Development and Validation of the System Trustworthiness Scale.

OBJECTIVE: We created and validated a scale to measure perceptions of system trustworthiness. BACKGROUND: Several scales exist in the literature that attempt to assess trustworthiness of system referents. However, existing measures suffer from limitations in their development and validation. The current study sought to develop a scale based on theory and methodological rigor. METHOD: We conducted exploratory and confirmatory factor analyses on data from two online studies to develop the System Trustworthiness Scale (STS). Additional analyses explored the manipulation of the factors and assessed convergent and divergent validity. RESULTS: The exploratory factor analyses resulted in a three-factor solution that represented the theoretical constructs of trustworthiness: performance, purpose, and process. Confirmatory factor analyses confirmed the three-factor solution. In addition, correlation and regression analyses demonstrated the scale's divergent and predictive validity. CONCLUSION: The STS is a psychometrically valid and predictive scale for assessing trustworthiness perceptions of system referents. APPLICATIONS: The STS assesses trustworthiness perceptions of systems. Importantly, the scale differentiates performance, purpose, and process constructs and is adaptable to a variety of system referents.

In-Vivo fluorescent nanosensor implants based on hydrogel-encapsulation: investigating the inflammation and the foreign-body response.

Nanotechnology-enabled sensors or nanosensors are emerging as promising new tools for various in-vivo life science applications such as biosensing, components of delivery systems, and probes for spatial bioimaging. However, as with a wide range of synthetic biomaterials, tissue responses have been observed depending on cell types and various nanocomponent properties. The tissue response is critical for determining the acute and long term health of the organism and the functional lifetime of the material in-vivo. While nanomaterial properties can contribute significantly to the tissue response, it may be possible to circumvent adverse reactions by formulation of the encapsulation vehicle. In this study, five formulations of poly (ethylene glycol) diacrylate (PEGDA) hydrogel-encapsulated fluorescent nanosensors were implanted into SKH-1E mice, and the inflammatory responses were tracked in order to determine the favorable design rules for hydrogel encapsulation and minimization of such responses. Hydrogels with higher crosslinking density were found to allow faster resolution of acute inflammation. Five different immunocompromised mice lines were utilized for comparison across different inflammatory cell populations and responses. Degradation products of the gels were also characterized. Finally, the importance of the tissue response in determining functional lifetime was demonstrated by measuring the time-dependent nanosensor deactivation following implantation into animal models.

A Monte Carlo study of IRTree models' ability to recover item parameters.

Item response tree (IRTree) models are theorized to extract response styles from self-report data by utilizing multidimensional item response theory (IRT) models based on theoretical decision processes. Despite the growing popularity of the IRTree framework, there has been little research that has systematically examined the ability of its most popular models to recover item parameters across sample size and test length. This Monte Carlo simulation study explored the ability of IRTree models to recover item parameters based on data created from the midpoint primary process model. Results indicate the IRTree model can adequately recover item parameters early in the decision process model, specifically the midpoint node. However, as the model progresses through the decision hierarchy, item parameters have increased associated error variance. The authors ultimately recommend caution when employing the IRTree framework.

Molecular Recognition and In Vivo Detection of Temozolomide and 5-Aminoimidazole-4-carboxamide for Glioblastoma Using Near-Infrared Fluorescent Carbon Nanotube Sensors.

There is a pressing need for sensors and assays to monitor chemotherapeutic activity within the human body in real time to optimize drug dosimetry parameters such as timing, quantity, and frequency in an effort to maximize efficacy while minimizing deleterious cytotoxicity. Herein, we develop near-infrared fluorescent nanosensors based on single walled carbon nanotubes for the chemotherapeutic Temozolomide (TMZ) and its metabolite 5-aminoimidazole-4-carboxamide using Corona Phase Molecular Recognition as a synthetic molecular recognition technique. The resulting nanoparticle sensors are able to monitor drug activity in real-time even under in vivo conditions. Sensors can be engineered to be biocompatible by encapsulation in poly(ethylene glycol) diacrylate hydrogels. Selective detection of TMZ was demonstrated using U-87 MG human glioblastoma cells and SKH-1E mice with detection limits below 30 µM. As sensor implants, we show that such systems can provide spatiotemporal therapeutic information in vivo, as a valuable tool for pharmacokinetic evaluation. Sensor implants are also evaluated using intact porcine brain tissue implanted 2.1 cm below the cranium and monitored using a recently developed Wavelength-Induced Frequency Filtering technique. Additionally, we show that by taking the measurement of spatial and temporal analyte concentrations within each hydrogel implant, the direction of therapeutic flux can be resolved. In all, these types of sensors enable the real time detection of chemotherapeutic concentration, flux, directional transport, and metabolic activity, providing crucial information regarding therapeutic effectiveness.

Differential biases in human-human versus human-robot interactions.

The research on human-robot interactions indicates possible differences toward robot trust that do not exist in human-human interactions. Research on these differences has traditionally focused on performance degradations. The current study sought to explore differences in human-robot and human-human trust interactions with performance, consideration, and morality trustworthiness manipulations, which are based on ability/performance, benevolence/purpose, and integrity/process manipulations, respectively, from previous research. We used a mixed factorial hierarchical linear model design to explore the effects of trustworthiness manipulations on trustworthiness perceptions, trust intentions, and trust behaviors in a trust game. We found partner (human versus robot) differences across all three trustworthiness perceptions, indicating biases towards robots may be more expansive than previously thought. Additionally, there were marginal effects of partner differences on trust intentions. Interestingly, there were no differences between partners on trust behaviors. Results indicate human biases toward robots may be more complex than considered in the literature.

A wavelength-induced frequency filtering method for fluorescent nanosensors in vivo.

Fluorescent nanosensors hold the potential to revolutionize life sciences and medicine. However, their adaptation and translation into the in vivo environment is fundamentally hampered by unfavourable tissue scattering and intrinsic autofluorescence. Here we develop wavelength-induced frequency filtering (WIFF) whereby the fluorescence excitation wavelength is modulated across the absorption peak of a nanosensor, allowing the emission signal to be separated from the autofluorescence background, increasing the desired signal relative to noise, and internally referencing it to protect against artefacts. Using highly scattering phantom tissues, an SKH1-E mouse model and other complex tissue types, we show that WIFF improves the nanosensor signal-to-noise ratio across the visible and near-infrared spectra up to 52-fold. This improvement enables the ability to track fluorescent carbon nanotube sensor responses to riboflavin, ascorbic acid, hydrogen peroxide and a chemotherapeutic drug metabolite for depths up to 5.5 ± 0.1 cm when excited at 730 nm and emitting between 1,100 and 1,300 nm, even allowing the monitoring of riboflavin diffusion in thick tissue. As an application, nanosensors aided by WIFF detect the chemotherapeutic activity of temozolomide transcranially at 2.4 ± 0.1 cm through the porcine brain without the use of fibre optic or cranial window insertion. The ability of nanosensors to monitor previously inaccessible in vivo environments will be important for life-sciences research, therapeutics and medical diagnostics.

"I Think You Are Trustworthy, Need I Say More?" The Factor Structure and Practicalities of Trustworthiness Assessment.

Two popular models of trustworthiness have garnered support over the years. One has postulated three aspects of trustworthiness as state-based antecedents to trust. Another has been interpreted to comprise two aspects of trustworthiness. Empirical data shows support for both models, and debate remains as to the theoretical and practical reasons researchers may adopt one model over the other. The present research aimed to consider this debate by investigating the factor structure of trustworthiness. Taking items from two scales commonly employed to assess trustworthiness, we leveraged structural equation modeling to explore which theoretical model is supported by the data in an organizational trust context. We considered an array of first-order, second-order, and bifactor models. The best-fitting model was a bifactor model comprising one general trustworthiness factor and ability, benevolence, and integrity grouping factors. This model was determined to be essentially unidimensional, though this is qualified by the finding that the grouping variables accounted for significant variance with for several organizational outcome criteria. These results suggest that respondents typically employ a general factor when responding to items assessing trustworthiness, and researchers may be better served treating the construct as unidimensional or engaging in scale parceling of their models to reflect this response tendency more accurately. However, the substantial variance accounted by the grouping variables in hierarchical regression suggest there may be contexts in which it would be acceptable to consider the theoretical factors of ability, benevolence, and integrity independent of general trustworthiness.

COVID pandemic as an incubator for a renewed vision of pediatric value-based healthcare.

COVID-19 has stressed primary care pediatric practices. In addition, other market pressures that began before the pandemic make this an optimal time to re-examine pediatric payment models. CMS is encouraging changes in the Medicare market toward alternative payment models. However, success is limited for older adults, and while components of these models can work for pediatricians, the needs of children, young adults and their families are different from older adults. The rapid evolution of telemedicine, and the incursion of retail clinics and urgent care centers are eroding same day office visits and at the same time practices are merging or being acquired by larger organizations including hospitals and insurance companies. All of these changes will require a change in culture and approach in pediatric practice, and modified payment models must incentivize the best care for patients and families and create the opportunity for pediatricians to succeed.

Transcutaneous Measurement of Essential Vitamins Using Near-Infrared Fluorescent Single-Walled Carbon Nanotube Sensors.

Vitamins such as riboflavin and ascorbic acid are frequently utilized in a range of biomedical applications as drug delivery targets, fluidic tracers, and pharmaceutical excipients. Sensing these biochemicals in the human body has the potential to significantly advance medical research and clinical applications. In this work, a nanosensor platform consisting of single-walled carbon nanotubes (SWCNTs) with nanoparticle corona phases engineered to allow for the selective molecular recognition of ascorbic acid and riboflavin, is developed. The study provides a methodological framework for the implementation of colloidal SWCNT nanosensors in an intraperitoneal SKH1-E murine model by addressing complications arising from tissue absorption and scattering, mechanical perturbations, as well as sensor diffusion and interactions with the biological environment. Nanosensors are encapsulated in a polyethylene glycol diacrylate hydrogel and a diffusion model is utilized to validate analyte transport and sensor responses to local concentrations at the boundary. Results are found to be reproducible and stable after exposure to 10% mouse serum even after three days of in vivo implantation. A geometrical encoding scheme is used to reference sensor pairs, correcting for in vivo optical and mechanical artifacts, resulting in an order of magnitude improvement of p-value from 0.084 to 0.003 during analyte sensing.

Towards a streamlined synthesis of peptides containing α,ß-dehydroamino acids.

Investigation of a strategy to streamline the synthesis of peptides containing α,ß-dehydroamino acids (ΔAAs) is reported. The key step involves generating the alkene moiety via elimination of a suitable precursor after it has been inserted into a peptide chain. This process obviates the need to prepare ΔAA-containing azlactone dipeptides to facilitate coupling of these residues. Z-dehydroaminobutyric acid (Z-ΔAbu) could be constructed most efficiently via EDC/CuCl-mediated dehydration of Thr. Formation of Z-ΔPhe by this or other dehydration methods was unsuccessful. Production of the bulky ΔVal residue could be accomplished by DAST-promoted dehydrations of ß-OHVal or by DBU-triggered eliminations of sulfonium ions derived from penicillamine derivatives. However, competitive formation of an oxazoline byproduct remains problematic.

The Relationship of Insufficient Effort Responding and Response Styles: An Online Experiment.

While self-report data is a staple of modern psychological studies, they rely on participants accurately self-reporting. Two constructs that impede accurate results are insufficient effort responding (IER) and response styles. These constructs share conceptual underpinnings and both utilized to reduce cognitive effort when responding to self-report scales. Little research has extensively explored the relationship of the two constructs. The current study explored the relationship of the two constructs across even-point and odd-point scales, as well as before and after data cleaning procedures. We utilized IRTrees, a statistical method for modeling response styles, to examine the relationship between IER and response styles. To capture the wide range of IER metrics available, we employed several forms of IER assessment in our analyses and generated IER factors based on the type of IER being detected. Our results indicated an overall modest relationship between IER and response styles, which varied depending on the type of IER metric being considered or type of scale being evaluated. As expected, data cleaning also changed the relationships of some of the variables. We posit the difference between the constructs may be the degree of cognitive effort participants are willing to expend. Future research and applications are discussed.

A synthetic mimic of phosphodiesterase type 5 based on corona phase molecular recognition of single-walled carbon nanotubes.

Molecular recognition binding sites that specifically identify a target molecule are essential for life science research, clinical diagnoses, and therapeutic development. Corona phase molecular recognition is a technique introduced to generate synthetic recognition at the surface of a nanoparticle corona, but it remains an important question whether such entities can achieve the specificity of natural enzymes and receptors. In this work, we generate and screen a library of 24 amphiphilic polymers, preselected for molecular recognition and based on functional monomers including methacrylic acid, acrylic acid, and styrene, iterating upon a poly(methacrylic acid-co-styrene) motif. When complexed to a single-walled carbon nanotube, some of the resulting corona phases demonstrate binding specificity remarkably similar to that of phosphodiesterase type 5 (PDE5), an enzyme that catalyzes the hydrolysis of secondary messenger. The corona phase binds selectively to a PDE5 inhibitor, Vardenafil, as well as its molecular variant, but not to other potential off-target inhibitors. Our work herein examines the specificity and sensitivity of polymer "mutations" to the corona phase, as well as direct competitions with the native binding PDE5. Using structure perturbation, corona surface characterization, and molecular dynamics simulations, we show that the molecular recognition is associated with the unique three-dimensional configuration of the corona phase formed at the nanotube surface. This work conclusively shows that corona phase molecular recognition can mimic key aspects of biological recognition sites and drug targets, opening up possibilities for pharmaceutical and biological applications.

Implantable Nanosensors for Human Steroid Hormone Sensing In Vivo Using a Self-Templating Corona Phase Molecular Recognition.

Dynamic measurements of steroid hormones in vivo are critical, but steroid sensing is currently limited by the availability of specific molecular recognition elements due to the chemical similarity of these hormones. In this work, a new, self-templating synthetic approach is applied using corona phase molecular recognition (CoPhMoRe) targeting the steroid family of molecules to produce near infrared fluorescent, implantable sensors. A key limitation of CoPhMoRe has been its reliance on library generation for sensor screening. This problem is addressed with a self-templating strategy of polymer design, using the examples of progesterone and cortisol sensing based on a styrene and acrylic acid copolymer library augmented with an acrylated steroid. The pendant steroid attached to the corona backbone is shown to self-template the phase, providing a unique CoPhMoRE design strategy with high efficacy. The resulting sensors exhibit excellent stability and reversibility upon repeated analyte cycling. It is shown that molecular recognition using such constructs is viable even in vivo after sensor implantation into a murine model by employing a poly (ethylene glycol) diacrylate (PEGDA) hydrogel and porous cellulose interface to limit nonspecific absorption. The results demonstrate that CoPhMoRe templating is sufficiently robust to enable a new class of continuous, in vivo biosensors.

A kinetic mechanism for enhanced selectivity of membrane transport.

Membrane transport is generally thought to occur via an alternating access mechanism in which the transporter adopts at least two states, accessible from two different sides of the membrane to exchange substrates from the extracellular environment and the cytoplasm or from the cytoplasm and the intracellular matrix of the organelles (only in eukaryotes). In recent years, a number of high resolution structures have supported this general framework for a wide class of transport molecules, although additional states along the transport pathway are emerging as critically important. Given that substrate binding is often weak in order to enhance overall transport rates, there exists the distinct possibility that transporters may transport the incorrect substrate. This is certainly the case for many pharmaceutical compounds that are absorbed in the gut or cross the blood brain barrier through endogenous transporters. Docking studies on the bacterial sugar transporter vSGLT reveal that many highly toxic compounds are compatible with binding to the orthosteric site, further motivating the selective pressure for additional modes of selectivity. Motivated by recent work in which we observed failed substrate delivery in a molecular dynamics simulation where the energized ion still goes down its concentration gradient, we hypothesize that some transporters evolved to harness this 'slip' mechanism to increase substrate selectivity and reduce the uptake of toxic molecules. Here, we test this idea by constructing and exploring a kinetic transport model that includes a slip pathway. While slip reduces the overall productive flux, when coupled with a second toxic molecule that is more prone to slippage, the overall substrate selectivity dramatically increases, suppressing the accumulation of the incorrect compound. We show that the mathematical framework for increased substrate selectivity in our model is analogous to the classic proofreading mechanism originally proposed for tRNA synthase; however, because the transport cycle is reversible we identified conditions in which the selectivity is essentially infinite and incorrect substrates are exported from the cell in a 'detoxification' mode. The cellular consequences of proofreading and membrane slippage are discussed as well as the impact on future drug development.

A Fiber Optic Interface Coupled to Nanosensors: Applications to Protein Aggregation and Organic Molecule Quantification.

Fluorescent nanosensors hold promise to address analytical challenges in the biopharmaceutical industry. The monitoring of therapeutic protein critical quality attributes such as aggregation is a long-standing challenge requiring low detection limits and multiplexing of different product parameters. However, general approaches for interfacing nanosensors to the biopharmaceutical process remain minimally explored to date. Herein, we design and fabricate a integrated fiber optic nanosensor element, measuring sensitivity, response time, and stability for applications to the rapid process monitoring. The fiber optic-nanosensor interface, or optode, consists of label-free nIR fluorescent single-walled carbon nanotube transducers embedded within a protective yet porous hydrogel attached to the end of the fiber waveguide. The optode platform is shown to be capable of differentiating the aggregation status of human immunoglobulin G, reporting the relative fraction of monomers and dimer aggregates with sizes 5.6 and 9.6 nm, respectively, in under 5 min of analysis time. We introduce a lab-on-fiber design with potential for at-line monitoring with integration of 3D-printed miniaturized sensor tips having high mechanical flexibility. A parallel measurement of fluctuations in laser excitation allows for intensity normalization and significantly lower noise level (3.7 times improved) when using lower quality lasers, improving the cost effectiveness of the platform. As an application, we demonstrate the capability of the fully integrated lab-on-fiber system to rapidly monitor various bioanalytes including serotonin, norepinephrine, adrenaline, and hydrogen peroxide, in addition to proteins and their aggregation states. These results in total constitute an effective form factor for nanosensor-based transducers for applications in industrial process monitoring.

Real-time detection of wound-induced H2O2 signalling waves in plants with optical nanosensors.

Decoding wound signalling in plants is critical for understanding various aspects of plant sciences, from pest resistance to secondary metabolite and phytohormone biosynthesis. The plant defence responses are known to primarily involve NADPH-oxidase-mediated H2O2 and Ca2+ signalling pathways, which propagate across long distances through the plant vasculature and tissues. Using non-destructive optical nanosensors, we find that the H2O2 concentration profile post-wounding follows a logistic waveform for six plant species: lettuce (Lactuca sativa), arugula (Eruca sativa), spinach (Spinacia oleracea), strawberry blite (Blitum capitatum), sorrel (Rumex acetosa) and Arabidopsis thaliana, ranked in order of wave speed from 0.44 to 3.10 cm min-1. The H2O2 wave tracks the concomitant surface potential wave measured electrochemically. We show that the plant RbohD glutamate-receptor-like channels (GLR3.3 and GLR3.6) are all critical to the propagation of the wound-induced H2O2 wave. Our findings highlight the utility of a new type of nanosensor probe that is species-independent and capable of real-time, spatial and temporal biochemical measurements in plants.

Impact of Dehydroamino Acids on the Structure and Stability of Incipient 310-Helical Peptides.

A comparative study of the impact of small, medium-sized, and bulky α,ß-dehydroamino acids (ΔAAs) on the structure and stability of Balaram's incipient 310-helical peptide (1) is reported. Replacement of the N-terminal Aib residue of 1 with a ΔAA afforded peptides 2a-c that maintained the 310-helical shape of 1. In contrast, installation of a ΔAA in place of Aib-3 yielded peptides 3a-c that preferred a ß-sheet-like conformation. The impact of the ΔAA on peptide structure was independent of size, with small (ΔAla), medium-sized (Z-ΔAbu), and bulky (ΔVal) ΔAAs exerting similar effects. The proteolytic stabilities of 1 and its analogs were determined by incubation with Pronase. Z-ΔAbu and ΔVal increased the resistance of peptides to proteolysis when incorporated at the 3-position and had negligible impact on stability when placed at the 1-position, whereas ΔAla-containing peptides degraded rapidly regardless of position. Exposure of peptides 2a-c and 3a-c to the reactive thiol cysteamine revealed that ΔAla-containing peptides underwent conjugate addition at room temperature, while Z-ΔAbu- and ΔVal-containing peptides were inert even at elevated temperatures. These results suggest that both bulky and more accessible medium-sized ΔAAs should be valuable tools for bestowing rigidity and proteolytic stability on bioactive peptides.