Specialized proteomic responses and an ancient photoprotection mechanism sustain marine green algal growth during phosphate limitation.

Marine algae perform approximately half of global carbon fixation, but their growth is often limited by the availability of phosphate or other nutrients1,2. As oceans warm, the area of phosphate-limited surface waters is predicted to increase, resulting in ocean desertification3,4. Understanding the responses of key eukaryotic phytoplankton to nutrient limitation is therefore critical5,6. We used advanced photo-bioreactors to investigate how the widespread marine green alga Micromonas commoda grows under transitions from replete nutrients to chronic phosphate limitation and subsequent relief, analysing photosystem changes and broad cellular responses using proteomics, transcriptomics and biophysical measurements. We find that physiological and protein expression responses previously attributed to stress are critical to supporting stable exponential growth when phosphate is limiting. Unexpectedly, the abundance of most proteins involved in light harvesting does not change, but an ancient light-harvesting-related protein, LHCSR, is induced and dissipates damaging excess absorbed light as heat throughout phosphate limitation. Concurrently, a suite of uncharacterized proteins with narrow phylogenetic distributions increase multifold. Notably, of the proteins that exhibit significant changes, 70% are not differentially expressed at the mRNA transcript level, highlighting the importance of post-transcriptional processes in microbial eukaryotes. Nevertheless, transcript-protein pairs with concordant changes were identified that will enable more robust interpretation of eukaryotic phytoplankton responses in the field from metatranscriptomic studies. Our results show that P-limited Micromonas responds quickly to a fresh pulse of phosphate by rapidly increasing replication, and that the protein network associated with this ability is composed of both conserved and phylogenetically recent proteome systems that promote dynamic phosphate homeostasis. That an ancient mechanism for mitigating light stress is central to sustaining growth during extended phosphate limitation highlights the possibility of interactive effects arising from combined stressors under ocean change, which could reduce the efficacy of algal strategies for optimizing marine photosynthesis.

Assessment of a personalized and distributed patient guidance system.

OBJECTIVES: The MobiGuide project aimed to establish a ubiquitous, user-friendly, patient-centered mobile decision-support system for patients and for their care providers, based on the continuous application of clinical guidelines and on semantically integrated electronic health records. Patients would be empowered by the system, which would enable them to lead their normal daily lives in their regular environment, while feeling safe, because their health state would be continuously monitored using mobile sensors and self-reporting of symptoms. When conditions occur that require medical attention, patients would be notified as to what they need to do, based on evidence-based guidelines, while their medical team would be informed appropriately, in parallel. We wanted to assess the system's feasibility and potential effects on patients and care providers in two different clinical domains. MATERIALS AND METHODS: We describe MobiGuide's architecture, which embodies these objectives. Our novel methodologies include a ubiquitous architecture, encompassing a knowledge elicitation process for parallel coordinated workflows for patients and care providers; the customization of computer-interpretable guidelines (CIGs) by secondary contexts affecting remote management and distributed decision-making; a mechanism for episodic, on demand projection of the relevant portions of CIGs from a centralized, backend decision-support system (DSS), to a local, mobile DSS, which continuously delivers the actual recommendations to the patient; shared decision-making that embodies patient preferences; semantic data integration; and patient and care provider notification services. MobiGuide has been implemented and assessed in a preliminary fashion in two domains: atrial fibrillation (AF), and gestational diabetes Mellitus (GDM). Ten AF patients used the AF MobiGuide system in Italy and 19 GDM patients used the GDM MobiGuide system in Spain. The evaluation of the MobiGuide system focused on patient and care providers' compliance to CIG recommendations and their satisfaction and quality of life. RESULTS: Our evaluation has demonstrated the system's capability for supporting distributed decision-making and its use by patients and clinicians. The results show that compliance of GDM patients to the most important monitoring targets - blood glucose levels (performance of four measurements a day: 0.87±0.11; measurement according to the recommended frequency of every day or twice a week: 0.99±0.03), ketonuria (0.98±0.03), and blood pressure (0.82±0.24) - was high in most GDM patients, while compliance of AF patients to the most important targets was quite high, considering the required ECG measurements (0.65±0.28) and blood-pressure measurements (0.75±1.33). This outcome was viewed by the clinicians as a major potential benefit of the system, and the patients have demonstrated that they are capable of self-monitoring - something that they had not experienced before. In addition, the system caused the clinicians managing the AF patients to change their diagnosis and subsequent treatment for two of the ten AF patients, and caused the clinicians managing the GDM patients to start insulin therapy earlier in two of the 19 patients, based on system's recommendations. Based on the end-of-study questionnaires, the sense of safety that the system has provided to the patients was its greatest asset. Analysis of the patients' quality of life (QoL) questionnaires for the AF patients was inconclusive, because while most patients reported an improvement in their quality of life in the EuroQoL questionnaire, most AF patients reported a deterioration in the AFEQT questionnaire. DISCUSSION: Feasibility and some of the potential benefits of an evidence-based distributed patient-guidance system were demonstrated in both clinical domains. The potential application of MobiGuide to other medical domains is supported by its standards-based patient health record with multiple electronic medical record linking capabilities, generic data insertion methods, generic medical knowledge representation and application methods, and the ability to communicate with a wide range of sensors. Future larger scale evaluations can assess the impact of such a system on clinical outcomes. CONCLUSION: MobiGuide's feasibility was demonstrated by a working prototype for the AF and GDM domains, which is usable by patients and clinicians, achieving high compliance to self-measurement recommendations, while enhancing the satisfaction of patients and care providers.

Exploration of patterns predicting renal damage in patients with diabetes type II using a visual temporal analysis laboratory.

OBJECTIVE: To analyze the longitudinal data of multiple patients and to discover new temporal knowledge, we designed and developed the Visual Temporal Analysis Laboratory (ViTA-Lab). In this study, we demonstrate several of the capabilities of the ViTA-Lab framework through the exploration of renal-damage risk factors in patients with diabetes type II. MATERIALS AND METHODS: The ViTA-Lab framework combines data-driven temporal data mining techniques, with interactive, query-driven, visual analytical capabilities, to support, in an integrated fashion, an iterative investigation of time-oriented clinical data and of patterns discovered in them. Patterns discovered through the data mining mode can be explored visually, and vice versa. Both analysis modes are supported by a rich underlying ontology of clinical concepts, their relations, and their temporal properties. The knowledge enables us to apply a temporal-abstraction pre-processing phase that abstracts in a context-sensitive manner raw time-stamped data into interval-based clinically meaningful interpretations, increasing the results' significance. We demonstrate our approach through the exploration of risk factors associated with future renal damage (micro-albuminuria and macro-albuminuria) and their relationship to the hemoglobin A1C (HbA1C ) and creatinine level concepts, in the longitudinal records of 22 000 patients with diabetes type II followed for up to 5 years. RESULTS: The iterative ViTA-Lab analysis process was highly feasible. Higher ranges of either normal albuminuria or normal creatinine values and their combination were shown to be significantly associated with future micro-albuminuria and macro-albuminuria. The risk increased given high HbA1C levels for women in the lower range of normal albuminuria, and for men in the higher range of albuminuria. CONCLUSIONS: The ViTA-Lab framework can potentially serve as a virtual laboratory for investigations of large masses of longitudinal clinical databases, for discovery of new knowledge through interactive exploration, clustering, classification, and prediction.

Daily and seasonal dynamics of remotely sensed photosynthetic efficiency in tree canopies.

The photosynthesis of various species or even a single plant varies dramatically in time and space, creating great spatial heterogeneity within a plant canopy. Continuous and spatially explicit monitoring is, therefore, required to assess the dynamic response of plant photosynthesis to the changing environment. This is a very challenging task when using the existing portable field instrumentation. This paper reports on the application of a technique, laser-induced fluorescence transient (LIFT), developed for ground remote measurement of photosynthetic efficiency at a distance of up to 50 m. The LIFT technique was used to monitor the seasonal dynamics of selected leaf groups within inaccessible canopies of deciduous and evergreen tree species. Electron transport rates computed from LIFT measurements varied over the growth period between the different species studied. The LIFT canopy data and light-use efficiency measured under field conditions correlated reasonably well with the single-leaf pulse amplitude-modulated measurements of broadleaf species, but differed significantly in the case of conifer tree species. The LIFT method has proven to be applicable for a remote sensing assessment of photosynthetic parameters on a diurnal and seasonal scale; further investigation is, however, needed to evaluate the influence of complex heterogeneous canopy structures on LIFT-measured chlorophyll fluorescence parameters.

Remote chlorophyll fluorescence measurements with the laser-induced fluorescence transient approach.

The interaction of plants with their environment is very dynamic. Studying the underlying processes is important for understanding and modeling plant response to changing environmental conditions. Photosynthesis varies largely between different plants and at different locations within a canopy of a single plant. Thus, continuous and spatially distributed monitoring is necessary to assess the dynamic response of photosynthesis to the environment. Limited scale of observation with portable instrumentation makes it difficult to examine large numbers of plants under different environmental conditions. We report here on the application of a recently developed technique, laser-induced fluorescence transient (LIFT), for continuous remote measurement of photosynthetic efficiency of selected leaves at a distance of up to 50 m. The ability to make continuous, automatic, and remote measurements of photosynthetic efficiency of leaves with the LIFT provides a new approach for studying the interaction of plants with the environment and may become an important tool in phenotyping photosynthetic properties in field applications.

Intelligent visualization and exploration of time-oriented data of multiple patients.

OBJECTIVE: Clinicians and medical researchers alike require useful, intuitive, and intelligent tools to process large amounts of time-oriented multiple-patient data from multiple sources. For analyzing the results of clinical trials or for quality assessment purposes, an aggregated view of a group of patients is often required. To meet this need, we designed and developed the VISualizatIon of Time-Oriented RecordS (VISITORS) system, which combines intelligent temporal analysis and information visualization techniques. The VISITORS system includes tools for intelligent retrieval, visualization, exploration, and analysis of raw time-oriented data and derived (abstracted) concepts for multiple patient records. To derive meaningful interpretations from raw time-oriented data (known as temporal abstractions), we used the knowledge-based temporal-abstraction method. METHODS: The main module of the VISITORS system is an interactive, ontology-based exploration module, which enables the user to visualize raw data and abstract (derived) concepts for multiple patient records, at several levels of temporal granularity; to explore these concepts; and to display associations among raw and abstract concepts. A knowledge-based delegate function is used to convert multiple data points into one delegate value representing each temporal granule. To select the population of patients to explore, the VISITORS system includes an ontology-based temporal-aggregation specification language and a graphical expression-specification module. The expressions, applied by an external temporal mediator, retrieve a list of patients, a list of relevant time intervals, and a list of time-oriented patients' data sets, by using an expressive set of time and value constraints. RESULTS: Functionality and usability evaluation of the interactive exploration module was performed on a database of more than 1000 oncology patients by a group of 10 users-five clinicians and five medical informaticians. Both types of users were able in a short time (mean of 2.5+/-0.2min per question) to answer a set of clinical questions, including questions that require the use of specialized operators for finding associations among derived temporal abstractions, with high accuracy (mean of 98.7+/-2.4 on a predefined scale from 0 to 100). There were no significant differences between the response times and between accuracy levels of the exploration of the data using different time lines, i.e., absolute (i.e., calendrical) versus relative (referring to some clinical key event). A system usability scale (SUS) questionnaire filled out by the users demonstrated the VISITORS system to be usable (mean score for the overall group: 69.3), but the clinicians' usability assessment was significantly lower than that of the medical informaticians. CONCLUSIONS: We conclude that intelligent visualization and exploration of longitudinal data of multiple patients with the VISITORS system is feasible, functional, and usable.

A scalable architecture for incremental specification and maintenance of procedural and declarative clinical decision-support knowledge.

Clinical guidelines have been shown to improve the quality of medical care and to reduce its costs. However, most guidelines exist in a free-text representation and, without automation, are not sufficiently accessible to clinicians at the point of care. A prerequisite for automated guideline application is a machine-comprehensible representation of the guidelines. In this study, we designed and implemented a scalable architecture to support medical experts and knowledge engineers in specifying and maintaining the procedural and declarative aspects of clinical guideline knowledge, resulting in a machine comprehensible representation. The new framework significantly extends our previous work on the Digital electronic Guidelines Library (DeGeL) The current study designed and implemented a graphical framework for specification of declarative and procedural clinical knowledge, Gesher. We performed three different experiments to evaluate the functionality and usability of the major aspects of the new framework: Specification of procedural clinical knowledge, specification of declarative clinical knowledge, and exploration of a given clinical guideline. The subjects included clinicians and knowledge engineers (overall, 27 participants). The evaluations indicated high levels of completeness and correctness of the guideline specification process by both the clinicians and the knowledge engineers, although the best results, in the case of declarative-knowledge specification, were achieved by teams including a clinician and a knowledge engineer. The usability scores were high as well, although the clinicians' assessment was significantly lower than the assessment of the knowledge engineers.

Intelligent interactive visual exploration of temporal associations among multiple time-oriented patient records.

OBJECTIVES: To design, implement and evaluate the functionality and usability of a methodology and a tool for interactive exploration of time and value associations among multiple-patient longitudinal data and among meaningful concepts derivable from these data. METHODS: We developed a new, user-driven, interactive knowledge-based visualization technique, called Temporal Association Charts (TACs). TACs support the investigation of temporal and statistical associations within multiple patient records among both concepts and the temporal abstractions derived from them. The TAC methodology was implemented as part of an interactive system, called VISITORS, which supports intelligent visualization and exploration of longitudinal patient data. The TAC module was evaluated for functionality and usability by a group of ten users, five clinicians and five medical informaticians. Users were asked to answer ten questions using the VISITORS system, five of which required the use of TACs. RESULTS: Both types of users were able to answer the questions in reasonably short periods of time (a mean of 2.5 +/- 0.27 minutes) and with high accuracy (95.3 +/- 4.5 on a 0-100 scale), without a significant difference between the two groups. All five questions requiring the use of TACs were answered with similar response times and accuracy levels. Similar accuracy scores were achieved for questions requiring the use of TACs and for questions requiring the use only of general exploration operators. However, response times when using TACs were slightly longer. CONCLUSIONS: TACs are functional and usable. Their use results in a uniform performance level, regardless of the type of clinical question or user group involved.

Intelligent querying and exploration of multiple time-oriented medical records.

Querying and analyzing multiple time-oriented patient data is a key task during medical research, clinical trials or the assessment of the quality of therapy. In this paper, we present several aspects of the VISITORS system, which includes knowledge-based tools for graphical querying and exploration of multiple longitudinal patient records. We focus on the syntax and semantics of the knowledge-based aggregation query language for multiple time-oriented patient records, and on the graphical query-construction interface. The query language assumes an underlying computational method for deriving meaningful abstractions from single and multiple patient records, such as we had previously developed. The aggregation query language enables population querying using an expressive set of constraints. By using our underlying temporal mediator architecture, the time needed to answer typical temporal-abstraction aggregation queries on databases of 1000 to 10,000 patients was reasonable.

Measuring photosynthetic parameters at a distance: laser induced fluorescence transient (LIFT) method for remote measurements of photosynthesis in terrestrial vegetation.

We have developed a laser induced fluorescence transient (LIFT) technique and instrumentation to remotely measure photosynthetic properties in terrestrial vegetation at a distance of up to 50 m. The LIFT method uses a 665 nm laser to project a collimated, 100 mm diameter excitation beam onto leaves of the targeted plant. Fluorescence emission at 690 nm is collected by a 250 mm reflective telescope and processed in real time to calculate the efficiency of photosynthetic light utilization, quantum efficiency of PS II, and the kinetics of photosynthetic electron transport. Operating with peak excitation power of 125 W m-2, and duty cycle of 10-50%, the instrument conforms to laser safety regulations. The LIFT instrument is controlled via an Internet connection, allowing it to operate from remote locations or platforms. Here we describe the theoretical basis of the LIFT methodology, and demonstrate its applications in remote measurements of photosynthetic properties in the canopy of cottonwood and oak trees, and in the rosette of Arabidopsis mutants.

A framework for intelligent visualization of multiple time-oriented medical records.

Management of patients, especially chronic patients, requires presentation and processing of very large amounts of time-oriented clinical data. Using regular means such as text or tables is often ineffective, thus we propose to use the visual presentation of the information in decision support, especially in the medical domain. Displaying only raw data is not sufficient, because it still requires the user to derive meaningful conclusions from large amount of data. In order to support the computation process, we provide automated mechanisms for temporal abstraction. These mechanisms perform derivation of context-specific, interval-based abstract concepts from raw time-stamped clinical data, by using a domain-specific knowledge base. Then, these abstractions can be visualized and explored. In addition, in many cases (e.g. when comparing the effect of new drugs on various groups of patients) a view of multiple records is more effective than a view of each indi-vidual record separately. We have designed and implemented a system called VISITORS (VisualizatIon of Time-Oriented RecordS) which includes several tools for intelligent visualization and exploration of raw data and abstracted concepts for multiple patient records.