Amyloid protein aggregation is associated with many neurodegenerative diseases, including amyloid‐β (A
This content will become publicly available on July 11, 2024
- Award ID(s):
- 2106221
- NSF-PAR ID:
- 10434609
- Date Published:
- Journal Name:
- Frontiers in Immunology
- Volume:
- 14
- ISSN:
- 1664-3224
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
more » « less
Abstract β) in Alzheimer disease, human islet amyloid polypeptide (hIAPP) in type II diabetes, and human calcitonin (hCT) in medullary thyroid carcinoma. Significant efforts have been made to develop different diagnostic and prevention strategies for the early detection and intervention of these disease‐causative protein aggregates. However, conventional design wisdoms are mostly limited to the molecules with either single function (amyloid imaging or amyloid prevention) or single targeting protein (Aβ, hIAPP, or hCT). Here, a rational design strategy of an amyloid‐aggregation‐induced emission (AIE)‐active molecule is demonstrated by conjugating an amyloid fragment of GNNQQNY (G7) with an AIE fluorescent molecule of triphenylvinyl benzoic acid (namely, G7‐TBA), making G7‐TBA as multiple‐target, dual‐function, amyloid probes and amyloid modulators for detecting, monitoring, and altering amyloid aggregation of three different amyloid proteins (Aβ, hIAPP, and hCT). G7‐TBA probe shows conformationally specific binding affinities to amyloid aggregates, switching from an “off” state (low fluorescence) for amyloid monomers to an “on” state (high fluorescence) for β‐structure‐rich amyloid oligomers and fibrils in aqueous solution. Further surface immobilization of TBA probes on surface plasmon resonance surfaces allows to amplify detection sensitivity and binding affinity to amyloid aggregates formed at different aggregation stages. G7‐TBA as amyloid modulator enables acceleration of amyloid fibrillization and selectively protects cells from hIAPP‐induced toxicity. The distinct amyloid detection and modulation of G7‐TBA are essentially derived from the cross‐seeding between G7 and amyloid aggregation via β‐structure interaction, which by far exceed the binding affinity between commercial ThT and amyloid aggregates. Such design concepts of amyloid‐AIE conjugates can be further explored as multiple‐function and target probes and/or modulators for biomedical applications. -
ABSTRACT The spirochete Borrelia burgdorferi sensu lato is the causative agent of Lyme disease (LD). The spirochetes produce the CspZ protein that binds to a complement regulator, factor H (FH). Such binding downregulates activation of host complement to facilitate spirochete evasion of complement killing. However, vaccination with CspZ does not protect against LD infection. In this study, we demonstrated that immunization with CspZ-YA, a CspZ mutant protein with no FH-binding activity, protected mice from infection by several spirochete genotypes introduced via tick feeding. We found that the sera from CspZ-YA-vaccinated mice more efficiently eliminated spirochetes and blocked CspZ FH-binding activity than sera from CspZ-immunized mice. We also found that vaccination with CspZ, but not CspZ-YA, triggered the production of anti-FH antibodies, justifying CspZ-YA as an LD vaccine candidate. The mechanistic and efficacy information derived from this study provides insights into the development of a CspZ-based LD vaccine.more » « less
-
null (Ed.)Activation of the CB2 receptor has been shown to have anti-inflammatory and antinociceptive effects without causing psychoactive effects. Previously, we reported that the compound ethyl 2(2-(N-(2,3-dimethylphenyl) phenylsulfonamido)acetamido)benzoate (ABK5) is a CB2 subtype selective agonist with anti-inflammatory and antinociceptive effects. In the present study, we tested four ABK5 derivatives, ABK5-1, ABK5-2, ABK5-5, and ABK5-6, to analyze the structure of ABK5 to obtain CB2-selective agonists with higher affinity and efficacy. Affinity, subtype selectivity, and G-protein coupling were determined by radioligand binding assays. Selected compounds were then subjected to evaluation of anti-inflammatory effects using two different cell lines, Jurkat (ABK5-1 and 5-2) and BV-2 cells (ABK5-1), which are models of T cells and microglia, respectively. ABK5-1, ABK5-2, and ABK5-6 had comparable CB2 binding affinity with ABK5 (and stimulated G-protein coupling), while only ABK5-1 and ABK5-2 maintained CB2-subtype selectivity. ABK5-5 did not bind CB2 in the detectable range. RT-PCR and ELISA analysis showed that the two compounds also inhibit IL-2 and TNF-α production, and they were more efficacious than ABK5 in inhibiting TNF-α production. CXCL-12 mediated chemotaxis was also evaluated by the transwell migration assay, and both ABK5-1 and ABK5-2 inhibited chemotaxis with a stronger effect observed in ABK5-1. In the microglia cell line BV-2, ABK5-1 inhibited IL-1β and IL-6 production, which suggests this compound has anti-inflammatory effects through targeting multiple immune cells, and may be a candidate for treatment of inflammation.more » « less
-
more » « less
Abstract Urbanization often results in biodiversity loss and homogenization, but this result is not universal and there is substantial variability in the spatiotemporal effects of urbanization on wildlife across cities and taxa. Areas with lower population and housing density are some of the fastest-growing regions in the western United States; thus, more research in these areas could offer additional insight into the effects of urbanization on wildlife and the potential importance of wild spaces in maintaining a diverse biotic community surrounding developed areas. To address this need, we conducted a study to identify the effects of urbanization (i.e. housing density) on mammals along a housing density gradient from wilderness to suburbia in Missoula, Montana. We deployed 178 motion-activated trail cameras at random sites within urban/suburban, exurban, rural, and wild regions from May to October 2019 to 2020. We identified all mammals >150 g, then evaluated how housing density influenced: (i) occupancy and (ii) species richness using multispecies occupancy models; (iii) relative abundance using Poisson models; and (iv) diel activity patterns using kernel density estimation and logistic regression. Urbanization was the strongest driver of mammal distribution, with a linear decline in mammal species richness as housing density increased. Urbanization also had strong effects on occupancy and detection rates, with larger-bodied mammals generally having stronger negative associations. Overall, mammal relative abundance was highest in suburban regions; however, this effect was largely driven by White-tailed Deer. Natural environmental factors explained most changes in mammal nocturnal activity; however, urbanization strongly affected nocturnality in some species, with Black Bear and White-tailed Deer becoming more nocturnal and Red Fox and Northern Raccoon becoming less nocturnal as housing density increased. While our study confirms that some mammals can live and thrive in developed areas, it emphasizes the importance of maintaining wild areas for those species that cannot.
-
Herbert, De’Broski R. (Ed.)ABSTRACT Transmitted by ticks, the bacterium Borrelia burgdorferi sensu lato is the causative agent of Lyme disease (LD), the most common vector-borne disease in the Northern hemisphere. No effective vaccines are currently available. B. burgdorferi sensu lato produces the CspZ protein that binds to the complement inhibitor, factor H (FH), promoting evasion of the host complement system. We previously showed that while vaccination with CspZ did not protect mice from B. burgdorferi infection, mice can be protected after immunization with CspZ-Y207A/Y211A (CspZ-YA), a CspZ mutant protein without FH-binding activity. To further study the mechanism of this protection, herein we evaluated both poly- and monoclonal antibodies recognizing CspZ FH-binding or non-FH-binding sites. We found that the anti-CspZ antibodies that recognize the FH-binding sites (i.e., block FH-binding activity) eliminate B. burgdorferi sensu lato in vitro more efficiently than those that bind to the non-FH-binding sites, and passive inoculation with anti-FH-binding site antibodies eradicated B. burgdorferi sensu lato in vivo . Antibodies against non-FH-binding sites did not have the same effect. These results emphasize the importance of CspZ FH-binding sites in triggering a protective antibody response against B. burgdorferi sensu lato in future LD vaccines.more » « less
