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A blueprint for robust crosslinking of mobile species in biogels with weakly adhesive molecular anchors.

ABSTRACT: Biopolymeric matrices can impede transport of nanoparticulates and pathogens by entropic or direct adhesive interactions, or by harnessing "third-party" molecular anchors to crosslink nanoparticulates to matrix constituents. The trapping potency of anchors is dictated by association rates and affinities to both nanoparticulates and matrix; the popular dogma is that long-lived, high-affinity bonds to both species facilitate optimal trapping. Here we present a contrasting paradigm combining experimental evidence (using IgG antibodies and Matrigel®), a theoretical framework (based on multiple timescale analysis), and computational modeling. Anchors that bind and unbind rapidly from matrix accumulate on nanoparticulates much more quickly than anchors that form high-affinity, long-lived bonds with matrix, leading to markedly greater trapping potency of multiple invading species without saturating matrix trapping capacity. Our results provide a blueprint for engineering molecular anchors with finely tuned affinities to effectively enhance the barrier properties of biogels against diverse nanoparticulate species.Biological polymeric matrices often use molecular anchors, such as antibodies, to trap nanoparticulates. Here, the authors find that anchor-matrix bonds that are weak and short-lived confer superior trapping potency, contrary to the prevailing belief that effective molecular anchors should form strong bonds to both the matrix and the nanoparticulates.

SUBMITTER: Newby J

PROVIDER: S-EPMC5635012 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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A blueprint for robust crosslinking of mobile species in biogels with weakly adhesive molecular anchors.

Newby Jay J Schiller Jennifer L JL Wessler Timothy T Edelstein Jasmine J Forest M Gregory MG Lai Samuel K SK

Nature communications 20171010 1

Biopolymeric matrices can impede transport of nanoparticulates and pathogens by entropic or direct adhesive interactions, or by harnessing "third-party" molecular anchors to crosslink nanoparticulates to matrix constituents. The trapping potency of anchors is dictated by association rates and affinities to both nanoparticulates and matrix; the popular dogma is that long-lived, high-affinity bonds to both species facilitate optimal trapping. Here we present a contrasting paradigm combining experi ...[more]

PMID: 29018239

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Project description:Adhesion allows microbes to colonize surfaces and is the first stage in biofilm formation. Stable attachment of the freshwater alphaproteobacterium Caulobacter crescentus to surfaces requires an adhesive polysaccharide called holdfast, which is synthesized at a specific cell pole and ultimately found at the tip of cylindrical extensions of the cell envelope called stalks. Secretion and anchoring of holdfast to the cell surface are governed by proteins HfsDAB and HfaABD, respectively. The arrangement and organization of these proteins with respect to each other and the cell envelope, and the mechanism by which the holdfast is anchored on cells, are unknown. In this study, we have imaged a series of C. crescentus mutants using electron cryotomography, revealing the architecture and arrangement of the molecular machinery involved in holdfast anchoring in cells. We found that the holdfast is anchored to cells by a defined complex made up of the HfaABD proteins and that the HfsDAB secretion proteins are essential for proper assembly and localization of the HfaABD anchor. Subtomogram averaging of cell stalk tips showed that the HfaABD complex spans the outer membrane. The anchor protein HfaB is the major component of the anchor complex located on the periplasmic side of the outer membrane, while HfaA and HfaD are located on the cell surface. HfaB is the critical component of the complex, without which no HfaABD complex was observed in cells. These results allow us to propose a working model of holdfast anchoring, laying the groundwork for further structural and cell biological investigations.IMPORTANCE Adhesion and biofilm formation are fundamental processes that accompany bacterial colonization of surfaces, which are of critical importance in many infections. Caulobacter crescentus biofilm formation proceeds via irreversible adhesion mediated by a polar polysaccharide called holdfast. Mechanistic and structural details of how the holdfast is secreted and anchored on cells are still lacking. Here, we have assigned the location and described the arrangement of the holdfast anchor complex. This work increases our knowledge of the relatively underexplored field of polysaccharide-mediated adhesion by identifying structural elements that anchor polysaccharides to the cell envelope, which is important in a variety of bacterial species.

Project description:BackgroundPhysical and mental health benefits can be attained from persistent, long-term performance of mindfulness meditation with a mobile meditation app, but in general, few mobile health app users persistently engage at a level necessary to attain the corresponding health benefits. Anchoring or pairing meditation with a mobile app to an existing daily routine can establish an unconsciously initiated meditation routine that may improve meditation persistence.ObjectiveThe purpose of this study was to test the use of either personalized anchors or fixed anchors for establishing a persistent meditation app routine with the mobile app, Calm.MethodsWe conducted a randomized controlled trial and randomly assigned participants to one of 3 study groups: (1) a personalized anchor (PA) group, (2) fixed anchor (FA) group, or (3) control group that did not use the anchoring strategy. All participants received app-delivered reminder messages to meditate for at least 10 minutes a day using the Calm app for an 8-week intervention period, and app usage data continued to be collected for an additional 8-week follow-up period to measure meditation persistence. Baseline, week 8, and week 16 surveys were administered to assess demographics, socioeconomic status, and changes in self-reported habit strength.ResultsA total of 101 participants across the 3 study groups were included in the final analysis: (1) PA (n=56), (2) FA (n=49), and (3) control group (n=62). Participants were predominantly White (83/101, 82.2%), female (77/101, 76.2%), and college educated (ie, bachelor's or graduate degree; 82/101, 81.2%). The FA group had a significantly higher average odds of daily meditation during the intervention (1.14 odds ratio [OR]; 95% CI 1.02-1.33; P=.04), and all participants experienced a linear decline in their odds of daily meditation during the 8-week intervention (0.96 OR; 95% CI 0.95-0.96; P<.001). Importantly, the FA group showed a significantly smaller decline in the linear trend of their odds of daily meditation during the 8-week follow-up (their daily trend increased by 1.04 OR from their trend during the intervention; 95% CI 1.01-1.06; P=.03). Additionally, those who more frequently adhered to their anchoring strategy during the intervention typically used anchors that occurred in the morning and showed a significantly smaller decline in their odds of daily meditation during the 8-week follow-up period (1.13 OR; 95% CI 1.02-1.35; P=.007).ConclusionsThe FA group had more persistent meditation with the app, but participants in the FA or PA groups who more frequently adhered to their anchoring strategy during the intervention had the most persistent meditation routines, and almost all of these high anchorers used morning anchors. These findings suggest that the anchoring strategy can create persistent meditation routines with a mobile app. However, future studies should combine anchoring with additional intervention tools (eg, incentives) to help more participants successfully establish an anchored meditation routine.Trial registrationClinicalTrials.gov NCT04378530; https://clinicaltrials.gov/ct2/show/NCT04378530.

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A blueprint for robust crosslinking of mobile species in biogels with weakly adhesive molecular anchors.

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A blueprint for robust crosslinking of mobile species in biogels with weakly adhesive molecular anchors.

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