Amyloid Beta Pathology Exacerbates Weight Loss and Brain Cytokine Responses following Low-Dose Lipopolysaccharide in Aged Female Tg2576 Mice

Systemic inflammation has been implicated in the progression of Alzheimer’s disease (AD); however, less is understood about how existing AD pathology contributes to adverse outcomes following acute inflammatory insults. In the present study, our goal was to determine how AD-associated amyloid beta (Aβ) pathology influences the acute neuroinflammatory and behavioral responses to a moderate systemic inflammatory insult. We treated 16–18-month-old female Tg2576 (Tg) mice, which overproduce human Aβ and develop plaques, and age-matched wild-type (WT) littermate mice with an intraperitoneal injection of 0.33 mg/kg lipopolysaccharide (LPS) or saline. Mice were then evaluated over the next 28 h for sickness/depressive-like behaviors (food intake, weight loss, locomotion, and sucrose preference), systemic inflammation (serum amyloid A, SAA), blood-brain barrier (BBB) disruption, astrogliosis (glial fibrillary acidic protein/GFAP), Aβ, and cytokine levels in the brain. We found that LPS caused a larger reduction in body weight in Tg vs. WT mice, but that other behavioral responses to LPS did not differ by genotype. BBB disruption was not apparent in either genotype following LPS. Concentrations of the systemic inflammatory marker, SAA, in the blood and brain were significantly increased with LPS but did not significantly differ by genotype. GFAP was increased in Tg mice vs. WT but was not significantly affected by LPS in either genotype. Finally, LPS-induced increases of eight cytokines (IL-1β, IL-6, IL-12 (p40), IL-10, IL-17A, MIP-1α/CCL3, MIP-1β/CCL4, and RANTES/CCL5) were found to be significantly higher in Tg mice vs. WT. In summary, our data show that Aβ pathology exacerbates the neuroinflammatory response to LPS and identifies cytokines that are selectively regulated by Aβ. The association of worse neuroinflammation with greater weight loss in Tg mice suggests that Aβ pathology could contribute to poor outcomes following a systemic inflammatory insult.     

Proteomic Assessment of Extracellular Vesicles from Canine Tissue Explants as a Pipeline to Identify Molecular Targets in Osteosarcoma: PSMD14/Rpn11 as a Proof of Principle

Osteosarcoma (OS) is a highly malignant bone tumour that has seen little improvement in treatment modalities in the past 30 years. Understanding what molecules contribute to OS biology could aid in the discovery of novel therapies. Extracellular vesicles (EVs) serve as a mode of cell-to-cell communication and have the potential to uncover novel protein signatures. In our research, we developed a novel pipeline to isolate, characterize, and profile EVs from normal bone and osteosarcoma tissue explants from canine OS patients. Proteomic analysis of vesicle preparations revealed a protein signature related to protein metabolism. One molecule of interest, PSMD14/Rpn11, was explored further given its prognostic potential in human and canine OS, and its targetability with the drug capzimin. In vitro experiments demonstrated that capzimin induces apoptosis and reduces clonogenic survival, proliferation, and migration in two metastatic canine OS cell lines. Capzimin also reduces the viability of metastatic human OS cells cultured under 3D conditions that mimic the growth of OS cells at secondary sites. This unique pipeline can improve our understanding of OS biology and identify new prognostic markers and molecular targets for both canine and human OS patients.     

Bubble removal in centrifugal casting: Combined effects of buoyancy and diffusion

This article models bubble removal in centrifugal casting of the thermosetting silicone polydimethylsiloxane (PDMS). Given spin speeds, mold geometry, and resin properties for centrifugal casting, it is possible to predict the amount of spin time required to produce bubble‐free parts. For the particular conditions and materials considered in this work, required spin times range from seconds to minutes. The model itself balances two complementary physical behaviors: bubble dissolution and buoyancy. Diffusion dominates the removal of small bubbles below a critical size, while buoyancy dominates the removal of bubbles above a critical size. To simulate the removal of bubbles from a spinning solution, two first‐order nonlinear differential equations are solved numerically. To verify simulated results, designed sets of experiments related the number of remaining bubbles in cured parts to spin times and speeds. Dow Corning Sylgard 184, Sylgard 186, and 3‐6121 were the silicones tested in this work. POLYM. ENG. SCI., 2012. © 2011 Society of Plastics Engineers     

Further Studies on Sex Pheromones of Female Lygus and Related Bugs: Development of Effective Lures and Investigation of Species-Specificity

Mirid bugs (Heteroptera: Miridae) are important pests of many crops worldwide. In previous work by others and ourselves, several species of Lygus bugs were shown to produce blends of three compounds, hexyl butyrate, (E)-2-hexenyl butyrate, and (E)-4-oxo-2-hexenal. These have been proposed as components of the female-produced sex pheromones, but attraction of males to synthetic lures has been difficult to demonstrate. We studied the volatiles released by females of four species: Lygus rugulipennis, Lygus pratensis, Lygocoris pabulinus, and Liocoris tripustulatus. Analyses of volatiles from individual, undisturbed insects showed that the three compounds were produced in species-specific blends, by females only, or in greater quantities by females than by males. The three compounds were loaded into pipette tips, which released the defined blends over at least 30 days. Traps baited with the blend for L. rugulipennis caught more males than traps baited with virgin females, with all three compounds required for maximum attractiveness. Traps baited with the specific blends for each of the four species caught males of three of the species, indicating considerable cross-attraction. There is evidence that other, non-chemical factors, such as time-of-day of production of pheromone, contribute to species-specificity of attraction. This is the first report of consistent attraction of Lygus bugs to synthetic lures in the field.     

Hydrogen Peroxide Generation as an Underlying Response to High Extracellular Inorganic Phosphate (Pi) in Breast Cancer Cells

According to the growth rate hypothesis (GRH), tumour cells have high inorganic phosphate (Pi) demands due to accelerated proliferation. Compared to healthy individuals, cancer patients present with a nearly 2.5-fold higher Pi serum concentration. In this work, we show that an increasing concentration of Pi had the opposite effect on Pi-transporters only in MDA-MB-231 when compared to other breast cell lines: MCF-7 or MCF10-A (non-tumoural breast cell line). Here, we show for the first time that high extracellular Pi concentration mediates ROS production in TNBC (MDA-MB-231). After a short-time exposure (1 h), Pi hyperpolarizes the mitochondrial membrane, increases mitochondrial ROS generation, impairs oxygen (O₂) consumption and increases PKC activity. However, after 24 h Pi-exposure, the source of H₂O₂ seems to shift from mitochondria to an NADPH oxidase enzyme (NOX), through activation of PKC by H₂O₂. Exogenous-added H₂O₂ modulated Pi-transporters the same way as extracellular high Pi, which could be reversed by the addition of the antioxidant N-acetylcysteine (NAC). NAC was also able to abolish Pi-induced Epithelial-mesenchymal transition (EMT), migration and adhesion of MDA-MB-231. We believe that Pi transporters support part of the energy required for the metastatic processes stimulated by Pi and trigger Pi-induced H₂O₂ production as a signalling response to promote cell migration and adhesion.     

Psychometric evaluation of trauma and posttraumatic stress disorder assessments in persons with severe mental illness.

Interrater reliability, internal consistency, test-retest reliability, and convergent validity were examined for the Trauma History Questionnaire (THQ), the Clinician-Administered Posttraumatic Stress Disorder (PTSD) Scale (CAPS), and the PTSD Checklist (PCL) in 30 clients with severe mental illnesses. Interrater reliability for the THQ and CAPS was high, as was internal consistency of CAPS and PCL subscales. The test-retest reliability of the THQ was moderate to high for different traumas. PTSD diagnoses on the CAPS and PCL showed moderate test-retest reliability. Lower levels of test-retest reliability for PTSD diagnoses were related to psychosis diagnoses and symptoms. However, when more stringent criteria for PTSD were used on the CAPS, it had excellent test-retest reliability across all clients. CAPS and PCL diagnoses of PTSD showed moderate convergent validity. The results support the reliability of trauma and PTSD assessments in clients with severe mental illness. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Widespread natural perchlorate in unsaturated zones of the southwest United States

A substantial reservoir (up to 1 kg ha(-1)) of natural perchlorate is present in diverse unsaturated zones of the arid and semi-arid southwestern United States. The perchlorate co-occurs with meteoric chloride that has accumulated in these soils throughout the Holocene [0 to 10-15 ka (thousand years ago)] and possibly longer periods. Previously, natural perchlorate widely believed to be limited to the Atacama Desert, now appears widespread in steppe-to-desert ecoregions. The perchlorate reservoir becomes sufficiently large to affect groundwater when recharge from irrigation or climate change flushes accumulated salts from the unsaturated zone. This new source may help explain increasing reports of perchlorate in dry region agricultural products and should be considered when evaluating overall source contributions.     

Estimation of ethanol mass delivery to groundwater from silicone polymer mats

Hollow-fiber silicone tubing, coiled and shaped as mats, has been evaluated for its potential to provide predictable delivery of ethanol to aquifers to promote reducing conditions for enhanced bioremediation of a range of contaminants in groundwater. A model was developed to predict the steady-state mass flux of diffusional ethanol delivery to an external aqueous phase from an aqueous ethanol solution present inside the polymer tubing mat, and an effective diffusion coefficient of ethanol through the silicone tubing of 1.22 x 10(-6) cm2 s(-1) was determined experimentally. The model was then validated in column-scale laboratory and field experiments where polymer mats configured as permeable reactive barriers maintained uniform diffusive delivery of ethanol. Steady-state mass flux delivery ratios of ethanol through the polymer tubing wall of 1.45 (+/-0.18) x 10(6) to 1.64 (+/-0.17) x 10(6) s cm(-1) were determined under laboratory conditions, and 2.43 (+/-1.47) x 10(6) s cm(-1) under field conditions, which were found to be statistically similar to model-predicted ethanol mass flux delivery ratios.     

The Secretome of Preconditioned Mesenchymal Stem Cells Drives Polarization and Reprogramming of M2a Macrophages toward an IL-10-Producing Phenotype

The preconditioning of mesenchymal stem cells (MSCs) has been recognized as an attractive tool to improve their regenerative and immunomodulatory capacities based on their paracrine effects. In this study, we examined the potential of an MSC-conditioned medium (MSC-CM) to alter the phenotype of murine macrophages and to drive reprogramming toward an anti-inflammatory, M2-like state in vitro. We further explored the impact of MSC cytokine preconditioning on the immunosuppressive properties of the MSC secretome. The MSC-CM suppressed the expression of proinflammatory genes in murine M1 macrophages, but only the CM from preconditioned MSCs (preMSC-CM) downregulated their expression during M1 polarization. Remarkably, only the preMSC-CM significantly increased the expression of M2a-, M2b- and M2c-specific genes and proteins during M2a polarization. Further, macrophages were found to secrete high levels of anti-inflammatory IL-10. Similarly, M2a macrophages cultured in the presence of the preMSC-CM displayed an enhanced expression of M2b/M2c-specific markers, suggesting that the secretome of preMSC promotes the repolarization of M2a-like macrophages to M2b/M2c subtypes. The preMSC-CM was found to be enriched in molecules involved in M2 polarization. Additionally, a unique downregulation of extracellular matrix components was observed. Altogether, the preMSC-CM may provide an attractive strategy to dampen inflammation by suppressing the expression of proinflammatory mediators and promoting the polarization and phenotype switch of M2a cells to IL-10-secreting M2b/M2c-like macrophages.