Hybrid Aryl-Ether-Ketone and Hyperbranched Epoxy Networks

In this dissertation, relationships between chemical structures, cure kinetics and network architectures are correlated to bulk mechanical properties for novel, hybrid epoxy-amine networks. The work is split into two primary sections: the first is the synthesis and characterization of multifunctional glassy networks based on aryl-ether-ketone diamine curatives, while the second is based on the synthesis and characterization of hyperbranched epoxy polymers and their resulting networks. Three aryl-ether-ketone (AEK) diamines of increasing molecular weights were synthesized and used to cure 4,4’-tetraglycidylether of diaminodiphenylmethane (TGDDM); the resulting networks were compared to 4,4’-diaminodiphenyl sulfone cured TGDDM. Architectural differences were created by varying cure profiles, and characteristics such as sub-Tg motions and free volume were altered to study bulk properties such as thermal stability, glass transition, mechanical properties, and moisture resistance. Additional analysis coupled molecular dynamics simulations and free volume data to relate AEK molecular-level characteristics to bulk properties. Simulation showed that enhanced chain packing and conformational freedom provided networks with similar hole free volume characteristics but created increased fractional free volume with increase in Mc. Activation energies of the two sub-Tg relaxations correlated with the free volume findings. Conformational freedom was also related to mechanical properties, which was related to enhanced secondary interactions. Additionally, AEK diamines were copolymerized with DDS to form blended, hybrid networks with TGDDM. Blended networks offered further insight into the effects of chemical composition and Mc effects by varying AEK concentration. It was found that low concentrations of AEK-diamines could significantly alter DDS-cured networks. The second section of this work involved the blending of an epoxide-functional hyperbranched polymer (HBE) into a glassy epoxy network. It was found that the network-level incorporation and high concentration of secondary interactions allowed simultaneous improvements in modulus and toughness. Further thermal and mechanical improvements were found by incorporation of POSS-units onto the hyperbranched polymer. The bulk property improvements were found to correlate with the multiscale dispersion of POSS. Finally, POSS-HBE carbon-fiber composites were fabricated and tested. Composite properties were related to those of the matrix material

SARS-CoV-2 Beta and Delta variants trigger Fc effector function with increased cross-reactivity

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern (VOCs) exhibit escape from neutralizing antibodies, causing concern about vaccine effectiveness. However, while non-neutralizing cytotoxic functions of antibodies are associated with improved disease outcome and vaccine protection, Fc effector function escape from VOCs is poorly defined. Furthermore, whether VOCs trigger Fc functions with altered specificity, as has been reported for neutralization, is unknown. Here, we demonstrate that the Beta VOC partially evades Fc effector activity in individuals infected with the original (D614G) variant. However, not all functions are equivalently affected, suggesting differential targeting by antibodies mediating distinct Fc functions. Furthermore, Beta and Delta infection trigger responses with significantly improved Fc cross-reactivity against global VOCs compared with D614G-infected or Ad26.COV2.S-vaccinated individuals. This suggests that, as for neutralization, the infecting spike sequence affects Fc effector function. These data have important implications for vaccine strategies that incorporate VOCs, suggesting these may induce broader Fc effector responses.The EDCTP2 program of the European Union’s Horizon 2020 program, Wellcome Centre for Infectious Diseases Research in Africa, the SA-MRC, MRC UK, NRF, the Lily and Ernst Hausmann Trust, the South African Research Chairs Initiative of the Department of Science and Innovation and National Research Foundation of South Africa, the SA Medical Research Council SHIP program, the Center for the AIDS Program of Research (CAPRISA) and an L’Oreal/UNESCO Women in Science South Africa Young Talents award.http://www.cell.com/cell-host-microbe/homeam2023ImmunologyInternal Medicin

Identification and Validation of Novel Cerebrospinal Fluid Biomarkers for Staging Early Alzheimer's Disease

Ideally, disease modifying therapies for Alzheimer disease (AD) will be applied during the 'preclinical' stage (pathology present with cognition intact) before severe neuronal damage occurs, or upon recognizing very mild cognitive impairment. Developing and judiciously administering such therapies will require biomarker panels to identify early AD pathology, classify disease stage, monitor pathological progression, and predict cognitive decline. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF) proteome.CSF samples from individuals with mild AD (Clinical Dementia Rating [CDR] 1) (n = 24) and cognitively normal controls (CDR 0) (n = 24) were subjected to two-dimensional difference-in-gel electrophoresis. Within 119 differentially-abundant gel features, mass spectrometry (LC-MS/MS) identified 47 proteins. For validation, eleven proteins were re-evaluated by enzyme-linked immunosorbent assays (ELISA). Six of these assays (NrCAM, YKL-40, chromogranin A, carnosinase I, transthyretin, cystatin C) distinguished CDR 1 and CDR 0 groups and were subsequently applied (with tau, p-tau181 and Aβ42 ELISAs) to a larger independent cohort (n = 292) that included individuals with very mild dementia (CDR 0.5). Receiver-operating characteristic curve analyses using stepwise logistic regression yielded optimal biomarker combinations to distinguish CDR 0 from CDR>0 (tau, YKL-40, NrCAM) and CDR 1 from CDR<1 (tau, chromogranin A, carnosinase I) with areas under the curve of 0.90 (0.85-0.94 95% confidence interval [CI]) and 0.88 (0.81-0.94 CI), respectively.Four novel CSF biomarkers for AD (NrCAM, YKL-40, chromogranin A, carnosinase I) can improve the diagnostic accuracy of Aβ42 and tau. Together, these six markers describe six clinicopathological stages from cognitive normalcy to mild dementia, including stages defined by increased risk of cognitive decline. Such a panel might improve clinical trial efficiency by guiding subject enrollment and monitoring disease progression. Further studies will be required to validate this panel and evaluate its potential for distinguishing AD from other dementing conditions

Camouflage and Misdirection: The Full-On Assault of Ebola Virus Disease

Ebolaviruses cause a severe hemorrhagic fever syndrome that is rapidly fatal to humans and nonhuman primates. Ebola protein interactions with host cellular proteins disrupt type I and type II interferon responses, RNAi antiviral responses, antigen presentation, T-cell-dependent B cell responses, humoral antibodies, and cell-mediated immunity. This multifaceted approach to evasion and suppression of innate and adaptive immune responses in their target hosts leads to the severe immune dysregulation and “cytokine storm” that is characteristic of fatal ebolavirus infection. Here, we highlight some of the processes by which Ebola interacts with its mammalian hosts to evade antiviral defenses

Simultaneous Reinforcement and Toughness Improvement In an Aromatic Epoxy Network With an Aliphatic Hyperbranched Epoxy Modifier

Hyperbranched polymers have been shown to improve epoxy fracture toughness at the cost of other mechanical properties. In this study an aliphatic, epoxide-functional hyperbranched polymer was synthesized and incorporated at different concentrations into an aromatic epoxy-amine network without cure-induced phase separation. The resulting homogeneous network architecture and thermomechanical properties were studied using DSC, DMA and FTIR, while the mechanical properties were investigated using uniaxial compression and single edge notch beam 3-point bending. It was found that although the flexible hyperbranched structure decreased the glass transition temperature of the network, it also allowed for simultaneous enhancement in both fracture toughness and Young\u27s modulus. These findings were attributed to relationships between chemical structure, crosslink density and non-bond interactions, and indicate the potential for further glassy network fracture toughness improvement without loss of critical mechanical properties by tailoring of the hyperbranched structure

Hybrid POSS-Hyperbranched Polymer Additives for Simultaneous Reinforcement and Toughness Improvements In Epoxy Networks

Tremendous effort is focused on improving epoxy toughness, but common approaches diminish processability and mechanical properties. This work presents hybrid additives which simultaneously enhance toughness, modulus, and other mechanical properties without reducing the network\u27s processability. The hybrid herein was molecularly designed to contain “hard” nanoparticles and “soft” organic segments which both covalently bond and interact to form strong interfaces with epoxy networks. It is shown that a hyperbranched epoxy (HBE) reacted with a molecular silica, polyhedral oligomeric silsesquioxane (POSS), can provide the desired simultaneous reinforcement and toughness enhancements while maintaining processability. Epoxy network incorporation of the hybrid toughener led to a 220% increase in fracture toughness while also bringing about an increase in Young\u27s modulus of over 20%. These significant improvements are described by the cured network\u27s multi-scale morphologies and toughener dispersion states, and are related to strong interactions which occur between POSS\u27s pendants and the HBE

Regulation of gene expression in response to brain injury: Enhanced expression and alternative splicing of rat prosaposin (SGP-1) mRNA in injured brain

Prosaposin, the precursor of saposins or saps, is an injury-repair protein that acts on both neurons and glia. Previous studies identified the prosaposin gene as one of differentially expressed genes following nerve injury. In the present study, we investigated expression of prosaposin mRNA in injured brain utilizing rat models of focal cerebral ischemia and cortical stab wound in order to explore the significance of prosaposin in nerve injury. In ischemic brain, the level of prosaposin mRNA was elevated greater than 400% over controls within 5 days after ischemic insults. Importantly, this induction was accompanied by a 9-base splicing consistent with the alternative Exon-8 splicing of human prosaposin mRNA. In normal brain, two prosaposin mRNA species with and without the 9-base insertion were expressed at a ratio of 85:15; however, this equilibrium reverted to 5:95 following ischemic injury. Similar inductions were observed in stab wound brains. Immunohistochemical staining and in situ hybridization demonstrated an enhanced signal distribution of prosaposin mRNA and injury-induced prosaposin protein around the lesion. The data suggest the expression and processing of prosaposin mRNA may be crucially regulated not only for cerebral homeostasis but also during nerve regenerative and degenerative processes