Variation of terpene alkaloids in Daphniphyllum macropodum across plants and tissues.

Daphniphyllum macropodum produces alkaloids that are structurally complex with polycyclic, stereochemically rich carbon skeletons. Understanding how these compounds are formed by the plant may enable exploration of their biological function and bioactivities. We employed multiple metabolomics techniques, including a workflow to annotate compounds in the absence of standards, to compare alkaloid content across plants and tissues. Different alkaloid structural types were found to have distinct distributions between genotypes, between tissues and within tissues. Alkaloid structural types also showed different isotope labelling enrichments that matched their biosynthetic relationships. The work suggests that mevalonate derived 30-carbon alkaloids are formed in the phloem region before their conversion to 22-carbon alkaloids which accumulate in the epidermis. This sets the stage for further investigation into the biosynthetic pathway.

Developing a clinical decision support system software prototype that assists in the management of patients with self-harm in the emergency department: protocol of the PERMANENS project.

BACKGROUND: Self-harm presents a significant public health challenge. Emergency departments (EDs) are crucial healthcare settings in managing self-harm, but clinician uncertainty in risk assessment may contribute to ineffective care. Clinical Decision Support Systems (CDSSs) show promise in enhancing care processes, but their effective implementation in self-harm management remains unexplored. METHODS: PERMANENS comprises a combination of methodologies and study designs aimed at developing a CDSS prototype that assists clinicians in the personalized assessment and management of ED patients presenting with self-harm. Ensemble prediction models will be constructed by applying machine learning techniques on electronic registry data from four sites, i.e., Catalonia (Spain), Ireland, Norway, and Sweden. These models will predict key adverse outcomes including self-harm repetition, suicide, premature death, and lack of post-discharge care. Available registry data include routinely collected electronic health record data, mortality data, and administrative data, and will be harmonized using the OMOP Common Data Model, ensuring consistency in terminologies, vocabularies and coding schemes. A clinical knowledge base of effective suicide prevention interventions will be developed rooted in a systematic review of clinical practice guidelines, including quality assessment of guidelines using the AGREE II tool. The CDSS software prototype will include a backend that integrates the prediction models and the clinical knowledge base to enable accurate patient risk stratification and subsequent intervention allocation. The CDSS frontend will enable personalized risk assessment and will provide tailored treatment plans, following a tiered evidence-based approach. Implementation research will ensure the CDSS' practical functionality and feasibility, and will include periodic meetings with user-advisory groups, mixed-methods research to identify currently unmet needs in self-harm risk assessment, and small-scale usability testing of the CDSS prototype software. DISCUSSION: Through the development of the proposed CDSS software prototype, PERMANENS aims to standardize care, enhance clinician confidence, improve patient satisfaction, and increase treatment compliance. The routine integration of CDSS for self-harm risk assessment within healthcare systems holds significant potential in effectively reducing suicide mortality rates by facilitating personalized and timely delivery of effective interventions on a large scale for individuals at risk of suicide.

Why did Rubens add a parrot to Titian's The Fall of Man? A pictorial manipulation of joint attention.

Almost 400 years ago, Rubens copied Titian's The Fall of Man, albeit with important changes. Rubens altered Titian's original composition in numerous ways, including by changing the gaze directions of the depicted characters and adding a striking red parrot to the painting. Here, we quantify the impact of Rubens's choices on the viewer's gaze behavior. We displayed digital copies of Rubens's and Titian's artworks-as well as a version of Rubens's painting with the parrot digitally removed-on a computer screen while recording the eye movements produced by observers during free visual exploration of each image. To assess the effects of Rubens's changes to Titian's composition, we directly compared multiple gaze parameters across the different images. We found that participants gazed at Eve's face more frequently in Rubens's painting than in Titian's. In addition, gaze positions were more tightly focused for the former than for the latter, consistent with different allocations of viewer interest. We also investigated how gaze fixation on Eve's face affected the perceptual visibility of the parrot in Rubens's composition and how the parrot's presence versus its absence impacted gaze dynamics. Taken together, our results demonstrate that Rubens's critical deviations from Titian's painting have powerful effects on viewers' oculomotor behavior.

Minimal reporting guideline for research involving eye tracking (2023 edition).

A guideline is proposed that comprises the minimum items to be reported in research studies involving an eye tracker and human or non-human primate participant(s). This guideline was developed over a 3-year period using a consensus-based process via an open invitation to the international eye tracking community. This guideline will be reviewed at maximum intervals of 4 years.

Eye tracking: empirical foundations for a minimal reporting guideline.

In this paper, we present a review of how the various aspects of any study using an eye tracker (such as the instrument, methodology, environment, participant, etc.) affect the quality of the recorded eye-tracking data and the obtained eye-movement and gaze measures. We take this review to represent the empirical foundation for reporting guidelines of any study involving an eye tracker. We compare this empirical foundation to five existing reporting guidelines and to a database of 207 published eye-tracking studies. We find that reporting guidelines vary substantially and do not match with actual reporting practices. We end by deriving a minimal, flexible reporting guideline based on empirical research (Section "An empirically based minimal reporting guideline").

Mandating Limits on Workload, Duty, and Speed in Radiology.

Research has not yet quantified the effects of workload or duty hours on the accuracy of radiologists. With the exception of a brief reduction in imaging studies during the 2020 peak of the COVID-19 pandemic, the workload of radiologists in the United States has seen relentless growth in recent years. One concern is that this increased demand could lead to reduced accuracy. Behavioral studies in species ranging from insects to humans have shown that decision speed is inversely correlated to decision accuracy. A potential solution is to institute workload and duty limits to optimize radiologist performance and patient safety. The concern, however, is that any prescribed mandated limits would be arbitrary and thus no more advantageous than allowing radiologists to self-regulate. Specific studies have been proposed to determine whether limits reduce error, and if so, to provide a principled basis for such limits. This could determine the precise susceptibility of individual radiologists to medical error as a function of speed during image viewing, the maximum number of studies that could be read during a work shift, and the appropriate shift duration as a function of time of day. Before principled recommendations for restrictions are made, however, it is important to understand how radiologists function both optimally and at the margins of adequate performance. This study examines the relationship between interpretation speed and error rates in radiology, the potential influence of artificial intelligence on reading speed and error rates, and the possible outcomes of imposed limits on both caseload and duty hours. This review concludes that the scientific evidence needed to make meaningful rules is lacking and notes that regulating workloads without scientific principles can be more harmful than not regulating at all.

Gaze mechanisms enabling the detection of faint stars in the night sky.

For millennia, people have used "averted vision" to improve their detection of faint celestial objects, a technique first documented around 325 BCE. Yet, no studies have assessed gaze location during averted vision to determine what pattern best facilitates perception. Here, we characterized averted vision while recording eye-positions of dark-adapted human participants, for the first time. We simulated stars of apparent magnitudes 3.3 and 3.5, matching their brightness to Megrez (the dimmest star in the Big Dipper) and Tau Ceti. Participants indicated whether each star was visible from a series of fixation locations, providing a comprehensive map of detection performance in all directions. Contrary to prior predictions, maximum detection was first achieved at ~8° from the star, much closer to the fovea than expected from rod-cone distributions alone. These findings challenge the assumption of optimal detection at the rod density peak and provide the first systematic assessment of an age-old facet of human vision.

Long-term all-optical interrogation of cortical neurons in awake-behaving nonhuman primates.

Whereas optogenetic techniques have proven successful in their ability to manipulate neuronal populations-with high spatial and temporal fidelity-in species ranging from insects to rodents, significant obstacles remain in their application to nonhuman primates (NHPs). Robust optogenetics-activated behavior and long-term monitoring of target neurons have been challenging in NHPs. Here, we present a method for all-optical interrogation (AOI), integrating optical stimulation and simultaneous two-photon (2P) imaging of neuronal populations in the primary visual cortex (V1) of awake rhesus macaques. A red-shifted channel-rhodopsin transgene (ChR1/VChR1 [C1V1]) and genetically encoded calcium indicators (genetically encoded calmodulin protein [GCaMP]5 or GCaMP6s) were delivered by adeno-associated viruses (AAVs) and subsequently expressed in V1 neuronal populations for months. We achieved optogenetic stimulation using both single-photon (1P) activation of neuronal populations and 2P activation of single cells, while simultaneously recording 2P calcium imaging in awake NHPs. Optogenetic manipulations of V1 neuronal populations produced reliable artificial visual percepts. Together, our advances show the feasibility of precise and stable AOI of cortical neurons in awake NHPs, which may lead to broad applications in high-level cognition and preclinical testing studies.

The Storytelling Brain: How Neuroscience Stories Help Bridge the Gap between Research and Society.

Active communication between researchers and society is necessary for the scientific community's involvement in developing science-based policies. This need is recognized by governmental and funding agencies that compel scientists to increase their public engagement and disseminate research findings in an accessible fashion. Storytelling techniques can help convey science by engaging people's imagination and emotions. Yet, many researchers are uncertain about how to approach scientific storytelling, or feel they lack the tools to undertake it. Here we explore some of the techniques intrinsic to crafting scientific narratives, as well as the reasons why scientific storytelling may be an optimal way of communicating research to nonspecialists. We also point out current communication gaps between science and society, particularly in the context of neurodiverse audiences and those that include neurological and psychiatric patients. Present shortcomings may turn into areas of synergy with the potential to link neuroscience education, research, and advocacy.

Advanced Circuit and Cellular Imaging Methods in Nonhuman Primates.

Novel genetically encoded tools and advanced microscopy methods have revolutionized neural circuit analyses in insects and rodents over the last two decades. Whereas numerous technical hurdles originally barred these methodologies from success in nonhuman primates (NHPs), current research has started to overcome those barriers. In some cases, methodological advances developed with NHPs have even surpassed their precursors. One such advance includes new ultra-large imaging windows on NHP cortex, which are larger than the entire rodent brain and allow analysis unprecedented ultra-large-scale circuits. NHP imaging chambers now remain patent for periods longer than a mouse's lifespan, allowing for long-term all-optical interrogation of identified circuits and neurons over timeframes that are relevant to human cognitive development. Here we present some recent imaging advances brought forth by research teams using macaques and marmosets. These include technical developments in optogenetics; voltage-, calcium- and glutamate-sensitive dye imaging; two-photon and wide-field optical imaging; viral delivery; and genetic expression of indicators and light-activated proteins that result in the visualization of tens of thousands of identified cortical neurons in NHPs. We describe a subset of the many recent advances in circuit and cellular imaging tools in NHPs focusing here primarily on the research presented during the corresponding mini-symposium at the 2019 Society for Neuroscience annual meeting.

What do radiologists look for? Advances and limitations of perceptual learning in radiologic search.

Supported by guidance from training during residency programs, radiologists learn clinically relevant visual features by viewing thousands of medical images. Yet the precise visual features that expert radiologists use in their clinical practice remain unknown. Identifying such features would allow the development of perceptual learning training methods targeted to the optimization of radiology training and the reduction of medical error. Here we review attempts to bridge current gaps in understanding with a focus on computational saliency models that characterize and predict gaze behavior in radiologists. There have been great strides toward the accurate prediction of relevant medical information within images, thereby facilitating the development of novel computer-aided detection and diagnostic tools. In some cases, computational models have achieved equivalent sensitivity to that of radiologists, suggesting that we may be close to identifying the underlying visual representations that radiologists use. However, because the relevant bottom-up features vary across task context and imaging modalities, it will also be necessary to identify relevant top-down factors before perceptual expertise in radiology can be fully understood. Progress along these dimensions will improve the tools available for educating new generations of radiologists, and aid in the detection of medically relevant information, ultimately improving patient health.

Mendelian randomisation analysis of clustered causal effects of body mass on cardiometabolic biomarkers.

BACKGROUND: Recent advances in data analysis methods based on principles of Mendelian Randomisation, such as Egger regression and the weighted median estimator, add to the researcher's ability to infer cause-effect links from observational data. Now is the time to gauge the potential of these methods within specific areas of biomedical research. In this paper, we choose a study in metabolomics as an illustrative testbed. We apply Mendelian Randomisation methods in the analysis of data from the DILGOM (Dietary, Lifestyle and Genetic determinants of Obesity and Metabolic syndrome) study, in the context of an effort to identify molecular pathways of cardiovascular disease. In particular, our illustrative analysis addresses the question whether body mass, as measured by body mass index (BMI), exerts a causal effect on the concentrations of a collection of 137 cardiometabolic markers with different degrees of atherogenic power, such as the (highly atherogenic) lipoprotein metabolites with very low density (VLDLs) and the (protective) high density lipoprotein metabolites. RESULTS: We found strongest evidence of a positive BMI effect (that is, evidence that an increase in BMI causes an increase in the metabolite concentration) on those metabolites known to represent strong risk factors for coronary artery disease, such as the VLDLs, and evidence of a negative effect on protective biomarkers. CONCLUSIONS: The methods discussed represent a useful scientific tool, although they assume the validity of conditions that are (at best) only partially verifiable. This paper provides a rigorous account of such conditions. The results of our analysis provide a proof-of-concept illustration of the potential usefulness of Mendelian Randomisation in genomic biobank studies aiming to dissect the molecular causes of disease, and to identify candidate pharmacological targets.

The impact of microsaccades on vision: towards a unified theory of saccadic function.

When we attempt to fix our gaze, our eyes nevertheless produce so-called 'fixational eye movements', which include microsaccades, drift and tremor. Fixational eye movements thwart neural adaptation to unchanging stimuli and thus prevent and reverse perceptual fading during fixation. Over the past 10 years, microsaccade research has become one of the most active fields in visual, oculomotor and even cognitive neuroscience. The similarities and differences between microsaccades and saccades have been a most intriguing area of study, and the results of this research are leading us towards a unified theory of saccadic and microsaccadic function.

Gut microbiota composition correlates with diet and health in the elderly.

Alterations in intestinal microbiota composition are associated with several chronic conditions, including obesity and inflammatory diseases. The microbiota of older people displays greater inter-individual variation than that of younger adults. Here we show that the faecal microbiota composition from 178 elderly subjects formed groups, correlating with residence location in the community, day-hospital, rehabilitation or in long-term residential care. However, clustering of subjects by diet separated them by the same residence location and microbiota groupings. The separation of microbiota composition significantly correlated with measures of frailty, co-morbidity, nutritional status, markers of inflammation and with metabolites in faecal water. The individual microbiota of people in long-stay care was significantly less diverse than that of community dwellers. Loss of community-associated microbiota correlated with increased frailty. Collectively, the data support a relationship between diet, microbiota and health status, and indicate a role for diet-driven microbiota alterations in varying rates of health decline upon ageing.

Changes in visibility as a function of spatial frequency and microsaccade occurrence.

Fixational eye movements (FEMs), including microsaccades, drift, and tremor, shift our eye position during ocular fixation, producing retinal motion that is thought to help visibility by counteracting neural adaptation to unchanging stimulation. Yet, how each FEM type influences this process is still debated. Recent studies found little to no relationship between microsaccades and visual perception of spatial frequencies (SF). However, these conclusions were based on coarse analyses that make it hard to appreciate the actual effects of microsaccades on target visibility as a function of SF. Thus, how microsaccades contribute to the visibility of stimuli of different SFs remains unclear. Here, we asked how the visibility of targets of various SFs changed over time, in relationship with concurrent microsaccade production. Participants continuously reported on changes in target visibility, allowing us to time-lock ongoing changes in microsaccade parameters to perceptual transitions in visibility. Microsaccades restored/increased the visibility of low SF targets more efficiently than that of high SF targets. Yet, microsaccade rates rose before periods of increased visibility, and dropped before periods of diminished visibility, for all the SFs tested, suggesting that microsaccades boosted target visibility across a wide range of SFs. Our data also indicate that visual stimuli fade/become harder to see less often in the presence of microsaccades. In addition, larger microsaccades restored/increased target visibility more effectively than smaller microsaccades. These combined results support the proposal that microsaccades enhance visibility across a broad variety of SFs.

An oculomotor continuum from exploration to fixation.

During visual exploration, saccadic eye movements scan the scene for objects of interest. During attempted fixation, the eyes are relatively still but often produce microsaccades. Saccadic rates during exploration are higher than those of microsaccades during fixation, reinforcing the classic view that exploration and fixation are two distinct oculomotor behaviors. An alternative model is that fixation and exploration are not dichotomous, but are instead two extremes of a functional continuum. Here, we measured the eye movements of human observers as they either fixed their gaze on a small spot or scanned natural scenes of varying sizes. As scene size diminished, so did saccade rates, until they were continuous with microsaccadic rates during fixation. Other saccadic properties varied as function of image size as well, forming a continuum with microsaccadic parameters during fixation. This saccadic continuum extended to nonrestrictive, ecological viewing conditions that allowed all types of saccades and fixation positions. Eye movement simulations moreover showed that a single model of oculomotor behavior can explain the saccadic continuum from exploration to fixation, for images of all sizes. These findings challenge the view that exploration and fixation are dichotomous, suggesting instead that visual fixation is functionally equivalent to visual exploration on a spatially focused scale.

Highly informative natural scene regions increase microsaccade production during visual scanning.

Classical image statistics, such as contrast, entropy, and the correlation between central and nearby pixel intensities, are thought to guide ocular fixation targeting. However, these statistics are not necessarily task relevant and therefore do not provide a complete picture of the relationship between informativeness and ocular targeting. Moreover, it is not known whether either informativeness or classical image statistics affect microsaccade production; thus, the role of microsaccades in information acquisition is also unknown. The objective quantification of the informativeness of a scene region is a major challenge, because it can vary with both image features and the task of the viewer. Thus, previous definitions of informativeness suffered from subjectivity and inconsistency across studies. Here we developed an objective measure of informativeness based on fixation consistency across human observers, which accounts for both bottom-up and top-down influences in ocular targeting. We then analyzed fixations in more versus less informative image regions in relation to classical statistics. Observers generated more microsaccades on more informative than less informative image regions, and such regions also exhibited low redundancy in their classical statistics. Increased microsaccade production was not explained by increased fixation duration, suggesting that the visual system specifically uses microsaccades to heighten information acquisition from informative regions.