Adjuvance (United States)

This design-based research study examined the implementation fidelity and effectiveness of the SIMPLE Approach, a constructivist intervention integrating the bar model method with metacognitive scaffolding to enhance word problem-solving skills in Kosovo’s lower secondary classrooms. The study aims to address the research gap in that intervention studies in design-based research recognise the critical role of teachers but provide little insight into their actual work and the fidelity of their implementation. To address this research gap, the study investigated (1) alignment of the teachers’ implementation of the SIMPLE Approach and (2) teachers' and pupils' perceptions. Data from classroom observations, teacher diaries, and interviews revealed varying fidelity levels, improving over time. Teacher 1 showed the lowest fidelity, struggling with the bar model method and limiting group work, while Teacher 3 demonstrated the highest fidelity, effectively incorporating all aspects of the SIMPLE Approach and promoting active pupil engagement. Pupils reported initial difficulty with the bar model but ultimately expressed positive perceptions and a desire for continued use. While generalisability is limited, the findings suggest the SIMPLE Approach holds promise but highlights the need for comprehensive teacher training and ongoing support, particularly when introducing novel methods to ensure effective implementation and high fidelity.

Active immunization is being explored as a potential therapeutic to combat accidental overdose and to mitigate the abuse potential of opioids. Hapten design is one of the crucial factors that determines the efficacy of a candidate vaccine to substance abuse and remains one of the most active areas of research in vaccine development. Herein we report for the first time the synthesis of three novel opiate surrogates with the linker attachment site at C14, 1 (6,14-AmidoHap), 2 (14-AmidoMorHap), and 3 (14-AmidoHerHap) as novel heroin haptens. The compounds 1, 2, and 3 are analogues with different substituents at C6: an acetamide, a hydroxyl moiety, and an acetate, respectively. All three haptens had a phenolic hydroxyl group at C3. The haptens were conjugated to the tetanus toxoid carrier protein, adjuvanted with liposomal monophosphoryl lipid A/aluminum hydroxide and were tested in mice in terms of immunogenicity and efficacy. Immunization of mice resulted in antibody endpoint titers of >105 against all the haptens. Neither of the conjugates of 1, 2, and 3 had induced antibodies with selectivity broad enough to recognize and bind heroin, 6-AM, and morphine resulting in little to no protection against the antinociceptive effects of heroin in vivo. Only the mice immunized with conjugate 3 were partially protected against heroin-induced antinociception. These results contribute to the growing body of knowledge that the linker position and the subtle structural differences in the hapten scaffold impact the selectivity of the induced antibodies. Together, these highlight the importance of rational hapten design for heroin vaccine development.

Graphene-based materials are of increasing interest for their potential use in biomedical applications. However, there is a need to gain a deeper understanding of how graphene modulates biological responses before moving towards clinical application. Innate immune training is a recently described phenomenon whereby cells of the innate immune system are capable of being programmed to generate an increased non-specific response upon subsequent challenge. This has been well established in the case of certain microbes and microbial products. However, little is known about the capacity of particulate materials, such as pristine graphene (pGr), to promote innate immune training. Here we report for the first time that while stimulation with pGr alone does not directly induce cytokine secretion by bone-marrow derived macrophages (BMDMs), it programs them for enhanced secretion of proinflammatory cytokines (IL-6, TNF-α) and a concomitant decrease in production of the regulatory cytokine, IL-10 after Toll-like receptor (TLR) ligand stimulation. This capacity of pGr to program cells for enhanced inflammatory responses could be overcome if the nanomaterial is incorporated in a collagen matrix. Our findings thus demonstrate the potential of graphene to modulate innate immunity over long timescales and have implications for the design and biomedical use of pGr-based materials.

Autophagy is a key regulator of cellular homeostasis that can be activated by pathogen-associated molecules and recently has been shown to influence IL-1β secretion by macrophages. However, the mechanisms behind this are unclear. Here, we describe a novel role for autophagy in regulating the production of IL-1β in antigen-presenting cells. After treatment of macrophages with Toll-like receptor ligands, pro-IL-1β was specifically sequestered into autophagosomes, whereas further activation of autophagy with rapamycin induced the degradation of pro-IL-1β and blocked secretion of the mature cytokine. Inhibition of autophagy promoted the processing and secretion of IL-1β by antigen-presenting cells in an NLRP3- and TRIF-dependent manner. This effect was reduced by inhibition of reactive oxygen species but was independent of NOX2. Induction of autophagy in mice in vivo with rapamycin reduced serum levels of IL-1β in response to challenge with LPS. These data demonstrate that autophagy controls the production of IL-1β through at least two separate mechanisms: by targeting pro-IL-1β for lysosomal degradation and by regulating activation of the NLRP3 inflammasome.

The neuropeptides galanin (GAL), neuropeptide Y (NPY) or neurotensin (NT) exhibit anticonvulsant activities mediated by their respective receptors in the brain. To transform these peptides into potential neurotherapeutics, their systemic bioavailability and metabolic stability must be improved. Our recent studies with GAL analogs suggested that an introduction of lipoamino acids in the context of oligo-Lys residues (lipidization-cationization motif) significantly increases their penetration into the brain, yielding potent antiepileptic compounds. Here, we describe an extension of this strategy to NPY and NT. Rationally designed analogs of NPY and NT containing the lipidization-cationization motif were chemically synthesized and their physicochemical and pharmacological properties were characterized. The analogs NPY-BBB2 and NT-BBB1 exhibited increased serum stability, possessed log D > 1.1, retained high affinities toward their native receptors and produced potent antiseizure activities in animal models of epilepsy following intraperitoneal administration. Our results suggest that the combination of lipidization and cationization may be an effective strategy for improving systemic bioavailability and metabolic stability of various neuroactive peptides.

The pharmacokinetics of morphine in ten infants less than or equal to 10 weeks of age who were receiving morphine infusions were determined. Infants 1-4 days of age (newborns) showed longer elimination half-lives than the older infants (6.8 vs. 3.9 h). Clearance in the newborns is less than one-half that found in older infants (6.3 vs. 23.8 ml X min-1 X kg-1). The combination of lower clearance and longer elimination half-life in newborns (0-7 days) may well explain a prolonged duration of action for morphine in very young infants, but other etiologies are needed to explain the respiratory sensitivity believed to persist in older infants.