The Neurovascular Unit Dysfunction in Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. Histopathologically, AD presents with two hallmarks: neurofibrillary tangles (NFTs), and aggregates of amyloid β peptide (Aβ) both in the brain parenchyma as neuritic plaques, and around blood vessels as cerebral amyloid angiopathy (CAA). According to the vascular hypothesis of AD, vascular risk factors can result in dysregulation of the neurovascular unit (NVU) and hypoxia. Hypoxia may reduce Aβ clearance from the brain and increase its production, leading to both parenchymal and vascular accumulation of Aβ. An increase in Aβ amplifies neuronal dysfunction, NFT formation, and accelerates neurodegeneration, resulting in dementia. In recent decades, therapeutic approaches have attempted to decrease the levels of abnormal Aβ or tau levels in the AD brain. However, several of these approaches have either been associated with an inappropriate immune response triggering inflammation, or have failed to improve cognition. Here, we review the pathogenesis and potential therapeutic targets associated with dysfunction of the NVU in AD.     

Ivabradine Induces Cardiac Protection against Myocardial Infarction by Preventing Cyclophilin-A Secretion in Pigs under Coronary Ischemia/Reperfusion

In response to cardiac ischemia/reperfusion, proteolysis mediated by extracellular matrix metalloproteinase inducer (EMMPRIN) and its secreted ligand cyclophilin-A (CyPA) significantly contributes to cardiac injury and necrosis. Here, we aimed to investigate if, in addition to the effect on the funny current (I(f)), Ivabradine may also play a role against cardiac necrosis by reducing EMMPRIN/CyPA-mediated cardiac inflammation. In a porcine model of cardiac ischemia/reperfusion (IR), we found that administration of 0.3 mg/kg Ivabradine significantly improved cardiac function and reduced cardiac necrosis by day 7 after IR, detecting a significant increase in cardiac CyPA in the necrotic compared to the risk areas, which was inversely correlated with the levels of circulating CyPA detected in plasma samples from the same subjects. In testing whether Ivabradine may regulate the levels of CyPA, no changes in tissue CyPA were found in healthy pigs treated with 0.3 mg/kg Ivabradine, but interestingly, when analyzing the complex EMMPRIN/CyPA, rather high glycosylated EMMPRIN, which is required for EMMPRIN-mediated matrix metalloproteinase (MMP) activation and increased CyPA bonding to low-glycosylated forms of EMMPRIN were detected by day 7 after IR in pigs treated with Ivabradine. To study the mechanism by which Ivabradine may prevent secretion of CyPA, we first found that Ivabradine was time-dependent in inhibiting co-localization of CyPA with the granule exocytosis marker vesicle-associated membrane protein 1 (VAMP1). However, Ivabradine had no effect on mRNA expression nor in the proteasome and lysosome degradation of CyPA. In conclusion, our results point toward CyPA, its ligand EMMPRIN, and the complex CyPA/EMMPRIN as important targets of Ivabradine in cardiac protection against IR.     

Human-Induced Neural and Mesenchymal Stem Cell Therapy Combined with a Curcumin Nanoconjugate as a Spinal Cord Injury Treatment

We currently lack effective treatments for the devastating loss of neural function associated with spinal cord injury (SCI). In this study, we evaluated a combination therapy comprising human neural stem cells derived from induced pluripotent stem cells (iPSC-NSC), human mesenchymal stem cells (MSC), and a pH-responsive polyacetal–curcumin nanoconjugate (PA-C) that allows the sustained release of curcumin. In vitro analysis demonstrated that PA-C treatment protected iPSC-NSC from oxidative damage in vitro, while MSC co-culture prevented lipopolysaccharide-induced activation of nuclear factor-κB (NF-κB) in iPSC-NSC. Then, we evaluated the combination of PA-C delivery into the intrathecal space in a rat model of contusive SCI with stem cell transplantation. While we failed to observe significant improvements in locomotor function (BBB scale) in treated animals, histological analysis revealed that PA-C-treated or PA-C and iPSC-NSC + MSC-treated animals displayed significantly smaller scars, while PA-C and iPSC-NSC + MSC treatment induced the preservation of β-III Tubulin-positive axons. iPSC-NSC + MSC transplantation fostered the preservation of motoneurons and myelinated tracts, while PA-C treatment polarized microglia into an anti-inflammatory phenotype. Overall, the combination of stem cell transplantation and PA-C treatment confers higher neuroprotective effects compared to individual treatments.     

FAIRIO: A Throughput-oriented Algorithm for Differentiated I/O Performance

Providing differentiated service in a consolidated storage environment is a challenging task. To address this problem, we introduce FAIRIO, a cycle-based I/O scheduling algorithm that provides differentiated service to workloads concurrently accessing a consolidated RAID storage system. FAIRIO enforces proportional sharing of I/O service through fair scheduling of disk time. During each cycle of the algorithm, I/O requests are scheduled according to workload weights and disk-time utilization history. Experiments, which were driven by the I/O request streams of real and synthetic I/O benchmarks and run on a modified version of DiskSim, provide evidence of FAIRIO’s effectiveness and demonstrate that fair scheduling of disk time is key to achieving differentiated service in a RAID storage system. In particular, the experimental results show that, for a broad range of workload request types, sizes, and access characteristics, the algorithm provides differentiated storage throughput that is within 10% of being perfectly proportional to workload weights; and, it achieves this with little or no degradation of aggregate throughput. The core design concepts of FAIRIO, including service-time allocation and history-driven compensation, potentially can be used to design I/O scheduling algorithms that provide workloads with differentiated service in storage systems comprised of RAIDs, multiple RAIDs, SANs, and hypervisors for Clouds.     

Extraction of Lipids from Municipal Wastewater Plant Microorganisms for Production of Biodiesel

Municipal wastewater treatment plants in the USA produce over 6.2 × 10⁶ t of dried sewage sludge every year. This microorganism-rich sludge is often landfilled or used as fertilizer. Recent restrictions on the use of sewage sludge, however, have resulted in increased disposal problems. Extraction of lipids from sludge yields an untapped source of cheap feedstock for biodiesel production. Solvents used for extraction in this study include n-hexane, methanol, acetone, and supercritical CO₂. The gravimetric yield of oil was low for nonpolar solvents, but use of polar solvents gave a considerably increased yield; however, the percentage of saponifiable material was less. Extraction of lipids with a mixture of n-hexane, methanol, and acetone gave the largest conversion to biodiesel compared with other solvent systems, 4.41% based on total dry weight of sludge. In situ transesterification of dried sludge resulted in a yield of 6.23%. If a 10% dry weight yield of fatty acid methyl esters is assumed, the amount of biodiesel available for production in the USA is 1.4 × 10⁶ m³/year. Outfitting 50% of municipal wastewater plants for lipid extraction and transesterification could result in enough biodiesel production to replace 0.5% of the national petroleum diesel demand (0.7 × 10⁶ m³).     

Degradation of Leaf Litter Phenolics by Aquatic and Terrestrial Isopods

To investigate species-specific decomposition rates of litter from native (Quercus faginea) and introduced (Eucalyptus globulus) tree species in Portugal, we monitored changes in the phenolic signature of leaf litter during decomposition as mediated by an aquatic, Proasellus coxalis (Isopoda: Asellota), and two terrestrial, Porcellio dispar and Eluma caelatum (Isopoda: Oniscidea), detritivores. Although the litter of Eucalyptus and Quercus did not differ in overall protein precipitation capacity, we detected differences in terms of contents of particular phenolic compounds and phenol oxidation products. Accordingly, we observed food-specific consumption rates in Proasellus, but not in the terrestrial isopods. Proasellus digested Eucalyptus at significantly higher rates than Quercus, whereas the opposite was the case for Eluma, and Porcellio digested both litter types equally well. Despite slight differences in detail, effects of Proasellus on changes in the signature of litter phenolics were similar for both litter types, whereas terrestrial isopods—Porcellio and Eluma, although they differed from each other—digestively degraded phenolic compounds in Eucalyptus and Quercus litter, respectively, in different ways. Overall, however, degradation of litter phenolics was similarly effective on both litter types. From these data, we conclude that decomposition of Eucalyptus litter does not proceed more slowly than of litter from native Portuguese trees.     

Digestibility and nutritional value of crude oil from three amaranth species

Oils from a selection ofAmaranthus caudatus, A. hypochondriacus andA. cruentus were extracted with hexane. The crude oils were analyzed for acid value, saponification and iodine number, and were included in basal casein diets for rat studies at 5 and 10% levels to replace equal amounts of refined cottonseed oil. The oils fromA. cruentus andA. hypochondriacus were similar in the oil properties studied and different fromA. caudatus. At either 5 or 10% food intake levels, weight gain and PER were not statistically different from values reported for cottonseed oil. True digestibility of amaranth oil was lower than that of cottonseed oil.A. cruentus oil gave the lowest digestibility. Oil levels induced statistical differences in food intake and digestibility. Oils fromA. caudatus, A. hypochondriacus and cottonseed induced similar serum cholesterol levels, while oil fromA. cruentus gave statistically higher values. Hemoglobin, hematocrit and serum proteins were similar among all groups. Microscopic analysis of the organs of the rats revealed some changes that were also found in cottonseed oil-fed rats. It was concluded that crude amaranth oil has lower digestibility than cottonseed oil, but that it is not responsible for growth-depressing effects when the seed is fed raw as compared to processed materials.