Exploiting Focused Ultrasound to Aid Intranasal Drug Delivery for Brain Therapy

Novel effective therapeutic strategies are needed to treat brain neurodegenerative diseases and to improve the quality of life of patients affected by Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral sclerosis (ALS) as well as other brain conditions. At present no effective treatment options are available; current therapeutics for neurodegenerative diseases (NDs) improve cognitive symptoms only transiently and in a minor number of patients. Further, most of the amyloid-based phase III clinical trials recently failed in AD, in spite of promising preclinical and phase I-II clinical trials, further pinpointing the need for a better knowledge of the early mechanisms of disease as well as of more effective routes of drug administration. In fact, beyond common pathological events and molecular substrates, each of these diseases preferentially affect defined subpopulations of neurons in specific neuronal circuits (selective neuronal vulnerability), leading to the typical age-related clinical profile. In this perspective, key to successful drug discovery is a robust and reproducible biological validation of potential new molecular targets together with a concomitant set up of protocols/tools for efficient and targeted brain delivery to a specific area of interest. Here we propose and discuss Focused UltraSound aided drug administration as a specific and novel technical approach to achieve optimal concentration of the drug at the target area of interest. We will focus on drug delivery to the brain through the nasal route coupled to FUS as a promising approach to achieve neuroprotection and rescue of cognitive decline in several NDs

Fate and Characteristics of Dissolved Organic Nitrogen through Wastewater Treatment Systems

Dissolved organic nitrogen (DON) represents a significant portion (25-80%) of total dissolved nitrogen in the final effluent of wastewater treatment plants (WWTPs). DON in treated wastewater, once degraded, causes oxygen depletion and/or eutrophication in receiving waters and should be reduced prior to discharge. Biodegradability, bioavailability, and photodegradability are important characteristics of wastewater derived DON and are subjects of research in this dissertation. Four research tasks were performed. In the first task, laboratory-scale chemostat experiments were conducted to examine whether solids retention time (SRT) could be used to control DON and biodegradable DON (BDON) in treated wastewater. Nine different SRTs from 0.3 to 13 were studied. There was no correlation between effluent DON and SRTs. However, BDONs at SRTs of 0.3 to 4 days were comparable and had a decreasing trend with SRTs after that. These results indicate the benefit of high SRTs in term of producing effluent with less BDON. The second task was a comprehensive year-round data collection to study the fate of DON and BDON through the treatment train of a trickling filter (TF) WWTP. The plant removed substantial amounts of DON (62%) and BDON (76%) mainly through the biological process. However, the discharged concentrations in the effluent were still high enough to be critical for a stringent total nitrogen discharge limit (below 5 mg-N/L). Evolution of bioavailable DON (ABDON) along the treatment trains of activated sludge (AS) and TF WWTPs and relationship between ABDON and BDON were examined in the third task. ABDON exerted from a combination of bacteria and algae inocula was higher than algae inoculated ABDON and bacteria inoculated BDON suggesting the use of algae as a treatment organism along with bacteria to minimize effluent DON. The TF and AS WWTPs removed 88% and 64% of ABDON, respectively. In the last task, photodegradable DON (PDON) in primary wastewater and final effluent from TF and AS WWTPs was studied. PDON and BDON fractions of DON data in the final effluent of TF and AS WWTP samples elucidate that photodegradation is as critically important as biodegradation when mineralization of effluent DON is a concern in receiving waters

Lexicographical polytopes

Within a fixed integer box of Rn, lexicographical polytopes are the convex hulls of the integer points that are lexicographically between two given integer points. We provide their descriptions by means of linear inequalities

Al-based foams as permanent cores in al castings: Effect of surface skin thickness and composition on infiltration and core-shell bonding

An emerging and still poorly explored application of aluminum foams is their potential use as permanent cores (inserts) in the casting of aluminum alloys. In this context, Al-based foams can introduce a weight reduction, the obtainment of cavities, a strength increase, the ability to absorb impact energy and vibration, acoustic insulation ability, the possibility to simplify the technological processes (no removal/recycling of traditional sand cores), and finally, they can be fully recyclable. Cymat-type Al foams with thin outer skin were used as permanent cores in Al-alloy gravity casting in the present research. Al-foams were characterized in terms of porosity, density, cell wall and skin thickness, surface chemical composition and morphology, and compression resistance. Cast objects with foam inserts were characterized by means of optical microscopy. The preservation of up to 50% of the initial porosity was observed for foam inserts with higher density. Metallurgical bonding between the foam core and the cast metal was observed in some regions

Mitochondrial dysfunction and oxidative stress caused by cryopreservation in reproductive cells

Mitochondria, fundamental organelles in cell metabolism, and ATP synthesis are respon-sible for generating reactive oxygen species (ROS), calcium homeostasis, and cell death. Mitochon-dria produce most ROS, and when levels exceed the antioxidant defenses, oxidative stress (OS) is generated. These changes may eventually impair the electron transport chain, resulting in decreased ATP synthesis, increased ROS production, altered mitochondrial membrane permeability, and dis-ruption of calcium homeostasis. Mitochondria play a key role in the gamete competence to facilitate normal embryo development. However, iatrogenic factors in assisted reproductive technologies (ART) may affect their functional competence, leading to an abnormal reproductive outcome. Cry-opreservation, a fundamental technology in ART, may compromise mitochondrial function leading to elevated intracellular OS that decreases sperm and oocytes’ competence and the dynamics of fertilization and embryo development. This article aims to review the role played by mitochondria and ROS in sperm and oocyte function and the close, biunivocal relationships between mitochon-drial damage and ROS generation during cryopreservation of gametes and gonadal tissues in different species. Based on current literature, we propose tentative hypothesis of mechanisms involved in cryopreservation-associated mitochondrial dysfunction in gametes, and discuss the role played by antioxidants and other agents to retain the competence of cryopreserved reproductive cells and tissues

Thylakoid proteome variation of Eutrema salsugineum in response to drought and salinity combined stress

It is well known that plant responses to stress involve different events occurring at different places of the cell/leaf and at different time scales in relation with the plant development. In fact, the organelles proteomes include a wide range of proteins that could include a wide range of proteins showing a considerable change in cellular functions and metabolism process. On this basis, a comparative proteomics analysis and fluorescence induction measurements were performed to investigate the photosynthetic performance and the relative thylakoid proteome variation in Eutrema salsugineum cultivated under salt stress (200 mM NaCl), water deficit stress (PEG) and combined treatment (PEG + NaCl) as a hyperosmotic stress. The obtained results showed a significant decrease of plant growth under drought stress conditions, with the appearance of some toxicity symptoms, especially in plants subjected to combined treatment. Application of salt or water stress alone showed no apparent change in the chlorophyll a fluorescence transients, primary photochemistry (fluorescence kinetics of the O-J phase), the PQ pool state (J-I phase changes), (Fv/Fm) and (Fk/Fj) ratios. However, a considerable decrease of all these parameters was observed under severe osmotic stress (PEG + NaCl). The thylakoid proteome analysis revealed 58 proteins showing a significant variation in their abundance between treatments (up or down regulation). The combined treatment (PEG + NaCl) induced a decrease in the expression of the whole PSII core subunit (D1, D2, CP43, CP47, PsbE and PsbH), whereas the OEC subunits proteins remained constant. An increase in the amount of PsaD, PsaE, PsaF, PsaH, PsaK and PsaN was detected under drought stress (PEG5%). No significant change in the accumulation of Cyt b6 and Cyt f was observed. Some regulated proteins involved in cellular redox homeostasis were detected (glutamine synthetase, phosphoglycerate kinase, transketolase), and showed a significant decrease under the combined treatment. Some oxidative stress related proteins were significantly up-regulated under salt or drought stress and could play a crucial role in the PSI photoprotection and the control of ROS production level