Insights into the Nature of Synergistic Effects in Proton-Conducting 4,4−1H,1H-Bitriazole-Poly(ethylene oxide) Composites

A nitrogen-containing heterocycle (NCH), 4,4-1H-1H-bi-1,2,3-triazole (bitriazole), capable of mimicking the hydrogen bonding of water in the solid state is synthesized and its ability to conduct protons in the presence of poly(ethylene oxides) under anhydrous conditions is investigated. Bitriazole is shown to have sufficient thermal and electrochemical stability for fuel cell applications. The composites formed between bitriazole and poly(ethylene oxides) give proton conductivities that can be described by the Vogel−Tamman−Fulcher (VTF) equation. These characteristics suggest coupling between polymer segmental motion and ion transport. The bitriazole N-H proton is shown to be the source of conductivity, and bitriazole and poly(ethylene oxides) function synergistically through specific intermolecular interactions and polymer-induced segmental motion to create a pathway for proton transport via structural diffusion

Proton-Conducting Solid Electrolyte via Ozonolysis of Cationic Ammonium Organoalkoxysilane Surfactant-Templated MCM-41

A functional polymerizable surfactant has been synthesized and used as a template to prepare MCM-41. Ozonolysis of the olefin functional group in the composite material generates a nonporous proton-conducting solid acid that has a conductivity of ca. 6 mS cm^(-1) at 95 °C and an activation energy of 14.2 kJ/mol

Development of siRNA-probes for studying intracellular trafficking of siRNA nanoparticles

One important barrier facing the delivery of short interfering RNAs (siRNAs) via synthetic nanoparticles is the rate of nanoparticle disassembly. However, our ability to optimize the release kinetics of siRNAs from nanoparticles for maximum efficacy is limited by the lack of methods to track their intracellular disassembly. Towards this end, we describe the design of two different siRNA-based fluorescent probes whose fluorescence emission changes in response to the assembly state of the nanoparticle. The first probe design involves a redox-sensitive fluorescence-quenched probe that fluoresces only when the nanoparticle is disassembled in a reductive environment. The second probe design is based on a FRET-labeled siRNA pair that fluoresces due to the proximity of the siRNA pair when the nanoparticle is intact. In both approaches, the delivery vehicle need not be labeled. The utility of these probes was investigated with a lipidoid nanoparticle (LNP) as proof-of-concept in both extracellular and intracellular environments. Fluorescence kinetic data from both probes were fit to a two-phase release and decay curve and subsequently quantified to give intracellular disassembly rate constants. Quantitative analysis revealed that the rate constant of siRNA release measured via the fluorescence-quenched probe was almost identical to the rate constant for nanoparticle disassembly measured via the FRET-labeled probes. Furthermore, these probes were utilized to determine subcellular localization of LNPs with the use of automated high-resolution microscopy as they undergo dissociation. Interestingly, this work shows that large amounts of siRNA remain inside vesicular compartments. Altogether, we have developed new siRNA probes that can be utilized with multiple nanocarriers for quantitative and qualitative analysis of nanoparticle dissociation that may serve as a design tool for future delivery systems.National Institutes of Health (U.S.) (Grant R37-EB000244)National Institutes of Health (U.S.) (Grant R01-CA132091)National Institutes of Health (U.S.) (Grant R01-CA132091)National Institutes of Health (U.S.) (Postdoctoral Fellowship

Degradable Terpolymers with Alkyl Side Chains Demonstrate Enhanced Gene Delivery Potency and Nanoparticle Stability

Degradable, cationic poly(β-amino ester)s (PBAEs) with alkyl side chains are developed for non-viral gene delivery. Nanoparticles formed from these PBAE terpolymers exhibit significantly enhanced DNA transfection potency and resistance to aggregation. These hydrophobic PBAE terpolymers, but not PBAEs lacking alkyl side chains, support interaction with PEG-lipid conjugates, facilitating their functionalization with shielding and targeting moieties and accelerating the in vivo translation of these materials.National Heart, Lung, and Blood InstituteNational Institutes of Health (U.S.) (Program of Excellence in Nanotechnology (PEN) Award, Contract #HHSN268201000045C)National Institutes of Health (U.S.) (NIH Grant R01-EB000244-27)National Institutes of Health (U.S.) (NIH Grant 5-R01-CA132091-04)National Institutes of Health (U.S.) (NIH Grant R01-DE016516-03)National Science Foundation (U.S.) (Graduate Research Fellowship)Juvenile Diabetes Research Foundation International (Grant 17–2007-1063

Effect of molecular weight of amine end-modified poly(β-amino ester)s on gene delivery efficiency and toxicity

Amine end-modified poly(β-amino ester)s (PBAEs) have generated interest as efficient, biodegradable polymeric carriers for plasmid DNA (pDNA). For cationic, non-degradable polymers, such as polyethylenimine (PEI), the polymer molecular weight (MW) and molecular weight distribution (MWD) significantly affect transfection activity and cytotoxicity. The effect of MW on DNA transfection activity for PBAEs has been less well studied. We applied two strategies to obtain amine end-modified PBAEs varying in MW. In one approach, we synthesized four amine end-modified PBAEs with each at 15 different monomer molar ratios, and observed that polymers of intermediate length mediated optimal DNA transfection in HeLa cells. Biophysical characterization of these feed ratio variants suggested that optimal performance was related to higher DNA complexation efficiency and smaller nanoparticle size, but not to nanoparticle charge. In a second approach, we used preparative size exclusion chromatography (SEC) to obtain well-defined, monodisperse polymer fractions. We observed that the transfection activities of size-fractionated PBAEs generally increased with MW, a trend that was weakly associated with an increase in DNA binding efficiency. Furthermore, this approach allowed for the isolation of polymer fractions with greater transfection potency than the starting material. For researchers working with gene delivery polymers synthesized by step-growth polymerization, our data highlight the potentially broad utility of preparative SEC to isolate monodisperse polymers with improved properties. Overall, these results help to elucidate the influence of polymer MWD on nucleic acid delivery and provide insight toward the rational design of next-generation materials for gene therapy.Alnylam Pharmaceuticals (Firm)National Institutes of Health (U.S.) (Grant R01-EB000244-27)National Institutes of Health (U.S.) (Grant 5-R01-CA132091-04)National Science Foundation (U.S.). Graduate Research FellowshipNational Institutes of Health (U.S.). Ruth L. Kirschstein National Research Service Award (F32-EB011867

Associations between Cognition, Gender and Monocyte Activation among HIV Infected Individuals in Nigeria.

The potential role of gender in the occurrence of HIV-related neurocognitive impairment (NCI) and associations with markers of HIV-related immune activity has not been previously examined. In this study 149 antiretroviral-naïve seropositive subjects in Nigeria (SP, 92 women and 57 men) and 58 seronegative (SN, 38 women and 20 men) were administered neuropsychological testing that assessed 7 ability domains. From the neuropsychological test scores was calculated a global deficit score (GDS), a measure of overall NCI. Percentages of circulating monocytes and plasma HIV RNA, soluble CD163 and soluble CD14 levels were also assessed. HIV SP women were found to be younger, more educated and had higher CD4+ T cell counts and borderline higher viral load measures than SP men. On the neuropsychological testing, SP women were more impaired in speed of information processing and verbal fluency and had a higher mean GDS than SN women. Compared to SP men, SP women were also more impaired in speed of information processing and verbal fluency as well as on tests of learning and memory. Numbers of circulating monocytes and plasma sCD14 and sCD163 levels were significantly higher for all SP versus all SN individuals and were also higher for SP women and for SP men versus their SN counterparts. Among SP women, soluble CD14 levels were slightly higher than for SP men, and SP women had higher viral load measurements and were more likely to have detectable virus than SP men. Higher sCD14 levels among SP women correlated with more severe global impairment, and higher viral load measurements correlated with higher monocyte numbers and sCD14 and sCD14 levels, associations that were not observed for SP men. These studies suggest that the risk of developing NCI differ for HIV infected women and men in Nigeria and, for women, may be linked to effects from higher plasma levels of HIV driving activation of circulating monocytes

Assistive Technologies (AT) Preferences of People Living with Visual Disability as Information Access Tools in Academic Libraries

Assistive technologies are necessary for ensuring independent living and equal participation in an information-based society for people living with disabilities (PLWD). This study investigated the assistive technology preference of students with visual disabilities, and the approach academic libraries should adopt in procuring assistive technologies. The study adopted a quantitative research method, with a survey as the research design. The study was conducted among visually disabled students in four public universities in Nigeria. Using the total enumeration method, an online questionnaire was used to obtain information from 151 students who voluntarily agreed to partake in the survey. The study found that access to electronic resources, scanning/conversion of print resources to electronic formats and access to information on the Web were among the technology-based services provided to visually disabled students. COBRA, ZoomText, Supernova and Dragon Naturally Speaking are the most preferred assistive technologies (software). At the same time, handheld scanners (x̅ =4.40) and braille keyboards (x̅ =4.60) are the most preferred assistive technologies in the hardware category by visually challenged students. The study further revealed that the library management should consult with students living with a visual disability before procuring assistive technology. Findings from this study thus provide further evidence of the need for librarians to fulfil their moral and legal obligation in advocating the provision of assistive technologies. Library administrators and university stakeholders should expedite actions on meeting the assistive technology needs of people living with visual disabilities. These actions should transcend mere policy formulation on the provision of assistive technologies to restructuring their services and spaces to accommodate assistive technologies as information service delivery tools for people with visual disabilities

Training Needs and Management of National and Institutional Archives and Records for National Development

This study critically examined the role and impact of training on records and archives managers for effective management of national and institutional records and archives for national development. It highlighted and defined some basic concepts such as training, records, archives, national archives, institutional archives. The needs for training of managers of national and institutional records and archives were examined and their relevance for national development x-rayed. Sources of archival records and the context in which there are organized were indicated. The paper further appraised the processing of organizing archival materials to include packing, labeling, shelvings which are considered crucial in the management of archives and records. It is observed that management of archival materials differ from that of library materials because their organization followed some basic principles such as provenance, sanctity of original order, arrangement determines description and description moves from general to specific. Some challenges relating to institutional and national archives identified. The paper concluded by recommending that: adequate funds, training, opportunities, creation of an ideal classification schemes and provisions of conducive working condition for Archives and records managers to operate successfully have become essential. Keywords: Training, records, archives, national archives, institutional archives

Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling

Despite substantial efforts to understand the interactions between nanoparticles and cells, the cellular processes that determine the efficiency of intracellular drug delivery remain largely unclear. Here we examined cellular uptake of siRNA delivered in lipid nanoparticles (LNPs) using cellular trafficking probes in combination with automated high-throughput confocal microscopy as well as defined perturbations of cellular pathways paired with systems biology approaches to uncover protein-protein and protein-small molecule interactions. We show that multiple cell signaling effectors are required for initial cellular entry of LNPs through macropinocytosis, including proton pumps, mTOR, and cathepsins. SiRNA delivery is substantially reduced as ≅70% of the internalized siRNA undergoes exocytosis through egress of LNPs from late endosomes/lysosomes. Niemann Pick type C1 (NPC1) is shown to be an important regulator of the major recycling pathways of LNP-delivered siRNAs. NPC1-deficient cells show enhanced cellular retention of LNPs inside late endosomes/lysosomes and increased gene silencing of the target gene. Our data suggests that siRNA delivery efficiency might be improved by designing delivery vehicles that can escape the recycling pathways

Proton-Conducting Solid Electrolyte via Ozonolysis of Cationic Ammonium Organoalkoxysilane Surfactant-Templated MCM-41

A functional polymerizable surfactant has been synthesized and used as a template to prepare MCM-41. Ozonolysis of the olefin functional group in the composite material generates a nonporous proton-conducting solid acid that has a conductivity of ca. 6 mS cm^(-1) at 95 °C and an activation energy of 14.2 kJ/mol