Smart materials that
can switch between different states under
the influence of chemical triggers are highly demanded in biomedicine,
where specific responsiveness to biomarkers is imperative for precise
diagnostics and therapy. Superior selectivity of drug delivery to
malignant cells may be achieved with the nanoagents that stay “inert”
until “activation” by the characteristic profile of
microenvironment cues (e.g., tumor metabolites, angiogenesis
factors, microRNA/DNA, etc.). However, despite a
wide variety and functional complexity of smart material designs,
their real-life applications are hindered by very limited sensitivity
to inputs. Here, we present ultrasensitive smart nanoagents with input-dependent
On/Off switchable affinity to a biomedical target based on a combination
of gold nanoparticles with low-energy polymer structures. In the proposed
method, a nanoparticle-based agent is surface coated with a custom
designed flexible polymer chain, which has an input-switchable structure
that regulates accessibility of the terminal receptor for target binding.
Implementation of the concept with a DNA-model of such polymer has
yielded nanoagents that have input-dependent cell-targeting capabilities
and responsiveness to as little as 30 fM of DNA input in 15 min lateral
flow assay. Thus, we show that surface phenomena can augment nanoagents
with capability for switchable affinity without compromising the sensitivity
to inputs. The proposed approach is promising for development of next-generation
theranostic agents and ultrasensitive nanosensors for point-of-care
diagnostics.
The lux-operon of the psychrophilic bioluminescent bacterium Aliivibrio logei is regulated by quorum sensing (QS). The key components of this system are LuxI, which catalyses synthesis of the autoinducer (AI), and LuxR, which activates transcription of the entire lux-operon. The lux-operon of A. logei contains two copies of the lux R gene: luxR1 and luxR2. In the present study, lux-operon sequence analysis from 16 strains of A. logei, isolated from cold habitats of the White, Baltic, Okhotsk and Bering seas, was carried out. Phylogenetic analysis showed that all isolated strains of A. logei have both copies of luxR genes which are homologous to luxR genes of the related Aliivibrio salmonicida. Evaluation of LuxR1 and LuxR2 activity showed that LuxR2 remains active at significantly lower concentrations of AI (10 29 M) than LuxR1, which is active only at high AI concentrations (10 26 M). As the QS response is already prominent at AI concentrations as low as 10 28 to 10 29 M, we conclude that LuxR2 is the main activator of the lux-operon of A. logei. The thermolabilities of LuxR1 and LuxR2 are similar and exceed that of LuxR of the mesophilic bacterium Aliivibrio fischeri. In contrast to LuxR2, LuxR1 is not a substrate of Lon protease and does not require the chaperonin GroEL/ES for its folding. This study expands our current understanding of QS regulation in A. logei as it implies differential regulation by LuxR1 and LuxR2 proteins.
Interest in the therapeutic applications of ultrasound is significant and growing, with potential clinical targets ranging from cancer to Alzheimer's disease. Cavitation -the formation and subsequent motion of bubbles within an ultrasound fieldrepresents a key phenomenon underpinning many of these treatments. There remains, however, considerable uncertainty regarding the detailed mechanisms of action by which cavitation promotes therapeutic effects and there is a need to develop reliable monitoring techniques that can be implemented clinically. In particular, there is significant variation between studies in the exposure parameters reported as successfully delivering therapeutic effects and the corresponding acoustic emissions.The aim of this paper is to provide design guidelines and an experimental protocol using widely available components for performing studies of cavitation-mediated bioeffects, and include real-time acoustic monitoring. It is hoped that the protocol will enable more widespread incorporation of acoustic monitoring into therapeutic ultrasound experiments and facilitate easier comparison across studies of exposure conditions and their correlation to relevant bio-effects.
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