Novel Bio-Imaging Techniques Based on Molecular Switching

Fluorescence microscopy has been a fundamental imaging tool for life science research. Fluorescence basically involves only two molecular states: the ground molecular state and the first singlet excited state (the fluorescent state). Astonishingly, it greatly diversified the applicability of fluorescence microscopy in many different ways by incorporating additional molecular states and switching fluorescent molecules through these three or even more molecular states during the fluorescence process. This switching mechanism between additional molecular states, either long lifetime or short lifetime, and two original molecular states actually adds nonlinearity into the linear fluorescence process, which empowers fluorescence microscopy additional imaging capabilities. Herein, we developed four distinct new imaging techniques by taking advantage of this molecular switching mechanism: dark state dynamics sensing and imaging by fluorescence anomalous phase advance, genetically-encoded microviscosity sensor using protein-flexibility mediated photochromism, deep tissue imaging with super-nonlinear fluorescence microscopy, and light-driven fluorescent timer for simultaneous spatial-temporal mapping of protein dynamics in live cells. The first technique, dark state dynamics sensing and imaging, effectively correlates the first triplet state of fluorescent organic dyes with the fluorescence process to produce fluorescence emission with unexpected phase advance compared with the excitation light, that reflects the real-time information of organic dyes' dark states. The last three techniques all harness the unique on-off switch capability of the optical highlighter fluorescent proteins: Dronpa, a photo-switchable fluorescent protein, is demonstrated to experience medium friction during the chromophore's cis-trans isomerization process while photo-switching from the bright state to the dark state; multiphoton fluorescence microscope could achieve higher order nonlinearity and thus deeper image depth in the scattering sample by the population transfer kinetics of the photoinduced molecular switches, such as photo-activatable fluorescent protein etc.; a photo-convertible fluorescent protein, mEos2, shows slow color conversion from green to red under extremely weak near-UV light, that could be used to time protein age. No matter fluorescent organic dyes or optical highlighter fluorescent proteins, the nonlinearity has been demonstrated to create new fluorescence imaging techniques by switching fluorescent molecules between additional molecular states and two original molecular states involved in the fluorescence process

Incorporating geostrophic wind information for improved space-time short-term wind speed forecasting

Accurate short-term wind speed forecasting is needed for the rapid development and efficient operation of wind energy resources. This is, however, a very challenging problem. Although on the large scale, the wind speed is related to atmospheric pressure, temperature, and other meteorological variables, no improvement in forecasting accuracy was found by incorporating air pressure and temperature directly into an advanced space-time statistical forecasting model, the trigonometric direction diurnal (TDD) model. This paper proposes to incorporate the geostrophic wind as a new predictor in the TDD model. The geostrophic wind captures the physical relationship between wind and pressure through the observed approximate balance between the pressure gradient force and the Coriolis acceleration due to the Earth's rotation. Based on our numerical experiments with data from West Texas, our new method produces more accurate forecasts than does the TDD model using air pressure and temperature for 1- to 6-hour-ahead forecasts based on three different evaluation criteria. Furthermore, forecasting errors can be further reduced by using moving average hourly wind speeds to fit the diurnal pattern. For example, our new method obtains between 13.9% and 22.4% overall mean absolute error reduction relative to persistence in 2-hour-ahead forecasts, and between 5.3% and 8.2% reduction relative to the best previous space-time methods in this setting.Comment: Published in at http://dx.doi.org/10.1214/14-AOAS756 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

The association between victimization experiences and suicidality:The mediating roles of sleep and depression

Background Prior work suggests that multiple forms of victimization were associated with higher suicide risk among adolescents. However, the mechanisms underlying this association remain unclear. The present study aimed to understand the relationships between the multiple forms of victimization and suicidality by examining the potential mediators of sleep duration and depression. Methods Data for this study came from the 2019 Youth Risk Behavior Survey (YRBS). The hypothesized mediation model included 13,677 American adolescents in 9th through 12th-grade students (48.6 % female) were analyzed using Mplus 7.4, and suicidality (including suicidal ideation, plan, and attempts) as the outcome variables and the multiple forms of victimization (including bullying at school, being threatened at school, electronic bullying, sexual victimization, sexual dating victimization, and physical dating victimization) as the main explanatory variable. Results The relationships between the multiple forms of victimization and suicide risk were mediated by sleep duration, depression, and also serially mediated by sleep duration and depression. Limitations This is a cross-sectional study, and the results cannot inform the causality between these variables. This investigation only included adolescent sleep duration, and other specific sleep problem indicators should be included. Conclusions Longer sleep duration is an important protective factor, pointing the way forward for developing suicide prevention strategies and targeted interventions for adolescents

Developmental pathways of suicidality and self-harm among youth

Suicidality and self-harm among youth are significant public health concerns. This thesis seeks to elucidate the developmental pathways and predictors underpinning these issues, with a particular emphasis on the roles of bullying victimisation (or peer victimisation), parental mental health, youth problem behaviours, and screen time use. Chapter 2 utilised the Zurich Project on the Social Development from Childhood to Adulthood (z-proso) and employed random-intercept cross-lagged panel models to investigate whether bullying victimisation has associations with suicidal ideation and self-harm. The analysis suggested a positive within-person effect between general bullying victimisation at age 15 and suicidal ideation at age 17. Intriguingly, this association is bidirectional, with suicidal ideation at age 17 subsequently leading to general bullying victimisation at age 20. Building on these findings, Chapter 3 examined the mediating roles of depressive symptoms, anxiety symptoms, and substance use in the associations between bullying victimisation and suicidal ideation, focusing on within-person effects. Contrary to expectations, bullying victimisation did not predict subsequent within-person increases in suicidal ideation through these mediators. In Chapter 4, data from the UK’s Millennium Cohort Study (MCS) and a parallel-process latent class growth analysis (LCGA) were utilised to examine the co-developmental trajectories of parental mental health issues and child internalising and externalising problems from early childhood to middle adolescence, as well as their associations with self-harm and suicidal attempts in adolescence. The findings highlight the significance of taking parental distress (especially maternal) and child problem behaviours into account when addressing negative outcomes such as self-harm and suicidal attempts. Chapter 5 examined the role of developmental patterns of screen time during adolescence in suicidality, self-harm, and other mental health and behavioural issues in young adults. Analysis of the z-proso study and a parallel-process LCGA indicated that youths in the trajectory group of increasing videogame and internet use displayed a higher risk for suicidal ideation and self-harm at age 20. This highlights the critical role of screen usage patterns as potential markers of later suicidality and self-harm risk; however, additional examinations are needed to test this association. Overall, this work illuminates the multifaceted developmental predictors of suicidality and self-harm in youth

Wind Speed Forecasting for Power System Operation

In order to support large-scale integration of wind power into current electric energy system, accurate wind speed forecasting is essential, because the high variation and limited predictability of wind pose profound challenges to the power system operation in terms of the efficiency of the system. The goal of this dissertation is to develop advanced statistical wind speed predictive models to reduce the uncertainties in wind, especially the short-term future wind speed. Moreover, a criterion is proposed to evaluate the performance of models. Cost reduction in power system operation, as proposed, is more realistic than prevalent criteria, such as, root mean square error (RMSE) and absolute mean error (MAE). Two advanced space-time statistical models are introduced for short-term wind speed forecasting. One is a modified regime-switching, space-time wind speed fore- casting model, which allows the forecast regimes to vary according to the dominant wind direction and seasons. Thus, it avoids a subjective choice of regimes. The other one is a novel model that incorporates a new variable, geostrophic wind, which has strong influence on the surface wind, into one of the advanced space-time statistical forecasting models. This model is motivated by the lack of improvement in forecast accuracy when using air pressure and temperature directly. Using geostrophic wind in the model is not only critical, it also has a meaningful geophysical interpretation. The importance of model evaluation is emphasized in the dissertation as well. Rather than using RMSE or MAE, the performance of both wind forecasting models mentioned above are assessed by economic benefits with real wind farm data from Pacific Northwest of the U.S and West Texas. Wind forecasts are incorporated into power system economic dispatch models, and the power system operation cost is used as a loss measure for the performance of the forecasting models. From another perspective, the new criterion leads to cost-effective scheduling of system-wide wind generation with potential economic benefits arising from the system-wide generation of cost savings and ancillary services cost savings. As an illustration, the integrated forecasts and economic dispatch framework are applied to the Electric Reliability Council of Texas (ERCOT) equivalent 24- bus system. Compared with persistence and autoregressive models, the first model suggests that cost savings from integration of wind power could be on the scale of tens of millions of dollars. For the second model, numerical simulations suggest that the overall generation cost can be reduced by up to 6.6% using look-ahead dispatch coupled with spatio-temporal wind forecast as compared with dispatch with persistent wind forecast model

Co-developmental trajectories of parental psychological distress and child internalizing and externalizing problems in childhood and adolescence:Associations with self-harm and suicide attempts

Growing evidence has suggested that parental mental illness and child internalizing and externalizing problems tend to co-occur and engender risk for adverse child outcomes; however, there is considerable heterogeneity in their joint developmental trajectories. This study aimed to evaluate the joint developmental trajectories of maternal and paternal psychological distress and child internalizing and externalizing problems from early childhood to middle adolescence. Given that suicide and self-harm are major public health issues in adolescence and often occur in the context of other mental health issues, we also characterized the association between these joint trajectories and these outcomes in adolescence. Parallel-process latent class growth analysis was applied to 14 years of follow-up data from a large-scale, nationally representative sample of youths participating in the UK’s Millennium Cohort Study (MCS; n=12520, 50.9% male). Results showed the best-fitting solution had four trajectory classes: (1) low symptoms, 59.0%; (2) moderate symptoms in children, 22.5%; (3) notable symptoms in fathers, 10.7%; and (4) co-occurring maternal and child symptoms, 7.8%. Children’s sex differences were also observed in the joint trajectory groups. The trajectory groups differed in their self-harm and suicide attempts in adolescence, underscoring the importance of the roles of both parental distress and child problem behaviors processes in these outcomes. Our findings suggest the need for two-generation mental health intervention programs that are tailored based on co-developmental trajectory group membership and sexes

Extending the fundamental imaging-depth limit of multi-photon microscopy by imaging with photo-activatable fluorophores

It is highly desirable to be able to optically probe biological activities deep inside live organisms. By employing a spatially confined excitation via a nonlinear transition, multiphoton fluorescence microscopy has become indispensable for imaging scattering samples. However, as the incident laser power drops exponentially with imaging depth due to scattering loss, the out-of-focus fluorescence eventually overwhelms the in-focal signal. The resulting loss of imaging contrast defines a fundamental imaging-depth limit, which cannot be overcome by increasing excitation intensity. Herein we propose to significantly extend this depth limit by multiphoton activation and imaging (MPAI) of photo-activatable fluorophores. The imaging contrast is drastically improved due to the created disparity of bright-dark quantum states in space. We demonstrate this new principle by both analytical theory and experiments on tissue phantoms labeled with synthetic caged fluorescein dye or genetically encodable photoactivatable GFP