A Distinctive Insight into Inorganic Sonosensitizers: Design Principles and Application Domains.

Sonodynamic therapy (SDT) as a promising non-invasive anti-tumor means features the preferable penetration depth, which nevertheless, usually can't work without sonosensitizers. Sonosensitizers produce reactive oxygen species (ROS) in the presence of ultrasound to directly kill tumor cells, and concurrently activate anti-tumor immunity especially after integration with tumor microenvironment (TME)-engineered nanobiotechnologies and combined therapy. Current sonosensitizers are classified into organic and inorganic ones, and current most reviews only cover organic sonosensitizers and highlighted their anti-tumor applications. However, there have few specific reviews that focus on inorganic sonosensitizers including their design principles, microenvironment regulation, etc. In this review, inorganic sonosensitizers are first classified according to their design rationales rather than composition, and the action rationales and underlying chemistry features are highlighted. Afterward, what and how TME is regulated based on the inorganic sonosensitizers-based SDT nanoplatform with an emphasis on the TME targets-engineered nanobiotechnologies are elucidated. Additionally, the combined therapy and their applications in non-cancer diseases are also outlined. Finally, the setbacks and challenges, and proposed the potential solutions and future directions is pointed out. This review provides a comprehensive and detailed horizon on inorganic sonosensitizers, and will arouse more attentions on SDT.

Atomic-Level Regulation of Cu-Based Electrocatalyst for Enhancing Oxygen Reduction Reaction: From Single Atoms to Polymetallic Active Sites.

The slow kinetics of cathodic oxygen reduction reactions (ORR) in fuel cells and the high cost of commercial Pt-based catalysts limit their large-scale application. Cu-based single-atom catalysts (SACs) have received increasing attention as a promising ORR catalyst due to their high atom utilization, high thermodynamic activity, adjustable electronic structure, and low cost. Herein, the recent research progress of Cu-based catalysts is reviewed from single atom to polymetallic active sites for ORR. First, the design and synthesis method of Cu-based SACs are summarized. Then the atomic-level structure regulation strategy of Cu-based catalyst is proposed to improve the ORR performance. The different ORR catalytic mechanism based on the different Cu active sites is further revealed. Finally, the design principle of high-performance Cu-based SACs is proposed for ORR and the opportunities and challenges are further prospected.

"Covalent-Disassembly"-Based Approaches For Sensing Applications.

The detection of analytes with small molecular probes is crucial for the analysis and understanding of chemical, medicinal, environmental and biological situations as well as processes. Classic detection approaches rely on the concept of molecular recognition and bond formation reactions. Bond breakage reactions have been less explored in similar contexts. This concept article introduces metal-salen and metal-imine complexes as "covalent-disassembly"-based (DB)-probes for detecting polyoxophosphates, thiols, amino acids, HCN and changes in pH. It discusses the roles, importance and combinations of structurally functionalized molecular building blocks in the construction of DB-probes. Applications of optimized DB-probes for analyte detection in live cells and foodstuff are also discussed. Furthermore, the mechanism of the disassembly of a Fe(III)-salen probe upon pyrophosphate binding is presented. Extraordinary selectivity for this analyte was achieved by a multistep disassembly sequence including an unprecedented structural change of the metal complex (i. e. "induced-fit" principle). Design principles of probes for sensing applications following the "covalent-disassembly" approach are summarized, which will help improving current systems, but will also facilitate the development of new DB-probes for challenging analytic targets.

Pillars of theoretical biology: "Biochemical systems analysis, I, II and III".

Michael Savageau's Biochemical Systems Analysis I, II, IIIpapers, published in volumes 25 and 26 of the journal,kickstarted a research programme that originated many of the core concepts and tools of Systems Biology. This article briefly summarizes these papers anddiscusses the most relevant developments in Biochemical Systems Theory since their publication.

Multimedia design for learner interest and achievement: a visual guide to pharmacology.

BACKGROUND: Medical education increasingly relies on digital learning materials. Despite recognition by the Association of American Medical Colleges Institute for Improving Medical Education, medical education design often fails to consider quality multimedia design principles. Further, the AAMC-IIME issued a call to study the role of design principles in medical education. Thus, the current study investigated the cognitive and affective effects of redesigning PowerPoint slides used to support pharmacology content during the preclinical years of medical school training. METHODS: Researchers implemented a quasi-experimental design, using traditionally-designed (original) slides with a Traditional group (n = 100) and slides redesigned to follow principles from the Cognitive Theory of Multimedia Learning with an Experimental group (n = 40). Participants in the Experimental group completed a post-survey incorporating the Situational Interest Survey for Multimedia to indicate motivational engagement with the media. Students in the Experimental group also responded to additional preference questions. Researchers analyzed survey responses and students' scores in pharmacology-related coursework across the preclinical Foundations Phase of training to determine the impact on achievement and motivation. RESULTS: Findings related to learner achievement showed a modest but significant increase in the Experimental group compared to the Traditional group in the Cardiac, Pulmonary, and Renal (CPR) educational block (105%, normalized to Traditional group, p = 0.013) and cumulative pharmacology grades (101%, normalized to Traditional group, p = 0.043). Additionally, participants in the Experimental group indicated a significantly higher average triggered situational interest in redesigned slides (M = 4.85, SD = 0.25) than the original slides (M = 3.23, SD = 1.40, t=-6.33, p < 0.001). Similarly, the interest rating of the redesigned slides (M = 4.87, SD = 0.24) was significantly greater than that of the original slides (M = 3.89, SD = 0.86, t=-6.824, p < 0.001). Moreover, results further indicated significant differences in the maintained-feeling and maintained-value constructs, and all participants in the Experimental group indicated a preference for the redesigned slides. CONCLUSIONS: The findings provide strong evidence in support of using the Cognitive Theory of Multimedia Learning design principles to intentionally design media in medical education. In addition to increased achievement scores, students in the Experimental group demonstrated significantly higher levels of situational interest in the redesigned slides, especially triggered interest and maintained-feeling interest. Medical education learning designers should seriously consider redesigning media to achieve similar results.

Selective Access to Decision Support as a Function of Event Uncertainty.

OBJECTIVE: We investigate the impact of event uncertainty, decision support (DS) display format, and DS sensitivity on participants' behavior, performance, subjective workload, and perception of DS usefulness and performance in a classification task. BACKGROUND: DS systems can positively and negatively affect decision accuracy, performance time, and workload. The ability to access DS selectively, based on informational needs, might improve DS effectiveness. METHOD: Participants performed a sensory classification task in which they were allowed to request DS on a trial-by-trial basis. DS was presented in separated-binary (SB), separated-likelihood (SL), or integrated-likelihood (IL) formats. Access preferences, task performance, performance time, subjective workload, and perceived DS usefulness and performance were recorded. RESULTS: Participants accessed DS more often when it was highly sensitive, stimulus information was highly uncertain, or the DS cue and stimulus information were perceptually integrated. Effective sensitivity was highest with the integrated likelihood DS. Although the separated likelihood DS provided more information than the binary likelihood DS, it was accessed less often, leading to lower sensitivity. CONCLUSION: Participants are most likely to access DS when raw stimulus information is highly uncertain and appear to make effective use of likelihood DS only when DS cues are integrated with raw stimulus information within a display. APPLICATION: Results suggest that DS use will be most effective when likelihood DS cues and raw stimulus information are perceptually integrated. When DS cues and raw stimuli cannot be perceptually integrated, binary cues from the DS will be more effective than likelihood cues.

Effects of In-Vehicle Touchscreen Location on Driver Task Performance, Eye Gaze Behavior, and Workload During Conditionally Automated Driving: Nondriving-Related Task and Take-Over.

OBJECTIVE: This study investigated the effects of nondriving-related task (NDRT) touchscreen location and NDRT difficulty level on the driver task performance, eye gaze behavior, and workload during SAE Level 3 conditionally automated driving. Two driver tasks were considered: a visuomanual NDRT and a take-over task. BACKGROUND: Touchscreens are expected to play important roles inside automated vehicles. However, few studies have investigated the driver-touchscreen interaction during automated driving. METHOD: A driving simulator experiment was conducted. The experimental task consisted of two successive subtasks: an NDRT followed by a take-over task. NDRT touchscreen location (Upper Left, Upper Right, and Lower Right) and NDRT difficulty level (Easy and Hard) were the independent variables. A set of driver task performance, eye gaze behavior, and perceived workload measures were employed for each subtask as the dependent variables. RESULTS: NDRT touchscreen location significantly affected both the NDRT and the take-over task performance. Lower Right was superior to Upper Right in the NDRT performance but was inferior in the take-over task performance. NDRT touchscreen location affected the perceived physical workload of the NDRT. NDRT difficulty level affected the perceived workload of the take-over task. CONCLUSION: The research findings enhance our understanding of how NDRT touchscreen location and NDRT difficulty level impact the driver task performance during conditionally automated driving, and, further provide useful design implications and knowledge. APPLICATION: The study results would inform the NDRT touchscreen interface design and the NDRT design for conditionally automated vehicles.

Finding a City Name in a Traffic Sign: Effects of Word Case and Visual Motion.

OBJECTIVES: To investigate the word recognition effects of the use of all-uppercase (e.g., VALENCIA) or titled-case (e.g., Valencia) for city names in traffic signs, controlling for word size, and comparing stationary and dynamic viewing situations. BACKGROUND: Prior studies provide mixed evidence regarding the effects of word case on the recognition of city names in traffic signs. Moreover, the evidence on the potential impact of visual motion on these effects is scarce. METHOD: We carried out an experimental study using simulated traffic signs. The task was to indicate, for each sign, whether it contained a given city name or not (word search task, 50% positive trials). Visual motion of signs was manipulated as a between-participants factor: stationary (the sign was still) versus dynamic (the sign expanded as if the participant was approaching to it). Word case was manipulated as a within-participants factor: all-uppercase versus two titled-case conditions varying in font size: width-matched titled-case and point size-matched titled-case. RESULTS: In both the stationary and dynamic conditions, all-uppercase resulted in more incorrect responses and slower latencies than width-matched titled-case. When compared to point size-matched titled-case, all-uppercase produced slower correct responses in the stationary condition, whereas faster in the dynamic condition. CONCLUSION: Other factors being equal, all-uppercase city names will be recognized worse than their titled-case versions in traffic signs, both in stationary and dynamic situations. APPLICATION: Results in the current experimental study would be of interest in the design of traffic signs and other circumstances in which text is presented in motion.

The Impact of Hazard Statement Design Elements in Procedures: Counterintuitive Findings and Implications for Standards.

OBJECTIVE: The objective of these studies was to identify hazard statement (HS) design elements in procedures that affected whether both workers and lab participants performed the associated hazard mitigation. BACKGROUND: Many of the incidents in high-risk industries are the result of issues with procedures (e.g., standard operating procedures; SOPs) workers use to support their performance. HSs in these procedures are meant to communicate potential work hazards and methods of mitigating those hazards. However, there is little empirical research regarding whether current hazard design guidelines for consumer products translate to procedures. METHOD: Two experimental studies-(1) a laboratory study and (2) a high-fidelity simulation-manipulated the HS design elements present in procedures participants used while performing tasks. Participants' adherence to the mitigation of the hazard was compared for the HS designs. RESULTS: The guidelines for HSs from consumer products did not translate to procedures. Specifically, the presence of an alert icon, a box around the statement, and highlighting the statement did not improve adherence to HSs. Indeed, the only consistent finding was for the Icon, with its presence reliably predicting nonadherence in both studies. Additionally, the total number of design elements did not have a positive effect on adherence. CONCLUSION: These findings indicate that more fundamental procedure HSs research is needed to identify effective designs as well as to understand the potential attentional mechanisms associated with these findings. APPLICATION: The findings from these studies indicate that current regulations and guidelines should be revisited regarding hazard presentation in procedures.

Little Evidence the Standard Genetic Code Is Optimized for Resource Conservation.

Selection for resource conservation can shape the coding sequences of organisms living in nutrient-limited environments. Recently, it was proposed that selection for resource conservation, specifically for nitrogen and carbon content, has also shaped the structure of the standard genetic code, such that the missense mutations the code allows tend to cause small increases in the number of nitrogen and carbon atoms in amino acids. Moreover, it was proposed that this optimization is not confounded by known optimizations of the standard genetic code, such as for polar requirement or hydropathy. We challenge these claims. We show the proposed optimization for nitrogen conservation is highly sensitive to choice of null model and the proposed optimization for carbon conservation is confounded by the known conservative nature of the standard genetic code with respect to the molecular volume of amino acids. There is therefore little evidence the standard genetic code is optimized for resource conservation. We discuss our findings in the context of null models of the standard genetic code.

Efficacy of Galvanic Vestibular Stimulation as a Display Modality Dissociated from Self-Orientation.

OBJECTIVE: We propose and assess galvanic vestibular stimulation (GVS) as a novel means to provide information dissociated from self-orientation. BACKGROUND: In modern user interfaces, visual and auditory modalities dominate information transfer so much that these "processing channels" become overloaded with information. Fortunately, the brain is capable of processing separate sensory sources in parallel enabling alternative display modalities to inform operators more effectively and without increasing cognitive strain. To date, the vestibular system, normally responsible for sensing self-orientation and helping with balance, has not been considered as a display modality. METHOD: Bilateral GVS was provided at 0.6 mA for 1-second intervals with moderately high-frequency sinusoidal waveforms, designed to not elicit sensations of self-motion. We assessed subjects' ability to differentiate between two cues of different frequencies. RESULTS: We found subjects were able to reliably distinguish between cues with an average just-noticeable difference threshold of only ±12 Hz (range across subjects: 5.4-19.6 Hz) relative to a pedestal cue of 50 Hz. Further, we found the GVS sensory modality to be robust to various environments: walking, standing, sitting, passive motion, and loud background noise. Finally, the application of the GVS cues did not have significant destabilizing effects when standing or walking. CONCLUSION: These results show that GVS may be an effective alternative display modality, using varying frequency to encode information. It is robust to various operational environments and non-destabilizing. APPLICATION: A fully functional display can convey information to operators of vehicles and other machinery as well as high-performance operators like astronauts and soldiers.

Co-designing a pedagogical framework and principles for a hybrid STEM learning environment design.

The importance of engaging and effective learning environments for science, technology, engineering and mathematics (STEM) has been internationally recognised. However, no comprehensive pedagogical frameworks exist that support STEM learning environment design. In this study, a pedagogical framework and principles for STEM learning environment design were created based on participatory focus groups involving 10-18-year-old students, teachers, school directors, parents, university students and STEM professionals. Representatives of key stakeholder groups in Belarus, Finland, Germany, Greece and Spain (total n = 132) were invited to focus group discussions in which their wishes related to the pedagogical framework were collected. A second focus group discussion session, engaging the same stakeholder groups (total n = 137), was implemented to validate the framework. A final review for the framework and its design principles was conducted in online focus group sessions, involving 20 experts in curriculum, STEM, educational policy and/or educational technology from all participant countries. The co-designed framework, which is strengthened by the research literature, entails the following design principle categories: (1) General principles, (2) Cross-curricular skills, (3) Ways of teaching and learning, (4) Socio-emotional aspects and (5) Educational compatibility. The design principles created in this study have been employed in developing a hybrid (virtual, physical, formal, non-formal and informal) STEM environment, but they can be employed in any (STEM) learning environment design. Instead of focusing on singular design principles, we recommend considering a wide range of different design principles in order to support multiple ways of teaching and learning and to develop both subject-related and cross-curricular competencies.

Design principles for conversational agents to support Emergency Management Agencies.

Widespread mis- and disinformation during the COVID-19 social media "infodemic" challenge the effective response of Emergency Management Agencies (EMAs). Conversational Agents (CAs) have the potential to amplify and distribute trustworthy information from EMAs to the general public in times of uncertainty. However, the structure and responsibilities of such EMAs are different in comparison to traditional commercial organizations. Consequently, Information Systems (IS) design approaches for CAs are not directly transferable to this different type of organization. Based on semi-structured interviews with practitioners from EMAs in Germany and Australia, twelve meta-requirements and five design principles for CAs for EMAs were developed. In contrast to the traditional view of CA design, social cues should be minimized. The study provides a basis to design robust CAs for EMAs.

Design principles and mechanistic explanation.

In this essay I propose that what design principles in systems biology and systems neuroscience do is to present abstract characterizations of mechanisms, and thereby facilitate mechanistic explanation. To show this, one design principle in systems neuroscience, i.e., the multilayer perceptron, is examined. However, Braillard (2010) contends that design principles provide a sort of non-mechanistic explanation due to two related reasons: they are very general and describe non-causal dependence relationships. In response to this, I argue that, on the one hand, all mechanisms are more or less general (or abstract), and on the other, many (if not all) design principles are causal systems.

Discovering autoinhibition as a design principle for the control of biological mechanisms.

Autoinhibition is a design principle realized in many molecular mechanisms in biology. After explicating the notion of a design principle and showing that autoinhibition is such a principle, we focus on how researchers discovered instances of autoinhibition, using research establishing the autoinhibition of the molecular motors kinesin and dynein as our case study. Research on kinesin and dynein began in the fashion described in accounts of mechanistic explanation but, once the mechanisms had been discovered, researchers discovered that they exhibited a second phenomenon, autoinhibition. The discovery of autoinhibition not only reverses the pattern in terms of which philosophers have understood mechanism discovery but runs counter to the one phenomenon-one mechanism principle assumed to relate mechanisms and the phenomena they explain. The ubiquity of autoinhibition as a design principle, therefore, necessitates a philosophical understanding of mechanisms that recognizes how they can participate in more than one phenomenon. Since mechanisms with this design are released from autoinhibition only when they are acted on by control mechanisms, we advance a revised account of mechanisms that accommodates attribution of multiple phenomena to the same mechanism and distinguishes them from other processes that control them.

Operating principles of circular toggle polygons.

Decoding the dynamics of cellular decision-making and cell differentiation is a central question in cell and developmental biology. A common network motif involved in many cell-fate decisions is a mutually inhibitory feedback loop between two self-activating 'master regulators' A and B, also called as toggle switch. Typically, it can allow for three stable states-(high A, low B), (low A, high B) and (medium A, medium B). A toggle triad-three mutually repressing regulators A, B and C, i.e. three toggle switches arranged circularly (between A and B, between B and C, and between A and C)-can allow for six stable states: three 'single positive' and three 'double positive' ones. However, the operating principles of larger toggle polygons, i.e. toggle switches arranged circularly to form a polygon, remain unclear. Here, we simulate using both discrete and continuous methods the dynamics of different sized toggle polygons. We observed a pattern in their steady state frequency depending on whether the polygon was an even or odd numbered one. The even-numbered toggle polygons result in two dominant states with consecutive components of the network expressing alternating high and low levels. The odd-numbered toggle polygons, on the other hand, enable more number of states, usually twice the number of components with the states that follow 'circular permutation' patterns in their composition. Incorporating self-activations preserved these trends while increasing the frequency of multistability in the corresponding network. Our results offer insights into design principles of circular arrangement of regulatory units involved in cell-fate decision making, and can offer design strategies for synthesizing genetic circuits.

Temperature robustness in Arabidopsis circadian clock models is facilitated by repressive interactions, autoregulation, and three-node feedbacks.

The biological interactions underpinning the Arabidopsis circadian clock have been systematically uncovered and explored by biological experiments and mathematical models. This is captured by a series of published ordinary differential equation (ODE) models, which describe plant clock dynamics in response to light/dark conditions. However, understanding the role of temperature in resetting the clock (entrainment) and the mechanisms by which circadian rhythms maintain a near-24 h period over a range of temperatures (temperature compensation) is still unclear. Understanding entrainment and temperature compensation may elucidate the principles governing the structure of the circadian clock network. Here we explore the design principles of the Arabidopsis clock and its responses to changes in temperature. We analyse published clock models of Arabidopsis, spanning a range of complexity, and incorporate temperature-dependent dynamics into the parameters of translation rates in these models, to discern which regulatory patterns may best explain clock function and temperature compensation. We additionally construct three minimal clock models and explore what key features govern their rhythmicity and temperature robustness via a series of random parameterisations. Results show that the highly repressive interactions between the components of the plant clock, together with autoregulation patterns and three-node feedback loops, are associated with circadian function of the clock in general, and enhance its robustness to temperature variation in particular. However, because the networks governing clock function vary with time due to light and temperature conditions, we emphasise the importance of studying plant clock functionality in its entirety rather than as a set of discrete regulation patterns.

Turing pattern design principles and their robustness.

Turing patterns have morphed from mathematical curiosities into highly desirable targets for synthetic biology. For a long time, their biological significance was sometimes disputed but there is now ample evidence for their involvement in processes ranging from skin pigmentation to digit and limb formation. While their role in developmental biology is now firmly established, their synthetic design has so far proved challenging. Here, we review recent large-scale mathematical analyses that have attempted to narrow down potential design principles. We consider different aspects of robustness of these models and outline why this perspective will be helpful in the search for synthetic Turing-patterning systems. We conclude by considering robustness in the context of developmental modelling more generally. This article is part of the theme issue 'Recent progress and open frontiers in Turing's theory of morphogenesis'.

Human Performance Benefits of The Automation Transparency Design Principle : Validation and Variation.

OBJECTIVE: Test the automation transparency design principle using a full-scope nuclear power plant simulator. BACKGROUND: Automation transparency is a long-held human factors design principle espousing that the responsibilities, capabilities, goals, activities, and/or effects of automation should be directly observable in the human-system interface. The anticipated benefits of transparency include more effective reliance, more appropriate trust, better understanding, and greater user satisfaction. Transparency has enjoyed a recent upsurge in use in the context of human interaction with agent-oriented automation. METHOD: Three full-scope nuclear power plant simulator studies were conducted with licensed operating crews. In the first two experiments, transparency was implemented for interlocks, controllers, limitations, protections, and automatic programs that operate at the local component level of the plant. In the third experiment, procedure automation assumed control of plant operations and was represented in dedicated agent displays. RESULTS: Results from Experiments 1 and 2 appear to validate the human performance benefits of automation transparency for automation at the component level. However, Experiment 3 failed to replicate these findings for automation that assumed control for executing procedural actions. CONCLUSION: Automation transparency appears to yield expected benefits for component-level automation, but caution is warranted in generalizing the design principle to agent-oriented automation. APPLICATION: The automation transparency design principle may offer a powerful means of compensating for the detrimental impacts of hidden automation influence at the component level of complex systems. However, system developers should exercise caution in assuming that the principle extends to agent-oriented automation.

Curved Versus Flat Monitors: Interactive Effects of Display Curvature Radius and Display Size on Visual Search Performance and Visual Fatigue.

OBJECTIVE: The aim of this study is to examine the interactive effects of display curvature radius and display size on visual search accuracy, visual search speed, and visual fatigue. BACKGROUND: Although the advantages of curved displays have been reported, little is known about the interactive effects of display curvature radius and size. METHOD: Twenty-seven individuals performed visual search tasks at a viewing distance of 50 cm using eight configurations involving four display curvature radii (400R, 600R, 1200R, and flat) and two display sizes (33″ and 50″). To simulate curved screens, five flat display panels were horizontally arranged with their centers concentrically repositioned following each display curvature radius. RESULTS: For accuracy, speed, and fatigue, 33″-600R and 50″-600R provided the best or comparable-to-best results, whereas 50″-flat provided the worst results. For accuracy and fatigue, 33″-flat was the second worst. The changes in the horizontal field of view and viewing angle due to display curvature as well as the association between effective display curvature radii and empirical horopter (loci of perceived equidistance) can explain these results. CONCLUSION: The interactive effects of display curvature radius and size were evident for visual search performance and fatigue. Beneficial effects of curved displays were maintained across 33″ and 50″, whereas increasing flat display size from 33″ to 50″ was detrimental. APPLICATION: For visual search tasks at a viewing distance of 50 cm, 33″-600R and 50″ 600R displays are recommended, as opposed to 33″ and 50″ flat displays. Wide flat displays must be carefully considered for visual display terminal tasks.