Astrocyte and neuronal plasticity in the somatosensory system

Changing the whisker complement on a rodent's snout can lead to two forms of experience-dependent plasticity (EDP) in the neurons of the barrel cortex, where whiskers are somatotopically represented. One form, termed coding plasticity, concerns changes in synaptic transmission and connectivity between neurons. This is thought to underlie learning and memory processes and so adaptation to a changing environment. The second, called homeostatic plasticity, serves to maintain a restricted dynamic range of neuronal activity thus preventing its saturation or total downregulation. Current explanatory models of cortical EDP are almost exclusively neurocentric. However, in recent years, increasing evidence has emerged on the role of astrocytes in brain function, including plasticity. Indeed, astrocytes appear as necessary partners of neurons at the core of the mechanisms of coding and homeostatic plasticity recorded in neurons. In addition to neuronal plasticity, several different forms of astrocytic plasticity have recently been discovered. They extend from changes in receptor expression and dynamic changes in morphology to alteration in gliotransmitter release. It is however unclear how astrocytic plasticity contributes to the neuronal EDP. Here, we review the known and possible roles for astrocytes in the barrel cortex, including its plasticity.

Development of photosensitive liposomes for the controlled release of drugs

The facility to controlled triggered release from a “cage” system remains a key requirement for novel drug delivery. Earlier studies have shown that Bis-Azo PC based photosensitive liposomes are beneficial for drug delivery. Thus, the aim of this project was to develop photosensitive liposomes that can be used for the controlled release of drugs through UV irradiation, particularly therapeutic agents for the treatment of psoriasis. Bis-Azo PC was successfully synthesized and incorporated into a range of liposomal formulations, and these liposomes were applied for the controlled release of BSA-FITC. Bis-Azo PC sensitized liposomes were prepared via interdigitation fusion method. IFV containing optimum cholesterol amount in terms of protein loading, stability and photo-trigger release of protein was investigated. Further studies investigated the stability and triggered release of the HMT from IFV. Finally, permeation behavior of HMT and HMT-entrapped IFV through rat skin was examined using Franz cell. Results from protein study indicated that the stable entrapment of the model protein was feasible as shown through fluorescence spectroscopy and maximum of 84% protein release from IFV after 12 min of UV irradiation. Moreover, stability studies indicated that IFV were more stable at 4 0C as compared to 25 0C. Hence, DPPC:Chol:Bis-Azo PC (16:2:1) based IFV was chosen for the controlled release of HMT and these studies exhibited that photo-trigger release and stability data of HMT-entrapped IFV are in line with the protein results. Franz cell work inferred that HMT-entrapped IFV attributed to slower skin permeation as compared to HMT. CLSM also demonstrated that HMT can be used as a fluorescent label for the in vitro skin study. Overall, the work highlighted in this thesis has given useful insight into the potentials of Bis-Azo PC based IFV as a promising carrier for the treatment of psoriasis.

Microporous polycaprolactone matrices for drug delivery and tissue engineering:the release behaviour of bioactives having extremes of aqueous solubility

Microporous polycaprolactone (PCL) matrices loaded with hydrophobic steroidal drugs or a hydrophilic drug - pilocarpine hydrochloride - were produced by precipitation casting using solutions of PCL in acetone. The efficiency of steroid incorporation in the final matrix (progesterone (56 %) testosterone (46 %) dexamethasone (80 %)) depended on the nature of the drug initially co-dissolved in the PCL solution. Approximately 90 % w/w of the initial load of progesterone, 85 % testosterone and 50 % dexamethasone was released from the matrices in PBS at 37°C over 8 days. Pilocarpine hydrochloride (PH)-loaded PCL matrices, prepared by dispersion of powder in PCL solution, released 70-90 % of the PH content over 12 days in PBS. Application of the Higuchi model revealed that the kinetics of steroid and PH release were consistent with a Fickian diffusion mechanism with corresponding diffusion coefficients of 5.8 × 10-9 (progesterone), 3.9 × 10 -9 (testosterone), 7.1 × 10-10 (dexamethasone) and 22 × 10-8 cm2/s (pilocarpine hydrochloride). The formulation techniques described are expected to be useful for production of implantable, insertable and topical devices for sustained delivery of a range of bioactive molecules of interest in drug delivery and tissue engineering.

Florida International University College of Medicine and Jackson Health System Partner to Establish New Teaching Program

Press Release from Florida International University 's Office of Media Relations on the partnership between the Florida International University College of Medicine and Jackson Health System to establish a new teaching program.

On arterial contractility, energetic requirements of the cardiovascular system, and the formation of arterial sclerosis

The aorta has been viewed as a passive distribution manifold for blood whose elasticity allows it to store blood during cardiac ejection (systole), and release it during relaxation (diastole). This capacitance, or compliance, lowers peak cardiac work input and maintains peripheral sanguine irrigation throughout the cardiac cycle. The compliance of the human and canine circulatory systems have been described either as constant throughout the cycle (Toy et al. 1985) or as some inverse function of pressure (Li et al. 1990, Cappelo et al. 1995). This work shows that a compliance value that is higher during systole than diastole (equivalent to a direct function of pressure) leads to a reduction in the energetic input to the cardiovascular system (CV), even when accounting for the energy required to change compliance. This conclusion is obtained numerically, based on a 3-element lumped-parameter model of the CV, then demonstrated in a physical model built for the purpose. It is then shown, based on the numerical and physical models, on analytical considerations of elastic tubes, and on the analysis of arterial volume as a function of pressure measured in vivo (Armentano et al. 1995), that the mechanical effects of a presupposed arterial contraction are consistent with those of energetically beneficial changes in compliance during the cardiac cycle. Although the amount of energy potentially saved with rhythmically contracting arteries is small (mean 0.55% for the cases studied) the importance of the phenomenon lies in its possible relation to another function of the arterial smooth muscle (ASM): synthesis of wall matrix macromolecules. It is speculated that a reduction in the rate of collagen synthesis by the ASM is implicated in the formation of arteriosclerosis. ^

Synthesis and Biological Evaluation of Novel Folic Acid Receptor-Targeted, β-Cyclodextrin-Based Drug Complexes for Cancer Treatment

Drug targeting is an active area of research and nano-scaled drug delivery systems hold tremendous potential for the treatment of neoplasms. In this study, a novel cyclodextrin (CD)-based nanoparticle drug delivery system has been assembled and characterized for the therapy of folate receptor-positive [FR(+)] cancer. Water-soluble folic acid (FA)-conjugated CD carriers (FACDs) were successfully synthesized and their structures were confirmed by 1D/2D nuclear magnetic resonance (NMR), matrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF-MS), high performance liquid chromatography (HPLC), Fourier transform infrared spectroscopy (FTIR), and circular dichroism. Drug complexes of adamatane (Ada) and cytotoxic doxorubicin (Dox) with FACD were readily obtained by mixed solvent precipitation. The average size of FACD-Ada-Dox was 1.5–2.5 nm. The host-guest association constant Ka was 1,639 M−1 as determined by induced circular dichroism and the hydrophilicity of the FACDs was greatly enhanced compared to unmodified CD. Cellular uptake and FR binding competitive experiments demonstrated an efficient and preferentially targeted delivery of Dox into FR-positive tumor cells and a sustained drug release profile was seen in vitro. The delivery of Dox into FR(+) cancer cells via endocytosis was observed by confocal microscopy and drug uptake of the targeted nanoparticles was 8-fold greater than that of non-targeted drug complexes. Our docking results suggest that FA, FACD and FACD-Ada-Dox could bind human hedgehog interacting protein that contains a FR domain. Mouse cardiomyocytes as well as fibroblast treated with FACD-Ada-Dox had significantly lower levels of reactive oxygen species, with increased content of glutathione and glutathione peroxidase activity, indicating a reduced potential for Dox-induced cardiotoxicity. These results indicate that the targeted drug complex possesses high drug association and sustained drug release properties with good biocompatibility and physiological stability. The novel FA-conjugated β-CD based drug complex might be promising as an anti-tumor treatment for FR(+) cancer.

Delivery and Scavenging of Nucleic Acids by Polycationic Polymers

Electrostatic interaction is a strong force that attracts positively and negatively charged molecules to each other. Such an interaction is formed between positively charged polycationic polymers and negatively charged nucleic acids. In this dissertation, the electrostatic attraction between polycationic polymers and nucleic acids is exploited for applications in oral gene delivery and nucleic acid scavenging. An enhanced nanoparticle for oral gene delivery of a human Factor IX (hFIX) plasmid is developed using the polycationic polysaccharide, chitosan (Ch), in combination with protamine sulfate (PS) to treat hemophilia B. For nucleic acid scavenging purposes, the development of an effective nucleic acid scavenging nanofiber platform is described for dampening hyper-inflammation and reducing the formation of biofilms.

Non-viral gene therapy may be an attractive alternative to chronic protein replacement therapy. Orally administered non-viral gene vectors have been investigated for more than one decade with little progress made beyond the initial studies. Oral administration has many benefits over intravenous injection including patient compliance and overall cost; however, effective oral gene delivery systems remain elusive. To date, only chitosan carriers have demonstrated successful oral gene delivery due to chitosan’s stability via the oral route. In this study, we increase the transfection efficiency of the chitosan gene carrier by adding protamine sulfate to the nanoparticle formulation. The addition of protamine sulfate to the chitosan nanoparticles results in up to 42x higher in vitro transfection efficiency than chitosan nanoparticles without protamine sulfate. Therapeutic levels of hFIX protein are detected after oral delivery of Ch/PS/phFIX nanoparticles in 5/12 mice in vivo, ranging from 3 -132 ng/mL, as compared to levels below 4 ng/mL in 1/12 mice given Ch/phFIX nanoparticles. These results indicate the protamine sulfate enhances the transfection efficiency of chitosan and should be considered as an effective ternary component for applications in oral gene delivery.

Dying cells release nucleic acids (NA) and NA-complexes that activate the inflammatory pathways of immune cells. Sustained activation of these pathways contributes to chronic inflammation related to autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease. Studies have shown that certain soluble, cationic polymers can scavenge extracellular nucleic acids and inhibit RNA-and DNA-mediated activation of Toll-like receptors (TLRs) and inflammation. In this study, the cationic polymers are incorporated onto insoluble nanofibers, enabling local scavenging of negatively charged pro-inflammatory species such as damage-associated molecular pattern (DAMP) molecules in the extracellular space, reducing cytotoxicity related to unwanted internalization of soluble cationic polymers. In vitro data show that electrospun nanofibers grafted with cationic polymers, termed nucleic acid scavenging nanofibers (NASFs), can scavenge nucleic acid-based agonists of TLR 3 and TLR 9 directly from serum and prevent the production of NF-ĸB, an immune system activating transcription factor while also demonstrating low cytotoxicity. NASFs formed from poly (styrene-alt-maleic anhydride) conjugated with 1.8 kDa branched polyethylenimine (bPEI) resulted in randomly aligned fibers with diameters of 486±9 nm. NASFs effectively eliminate the immune stimulating response of NA based agonists CpG (TLR 9) and poly (I:C) (TLR 3) while not affecting the activation caused by the non-nucleic acid TLR agonist pam3CSK4. Results in a more biologically relevant context of doxorubicin-induced cell death in RAW cells demonstrates that NASFs block ~25-40% of NF-ĸβ response in Ramos-Blue cells treated with RAW extracellular debris, ie DAMPs, following doxorubicin treatment. Together, these data demonstrate that the formation of cationic NASFs by a simple, replicable, modular technique is effective and that such NASFs are capable of modulating localized inflammatory responses.

An understandable way to clinically apply the NASF is as a wound bandage. Chronic wounds are a serious clinical problem that is attributed to an extended period of inflammation as well as the presence of biofilms. An NASF bandage can potentially have two benefits in the treatment of chronic wounds by reducing the inflammation and preventing biofilm formation. NASF can prevent biofilm formation by reducing the NA present in the wound bed, therefore removing large components of what the bacteria use to develop their biofilm matrix, the extracellular polymeric substance, without which the biofilm cannot develop. The NASF described above is used to show the effect of the nucleic acid scavenging technology on in vitro and in vivo biofilm formation of P. aeruginosa, S. aureus, and S. epidermidis biofilms. The in vitro studies demonstrated that the NASFs were able to significantly reduce the biofilm formation in all three bacterial strains. In vivo studies of the NASF on mouse wounds infected with biofilm show that the NASF retain their functionality and are able to scavenge DNA, RNA, and protein from the wound bed. The NASF remove DNA that are maintaining the inflammatory state of the open wound and contributing to the extracellular polymeric substance (EPS), such as mtDNA, and also removing proteins that are required for bacteria/biofilm formation and maintenance such as chaperonin, ribosomal proteins, succinyl CoA-ligase, and polymerases. However, the NASF are not successful at decreasing the wound healing time because their repeated application and removal disrupts the wound bed and removes proteins required for wound healing such as fibronectin, vibronectin, keratin, and plasminogen. Further optimization of NASF treatment duration and potential combination treatments should be tested to reduce the unwanted side effects of increased wound healing time.

Threatened common property resource system and factors for resilience: lessons drawn from serege-commons in Muhur, Ethiopia

This ethnographic case study of serege-commons, communal pasture and forest in Muhur, Ethiopia, demonstrates the socially complex nature of the common property resource (CPR) system, including the factors behind its resilience and sustained operation. It reveals the multifaceted and interacting local processes that maintain the commons in the face of political economic processes that challenge common property management. The study shows how CPR use, crop cultivation, alternative livelihood strategies, out-migration, collective herding practices, management practices, and alternative sources of compliance interact, and these interacting processes reinforce each other and maintain a resilient CPR system. This study argues that there is not one single cause for sustainable CPR regimes. Instead, the resilience and sustained operation of the CPR system are due to a mix of interdependent elements and inter-reinforcing linkages related to CPR operations, and their interactions within complex social-ecological systems.

Spiroacetals in the Colonization Behaviour of the Coffee Berry Borer: A 'Push-Pull' System

Coffee berries are known to release several volatile organic compounds, among which is the spiroacetal, conophthorin, an attractant for the coffee berry borer Hypothenemus hampei. Elucidating the effects of other spiroacetals released by coffee berries is critical to understanding their chemo-ecological roles in the host discrimination and colonization process of the coffee berry borer, and also for their potential use in the management of this pest. Here, we show that the coffee berry spiroacetals frontalin and 1,6-dioxaspiro [4.5] decane (referred thereafter as brocain), are also used as semiochemicals by the coffee berry borer for host colonization. Bioassays and chemical analyses showed that crowding coffee berry borers from 2 to 6 females per berry, reduced borer fecundity, which appeared to correlate with a decrease in the emission rates of conophthorin and frontalin over time. In contrast, the level of brocain did not vary significantly between borer-uninfested and infested berries. Brocain was attractive at lower doses, but repellent at higher doses while frontalin alone or in a blend was critical for avoidance. Field assays with a commercial attractant comprising a mixture of ethanol and methanol (1:1), combined with frontalin, confirmed the repellent effect of this compound by disrupting capture rates of H. hampei females by 77% in a coffee plantation. Overall, our results suggest that the levels of frontalin and conophthorin released by coffee berries determine the host colonization behaviour of H. hampei, possibly through a 'push-pull' system, whereby frontalin acts as the 'push' (repellent) and conophthorin acting as the 'pull' (attractant). Furthermore, our results reveal the potential use of frontalin as a repellent for management of this coffee pest.

Methane Clathrates in the Solar System

We review the reservoirs of methane clathrates that may exist in the different bodies of the Solar System. Methane was formed in the interstellar medium prior to having been embedded in the protosolar nebula gas phase. This molecule was subsequently trapped in clathrates that formed from crystalline water ice during the cooling of the disk and incorporated in this form into the building blocks of comets, icy bodies, and giant planets. Methane clathrates may play an important role in the evolution of planetary atmospheres. On Earth, the production of methane in clathrates is essentially biological, and these compounds are mostly found in permafrost regions or in the sediments of continental shelves. On Mars, methane would more likely derive from hydrothermal reactions with olivine-rich material. If they do exist, martian methane clathrates would be stable only at depth in the cryosphere and sporadically release some methane into the atmosphere via mechanisms that remain to be determined. In the case of Titan, most of its methane probably originates from the protosolar nebula, where it would have been trapped in the clathrates agglomerated by the satellite's building blocks. Methane clathrates are still believed to play an important role in the present state of Titan. Their presence is invoked in the satellite's subsurface as a means of replenishing its atmosphere with methane via outgassing episodes. The internal oceans of Enceladus and Europa also provide appropriate thermodynamic conditions that allow formation of methane clathrates. In turn, these clathrates might influence the composition of these liquid reservoirs. Finally, comets and Kuiper Belt Objects might have formed from the agglomeration of clathrates and pure ices in the nebula. The methane observed in comets would then result from the destabilization of clathrate layers in the nuclei concurrent with their approach to perihelion. Thermodynamic equilibrium calculations show that methane-rich clathrate layers may exist on Pluto as well. Key Words: Methane clathrate-Protosolar nebula-Terrestrial planets-Outer Solar System.

Preparation and In Vitro Release of Drug-Loaded Microparticles for Oral Delivery Using Wholegrain Sorghum Kafirin Protein

Kafirin microparticles have been proposed as an oral nutraceutical and drug delivery system. This study investigates microparticles formed with kafirin extracted from white and raw versus cooked red sorghum grains as an oral delivery system. Targeted delivery to the colon would be beneficial for medication such as prednisolone, which is used in the management of inflammatory bowel disease. Therefore, prednisolone was loaded into microparticles of kafirin from the different sources using phase separation. Differences were observed in the protein content, in vitro protein digestibility, and protein electrophoretic profile of the various sources of sorghum grains, kafirin extracts, and kafirin microparticles. For all of the formulations, the majority of the loaded prednisolone was not released in in vitro conditions simulating the upper gastrointestinal tract, indicating that most of the encapsulated drug could reach the target area of the lower gastrointestinal tract. This suggests that these kafirin microparticles may have potential as a colon-targeted nutraceutical and drug delivery system.

Bioadhesive drug delivery system of diltiazem hydrochloride for improved bioavailability in cardiac therapy

Purpose: To prepare and evaluate bioadhesive buccal films of diltiazem hydrochloride (a L-type calcium channel blocker) for overcoming the limitations of frequent dosing, low bioavailability and gastrointestinal discomfort of oral delivery. Methods: Buccal films were prepared by solvent casting technique using sodium carboxymethylcellulose, polyvinyl pyrrolidone K-30 and polyvinyl alcohol. The films were evaluated for weight, thickness, surface pH, swelling index, in vitro residence time, folding endurance, in vitro release, ex-vivo permeation (across porcine buccal mucosa) and drug content uniformity. Results: The drug content of the formulations was uniform with a range of 18.94 ± 0.066 (F2) to 20.08 ± 0.07 mg per unit film (F1). The films exhibited controlled release ranging from 58.76 ± 1.62 to 91.45 ± 1.02 % over a period > 6 h. The films containing 20 mg diltiazem hydrochloride, polyvinyl alcohol (10 %) and polyvinyl pyrrolidone (1 % w/v) i.e. formulation F5, showed moderate swelling, convenient residence time and promising drug release, and thus can be selected for further development of a buccal film for potential therapeutic uses. Conclusion: The developed formulation is a potential bioadhesive buccal system for delivering diltiazem directly to systemic circulation, circumventing first-pass metabolism, avoiding gastric discomfort and improving bioavailability at a minimal dose.

A NEW DC UPS FOR DC POWER DISTRIBUTION SYSTEM IN DATA CENTER

In recent years, the 380V DC and 48V DC distribution systems have been extensively studied for the latest data centers. It is widely believed that the 380V DC system is a very promising candidate because of its lower cable cost compared to the 48V DC system. However, previous studies have not adequately addressed the low reliability issue with the 380V DC systems due to large amount of series connected batteries. In this thesis, a quantitative comparison for the two systems has been presented in terms of efficiency, reliability and cost. A new multi-port DC UPS with both high voltage output and low voltage output is proposed. When utility ac is available, it delivers power to the load through its high voltage output and charges the battery through its low voltage output. When utility ac is off, it boosts the low battery voltage and delivers power to the load form the battery. Thus, the advantages of both systems are combined and the disadvantages of them are avoided. High efficiency is also achieved as only one converter is working in either situation. Details about the design and analysis of the new UPS are presented. For the main AC-DC part of the new UPS, a novel bridgeless three-level single-stage AC-DC converter is proposed. It eliminates the auxiliary circuit for balancing the capacitor voltages and the two bridge rectifier diodes in previous topology. Zero voltage switching, high power factor, and low component stresses are achieved with this topology. Compared to previous topologies, the proposed converter has a lower cost, higher reliability, and higher efficiency. The steady state operation of the converter is analyzed and a decoupled model is proposed for the converter. For the battery side converter as a part of the new UPS, a ZVS bidirectional DC-DC converter based on self-sustained oscillation control is proposed. Frequency control is used to ensure the ZVS operation of all four switches and phase shift control is employed to regulate the converter output power. Detailed analysis of the steady state operation and design of the converter are presented. Theoretical, simulation, and experimental results are presented to verify the effectiveness of the proposed concepts.