence of one and five bands of pectinase and cellulase activity, respectively, in the larval midgut extract.     

SPRINT: A new parallel framework for R

Background  

Microarray analysis allows the simultaneous measurement of thousands to millions of genes or sequences across tens to thousands of different samples. The analysis of the resulting data tests the limits of existing bioinformatics computing infrastructure. A solution to this issue is to use High Performance Computing (HPC) systems, which contain many processors and more memory than desktop computer systems. Many biostatisticians use R to process the data gleaned from microarray analysis and there is even a dedicated group of packages, Bioconductor, for this purpose. However, to exploit HPC systems, R must be able to utilise the multiple processors available on these systems. There are existing modules that enable R to use multiple processors, but these are either difficult to use for the HPC novice or cannot be used to solve certain classes of problems. A method of exploiting HPC systems, using R, but without recourse to mastering parallel programming paradigms is therefore necessary to analyse genomic data to its fullest.     

Designing Alginate/Chitosan Nanoparticles Containing Echinacea angustifolia: A Novel Candidate for Combating Multidrug-Resistant Staphylococcus aureus

Nanoparticles (NPs) may help treat multidrug-resistant Staphylococcus aureus (MDR). This study prepared and evaluated chitosan/alginate-encapsulated Echinacea angustifolia extract against MDR strains. Evaluating synthesized NPs with SEM, DLS, and FT-IR. Congo red agar and colorimetric plate techniques examined isolate biofilm formation. NP antibacterial power was assessed using well diffusion. Real-time PCR assessed biofilm-forming genes. MTT assessed the synthesized NPs′ toxicity. According to DLS measurements, spherical E. angustifolia NPs had a diameter of 335.3±1.43 nm. The PDI was 0.681, and the entrapment effectiveness (EE%) of the E. angustifolia extract reached 83.45 %. Synthesized NPs were most antimicrobial. S. aureus resistant to several treatments was 80 percent of 100 clinical samples. Biofilm production was linked to MDR in all strains. The ALG/CS-encapsulated extract had a 4 to 32-fold lower MIC than the free extract, which had no bactericidal action. They also significantly decreased the expression of genes involved in biofilm formation. E. angustifolia-encapsulated ALG/CS decreased IcaD, IcaA, and IcaC gene expression in all MDR strains (***p<0.001). Free extract, free NPs, and E. angustifolia-NPs had 57.5 %, 85.5 %, and 90.0 % cell viability at 256 μg/ml. These discoveries could assist generate stable plant extracts by releasing natural-derived substances under controlled conditions.     

Neutrality of the canonical NF-kappaB-dependent pathway for human and murine cytomegalovirus transcription and replication in vitro

Cytomegalovirus (CMV) is known to rapidly induce activation of nuclear factor kappaB (NF-kappaB) after infection of fibroblast and macrophage cells. NF-kappaB response elements are present in the enhancer region of the CMV major immediate-early promoter (MIEP), and activity of the MIEP is strongly upregulated by NF-kappaB in transient-transfection assays. Here we investigate whether the NF-kappaB-dependent pathway is required for initiating or potentiating human and murine CMV replication in vitro. We show that expression of a dominant negative mutant of the inhibitor of NF-kappaB-alpha (IkappaBalphaM) does not alter the replication kinetics of human or mouse CMV in cultured cells. In addition, mouse embryo fibroblasts genetically deficient for p65/RelA actually showed elevated levels of MCMV replication. Mutation of all NF-kappaB response elements within the enhancer of the MIEP in a recombinant mouse CMV containing the human MIEP (hMCMV-ES), which we have previously shown to replicate in murine fibroblasts with kinetics equivalent to that of wild-type mouse CMV, did not negatively affect replication in fibroblasts. Taken together, these data show that, for CMV replication in cultured fibroblasts activation of the canonical NF-kappaB pathway and binding of NF-kappaB to the MIEP are dispensable, and in the case of p65 may even interfere, thus uncovering a previously unrecognized level of complexity in the host regulatory network governing MIE gene expression in the context of a viral infection.     

Preclinical Analysis of JAA-F11, a Specific Anti–Thomsen-Friedenreich Antibody via Immunohistochemistry and In Vivo Imaging

The tumor specificity of JAA-F11, a novel monoclonal antibody specific for the Thomsen-Friedenreich cancer antigen (TF-Ag-alpha linked), has been comprehensively studied by in vitro immunohistochemical (IHC) staining of human tumor and normal tissue microarrays and in vivo biodistribution and imaging by micro-positron emission tomography imaging in breast and lung tumor models in mice. The IHC analysis detailed herein is the comprehensive biological analysis of the tumor specificity of JAA-F11 antibody performed as JAA-F11 is progressing towards preclinical safety testing and clinical trials. Wide tumor reactivity of JAA-F11, relative to the matched mouse IgG₃ (control), was observed in 85% of 1269 cases of breast, lung, prostate, colon, bladder, and ovarian cancer. Staining on tissues from breast cancer cases was similar regardless of hormonal or Her2 status, and this is particularly important in finding a target on the currently untargetable triple-negative breast cancer subtype. Humanization of JAA-F11 was recently carried out as explained in a companion paper “Humanization of JAA-F11, a Highly Specific Anti–Thomsen-Friedenreich Pancarcinoma Antibody and In Vitro Efficacy Analysis” (Neoplasia 19: 716-733, 2017), and it was confirmed that humanization did not affect chemical specificity. IHC studies with humanized JAA-F11 showed similar binding to human breast tumor tissues. In vivo imaging and biodistribution studies in a mouse syngeneic breast cancer model and in a mouse-human xenograft lung cancer model with humanized ¹²⁴I- JAA-F11 construct confirmed in vitro tumor reactivity and specificity. In conclusion, the tumor reactivity of JAA-F11 supports the continued development of JAA-F11 as a targeted cancer therapeutic for multiple cancers, including those with unmet need.