Overexpression of wild-type human APP in mice causes cognitive déficits and pathological features unrelated to Abeta levels

Transgenic mice expressing mutant human amyloid precursor protein (APP) develop an age-dependent amyloid pathology and memory deficits, but no overt neuronal loss. Here, in mice overexpressing wild-type human APP (hAPPwt) we found an early memory impairment, particularly in the water maze and to a lesser extent in the object recognition task, but β-amyloid peptide (Aβ42) was barely detectable in the hippocampus. In these mice, hAPP processing was basically non-amyloidogenic, with high levels of APP carboxy-terminal fragments, C83 and APP intracellular domain. A tau pathology with an early increase in the levels of phosphorylated tau in the hippocampus, a likely consequence of enhanced ERK1/2 activation, was also observed. Furthermore, these mice presented a loss of synapse-associated proteins: PSD95, AMPA and NMDA receptor subunits and phosphorylated CaMKII. Importantly, signs of neurodegeneration were found in the hippocampal CA1 subfield and in the entorhinal cortex that were associated to a marked loss of MAP2 immunoreactivity. Conversely, in mice expressing mutant hAPP, high levels of Aβ42 were found in the hippocampus, but no signs of neurodegeneration were apparent. The results support the notion of Aβ- independent pathogenic pathways in Alzheimer's disease

Early Changes in Hippocampal Eph Receptors Precede the Onset of Memory Decline in Mouse Models of Alzheimer’s Disease

Abstract. Synapse loss occurs early in Alzheimer’s disease (AD) and is considered the best pathological correlate of cognitive decline. Ephrins and Eph receptors are involved in regulation of excitatory neurotransmission and play a role in cytoskeleton remodeling. We asked whether alterations in Eph receptors could underlie cognitive impairment in an AD mouse model overexpressing human amyloid-β protein precursor (hAβPP) with familial mutations (hAβPPswe-ind mice). We found that EphA4 and EphB2 receptors were reduced in the hippocampus before the development of impaired object recognition and spatial memory. Similar results were obtained in another line of transgenic AβPP mice, Tg2576. A reduction in Eph receptor levels was also found in postmortem hippocampal tissue from patients with incipient AD. At the time of onset of memory decline in hAβPPswe-ind mice, no change in surface expression of AMPA or NMDA receptor subunits was apparent, but we found changes in Eph-receptor downstream signaling, in particular a decrease in membrane-associated phospho-cofilin levels that may cause cytoskeletal changes and disrupted synaptic activity. Consistent with this finding, Eph receptor activation in cell culture increased phospho-cofilin levels. The results suggest that alterations in Eph receptors may play a role in synaptic dysfunction in the hippocampus leading to cognitive impairment in a model of AD

Assessment of the Potential Shore to Ship Load Demand: The Italian Scenario

In this paper an investigation and a technical-economical assessment on the application of the port electrification in Italy is presented. The recent opening of the electricity regulations to energy community may represent a possible business case to create an economical solution for cold ironing in Italy. In order to assess this possibility, a methodology to estimate load demand, emissions and economic aspects of the ship's hotelling period in ports, is proposed. Specifically, the analysis is derived from data of Italian's maritime traffic recorded over one year. The estimations consider also fuel quality and ship category (RO-RO, Tanker, Bulk etc.). Based on the results, a first estimation of the potential impact of the operation of cold ironing in Italy is reported

Circulatory shear stress induces molecular changes and side population enrichment in primary tumor-derived lung cancer cells with higher metastatic potential

Abstract Cancer is a leading cause of death and disease worldwide. However, while the survival for patients with primary cancers is improving, the ability to prevent metastatic cancer has not. Once patients develop metastases, their prognosis is dismal. A critical step in metastasis is the transit of cancer cells in the circulatory system. In this hostile microenvironment, variations in pressure and flow can change cellular behavior. However, the effects that circulation has on cancer cells and the metastatic process remain unclear. To further understand this process, we engineered a closed-loop fluidic system to analyze molecular changes induced by variations in flow rate and pressure on primary tumor-derived lung adenocarcinoma cells. We found that cancer cells overexpress epithelial-to-mesenchymal transition markers TWIST1 and SNAI2, as well as stem-like marker CD44 (but not CD133, SOX2 and/or NANOG). Moreover, these cells display a fourfold increased percentage of side population cells and have an increased propensity for migration. In vivo, surviving circulatory cells lead to decreased survival in rodents. These results suggest that cancer cells that express a specific circulatory transition phenotype and are enriched in side population cells are able to survive prolonged circulatory stress and lead to increased metastatic disease and shorter survival

Overexpression of wild-type human APP in mice causes cognitive déficits and pathological features unrelated to Abeta levels

Transgenic mice expressing mutant human amyloid precursor protein (APP) develop an age-dependent amyloid pathology and memory deficits, but no overt neuronal loss. Here, in mice overexpressing wild-type human APP (hAPPwt) we found an early memory impairment, particularly in the water maze and to a lesser extent in the object recognition task, but β-amyloid peptide (Aβ42) was barely detectable in the hippocampus. In these mice, hAPP processing was basically non-amyloidogenic, with high levels of APP carboxy-terminal fragments, C83 and APP intracellular domain. A tau pathology with an early increase in the levels of phosphorylated tau in the hippocampus, a likely consequence of enhanced ERK1/2 activation, was also observed. Furthermore, these mice presented a loss of synapse-associated proteins: PSD95, AMPA and NMDA receptor subunits and phosphorylated CaMKII. Importantly, signs of neurodegeneration were found in the hippocampal CA1 subfield and in the entorhinal cortex that were associated to a marked loss of MAP2 immunoreactivity. Conversely, in mice expressing mutant hAPP, high levels of Aβ42 were found in the hippocampus, but no signs of neurodegeneration were apparent. The results support the notion of Aβ- independent pathogenic pathways in Alzheimer's disease

Migration Phenotype of Brain-Cancer Cells Predicts Patient Outcomes

SummaryGlioblastoma multiforme is a heterogeneous and infiltrative cancer with dismal prognosis. Studying the migratory behavior of tumor-derived cell populations can be informative, but it places a high premium on the precision of in vitro methods and the relevance of in vivo conditions. In particular, the analysis of 2D cell migration may not reflect invasion into 3D extracellular matrices in vivo. Here, we describe a method that allows time-resolved studies of primary cell migration with single-cell resolution on a fibrillar surface that closely mimics in vivo 3D migration. We used this platform to screen 14 patient-derived glioblastoma samples. We observed that the migratory phenotype of a subset of cells in response to platelet-derived growth factor was highly predictive of tumor location and recurrence in the clinic. Therefore, migratory phenotypic classifiers analyzed at the single-cell level in a patient-specific way can provide high diagnostic and prognostic value for invasive cancers

Non-virally engineered human adipose mesenchymal stem cells produce BMP4, target brain tumors, and extend survival

There is a need for enabling non-viral nanobiotechnology to allow safe and effective gene therapy and cell therapy, which can be utilized to treat devastating diseases such as brain cancer. Human adipose-derived mesenchymal stem cells (hAMSCs) display high anti-glioma tropism and represent a promising delivery vehicle for targeted brain tumor therapy. In this study, we demonstrate that non-viral, biodegradable polymeric nanoparticles (NPs) can be used to engineer hAMSCs with higher efficacy (75% of cells) than leading commercially available reagents and high cell viability. To accomplish this, we engineered a poly(beta-amino ester) (PBAE) polymer structure to transfect hAMSCs with significantly higher efficacy than Lipofectamine\u2122 2000. We then assessed the ability of NP-engineered hAMSCs to deliver bone morphogenetic protein 4 (BMP4), which has been shown to have a novel therapeutic effect by targeting human brain tumor initiating cells (BTIC), a source of cancer recurrence, in a human primary malignant glioma model. We demonstrated that hAMSCs genetically engineered with polymeric nanoparticles containing BMP4 plasmid DNA (BMP4/NP-hAMSCs) secrete BMP4 growth factor while maintaining their multipotency and preserving their migration and invasion capacities. We also showed that this approach can overcome a central challenge for brain therapeutics, overcoming the blood brain barrier, by demonstrating that NP-engineered hAMSCs can migrate to the brain and penetrate the brain tumor after both intranasal and systemic intravenous administration. Critically, athymic rats bearing human primary BTIC-derived tumors and treated intranasally with BMP4/NP-hAMSCs showed significantly improved survival compared to those treated with control GFP/NP-hAMCSs. This study demonstrates that synthetic polymeric nanoparticles are a safe and effective approach for stem cell-based cancer-targeting therapies

Challenges to evaluating complex interventions: a content analysis of published papers.

BACKGROUND: There is continuing interest among practitioners, policymakers and researchers in the evaluation of complex interventions stemming from the need to further develop the evidence base on the effectiveness of healthcare and public health interventions, and an awareness that evaluation becomes more challenging if interventions are complex.We undertook an analysis of published journal articles in order to identify aspects of complexity described by writers, the fields in which complex interventions are being evaluated and the challenges experienced in design, implementation and evaluation. This paper outlines the findings of this documentary analysis. METHODS: The PubMed electronic database was searched for the ten year period, January 2002 to December 2011, using the term "complex intervention*" in the title and/or abstract of a paper. We extracted text from papers to a table and carried out a thematic analysis to identify authors' descriptions of challenges faced in developing, implementing and evaluating complex interventions. RESULTS: The search resulted in a sample of 221 papers of which full text of 216 was obtained and 207 were included in the analysis. The 207 papers broadly cover clinical, public health and methodological topics. Challenges described included the content and standardisation of interventions, the impact of the people involved (staff and patients), the organisational context of implementation, the development of outcome measures, and evaluation. CONCLUSIONS: Our analysis of these papers suggests that more detailed reporting of information on outcomes, context and intervention is required for complex interventions. Future revisions to reporting guidelines for both primary and secondary research may need to take aspects of complexity into account to enhance their value to both researchers and users of research

The spatial structure of Antarctic biodiversity

Patterns of environmental spatial structure lie at the heart of the most fundamental and familiar patterns of diversity on Earth. Antarctica contains some of the strongest environmental gradients on the planet and therefore provides an ideal study ground to test hypotheses on the relevance of environmental variability for biodiversity. To answer the pivotal question, “How does spatial variation in physical and biological environmental properties across the Antarctic drive biodiversity?” we have synthesized current knowledge on environmental variability across terrestrial, freshwater, and marine Antarctic biomes and related this to the observed biotic patterns. The most important physical driver of Antarctic terrestrial communities is the availability of liquid water, itself driven by solar irradiance intensity. Patterns of biota distribution are further strongly influenced by the historical development of any given location or region, and by geographical barriers. In freshwater ecosystems, free water is also crucial, with further important influences from salinity, nutrient availability, oxygenation, and characteristics of ice cover and extent. In the marine biome there does not appear to be one major driving force, with the exception of the oceanographic boundary of the Polar Front. At smaller spatial scales, ice cover, ice scour, and salinity gradients are clearly important determinants of diversity at habitat and community level. Stochastic and extreme events remain an important driving force in all environments, particularly in the context of local extinction and colonization or recolonization, as well as that of temporal environmental variability. Our synthesis demonstrates that the Antarctic continent and surrounding oceans provide an ideal study ground to develop new biogeographical models, including life history and physiological traits, and to address questions regarding biological responses to environmental variability and change