Theory of moment propagation for quantum dynamics in single-particle description.

We present a novel theoretical formulation for performing quantum dynamics in terms of moments within the single-particle description. By expressing the quantum dynamics in terms of increasing orders of moments, instead of single-particle wave functions as generally done in time-dependent density functional theory, we describe an approach for reducing the high computational cost of simulating the quantum dynamics. The equation of motion is given for the moments by deriving analytical expressions for the first-order and second-order time derivatives of the moments, and a numerical scheme is developed for performing quantum dynamics by expanding the moments in the Taylor series as done in classical molecular dynamics simulations. We propose a few numerical approaches using this theoretical formalism on a simple one-dimensional model system, for which an analytically exact solution can be derived. The application of the approaches to an anharmonic system is also discussed to illustrate their generality. We also discuss the use of an artificial neural network model to circumvent the numerical evaluation of the second-order time derivatives of the moments, as analogously done in the context of classical molecular dynamics simulations.

Real-Time Time-Dependent Density Functional Theory for Simulating Nonequilibrium Electron Dynamics.

The explicit real-time propagation approach for time-dependent density functional theory (RT-TDDFT) has increasingly become a popular first-principles computational method for modeling various time-dependent electronic properties of complex chemical systems. In this Perspective, we provide a nontechnical discussion of how this first-principles simulation approach has been used to gain novel physical insights into nonequilibrium electron dynamics phenomena in recent years. Following a concise overview of the RT-TDDFT methodology from a practical standpoint, we discuss our recent studies on the electronic stopping of DNA in water and the Floquet topological phase as examples. Our discussion focuses on how RT-TDDFT simulations played a unique role in deriving new scientific understandings. We then discuss existing challenges and some new advances at the frontier of RT-TDDFT method development for studying increasingly complex dynamic phenomena and systems.

Ion-Type Dependence of DNA Electronic Excitation in Water under Proton, α-Particle, and Carbon Ion Irradiation: A First-Principles Simulation Study.

Understanding how the electronic excitation of DNA changes in response to different high-energy particles is central to advancing ion beam cancer therapy and other related approaches, such as boron neutron capture therapy. While protons have been the predominant ions of choice in ion beam cancer therapy, heavier ions, particularly carbon ions, have drawn significant attention over the past decade. Carbon ions are expected to transfer larger amounts of energy according to linear response theory. However, molecular-level details of the electronic excitation under heavier ion irradiation remain unknown. In this work, we use real-time time-dependent density functional theory simulations to examine the quantum-mechanical details of DNA electronic excitations in water under proton, α-particle, and carbon ion irradiation. Our results show that the energy transfer does indeed increase for the heavier ions, while the excitation remains highly conformal. However, the increase in the energy transfer rate, measured by electronic stopping power, does not match the prediction by the linear response model, even when accounting for the velocity dependence of the irradiating ion's charge. The simulations also reveal that while the number of holes generated on DNA increases for heavier ions, the increase is only partially responsible for the larger stopping power. Larger numbers of highly energetic holes formed from the heavier ions also contribute significantly to the increased electronic stopping power.

Electronic Excitation Response of DNA to High-Energy Proton Radiation in Water.

The lack of molecular-level understanding for the electronic excitation response of DNA to charged particle radiation, such as high-energy protons, remains a fundamental scientific bottleneck in advancing proton and other ion beam cancer therapies. In particular, the dependence of different types of DNA damage on high-energy protons represents a significant knowledge void. Here we employ first-principles real-time time-dependent density functional theory simulation, using a massively parallel supercomputer, to unravel the quantum-mechanical details of the energy transfer from high-energy protons to DNA in water. The calculations reveal that protons deposit significantly more energy onto the DNA sugar-phosphate side chains than onto the nucleobases, and greater energy transfer is expected onto the DNA side chains than onto water. As a result of this electronic stopping process, highly energetic holes are generated on the DNA side chains as a source of oxidative damage.

Nighttime Sleep Quality and Daytime Sleepiness Predicts Suicide Risk in Adults Admitted to an Inpatient Psychiatric Hospital.

As sleep problems have been identified as an important, yet understudied, predictor of suicide risk, the present study analyzed the relationship between daytime sleepiness and nighttime sleep disturbance in a high-risk population of adults admitted to an inpatient psychiatric hospital. Objectives were to (1) examine the time course of subjective daytime sleepiness, nighttime sleep disturbance, and suicide risk throughout inpatient psychiatric treatment, (2) examine pre- to post-treatment changes in sleep disturbance with treatment as usual in an inpatient psychiatric setting, and (3) investigate whether daytime sleepiness and nighttime sleep disturbance predicted suicide risk above and beyond anxiety and depression. Participants were 500 consecutively admitted adults admitted to an intermediate length of stay (4-6 weeks) inpatient psychiatric hospital (47% female; 18-87 years of age). Measures of sleep, suicide risk, depression, and anxiety were completed at admission, weeks 1 through 4, and at discharge. Latent growth curve modeling (LGM) and hierarchal linear modeling (HLM) were conducted. The LGM analysis demonstrated that daytime sleepiness, nighttime sleep disturbance, and suicide risk all improved throughout inpatient treatment. Further, HLM showed that daytime sleepiness predicted suicide risk above and beyond symptoms of anxiety, depression, major sleep medications, and prior suicidal ideation and attempts, while nighttime sleep disturbance predicted suicide risk above and beyond symptoms of anxiety, major sleep medications, and prior suicidal ideation and attempts. Findings indicate the need to reevaluate safety protocols that may impact sleep, particularly that may increase daytime sleepiness, and to develop evidence-based sleep interventions for individuals admitted to inpatient psychiatric hospitals.

Emotion Regulation Mediates the Relationship Between Therapeutic Alliance and Anxiety in Emerging Adults During Inpatient Psychiatric Treatment.

Emerging adulthood is a critical developmental period characterized by emotional growth and unstructured living. To date, there is little research on emerging adults-defined as those 18 to 25 years old-with serious mental illnesses and even less on emerging adults in psychiatric hospitals. This study analyzed therapeutic alliance with the clinical team and change in anxiety symptoms in emerging adult psychiatric inpatients with the goal of establishing whether emotion regulation could serve as a mediator between these 2 constructs. Participants were 913 emerging adults (46.7% female; 18 to 25 y of age) who were voluntarily admitted to an intermediate length-of-stay (6 to 8 wk) inpatient psychiatric hospital. Each patient completed measures assessing anxiety symptoms, emotion regulation strategies, and working alliance as an assessment of therapeutic alliance. The results indicated that working alliance had significant indirect effects on change in anxiety symptoms through emotion dysregulation and lack of awareness, limited access to emotion regulation strategies, and lack of emotional clarity. This study emphasizes the need to understand emerging adults and the difficulties characteristic of this developmental period, and that clinicians should be aware that cognitive factors involved in emotion regulation may impact anxiety symptoms in emerging adult populations.

Nonlinear electronic excitation in water under proton irradiation: a first principles study.

Nonlinear dynamics of electronic excitation bridge physical and physicochemical stages of water radiolysis under proton irradiation, a multi-scale physicochemical process that is fundamental to a wide range of technological and medical applications of high-energy protons. We study the spatial and temporal changes to the excited holes generated in this ionization event using first-principles theory simulation. A significant majority of holes are formed in the immediate vicinity of the irradiating proton paths, and these holes decay rapidly, while secondary excitations are simultaneously induced in regions farther away. While the hole population remains constant, the observed spatially spreading hole distribution cannot be described as concentration-dependent diffusion current. Compared to the primary excitation induced by the irradiating protons, the secondary excitation farther away is somewhat less energetic. The first-principles theory simulation here provides a detailed description of how the primary excitation by proton radiation precedes the formation of cationic holes, which undergo ultrafast chemical processes in water radiolysis.

Simulating electronic excitation and dynamics with real-time propagation approach to TDDFT within plane-wave pseudopotential formulation.

We give a perspective on simulating electronic excitation and dynamics using the real-time propagation approach to time-dependent density functional theory (RT-TDDFT) in the plane-wave pseudopotential formulation. RT-TDDFT is implemented in various numerical formalisms in recent years, and its practical application often dictates the most appropriate implementation of the theory. We discuss recent developments and challenges, emphasizing numerical aspects of studying real systems. Several applications of RT-TDDFT simulation are discussed to highlight how the approach is used to study interesting electronic excitation and dynamics phenomena in recent years.

TLR9 in MAFLD and NASH: At the Intersection of Inflammation and Metabolism.

Toll-Like Receptor 9 (TLR9) is an ancient receptor integral to the primordial functions of inflammation and metabolism. TLR9 functions to regulate homeostasis in a healthy system under acute stress. The literature supports that overactivation of TLR9 under the chronic stress of obesity is a critical driver of the pathogenesis of NASH and NASH-associated fibrosis. Research has focused on the core contributions of the parenchymal and non-parenchymal cells in the liver, adipose, and gut compartments. TLR9 is activated by endogenous circulating mitochondrial DNA (mtDNA). Chronically elevated circulating levels of mtDNA, caused by the stress of overnutrition, are observed in obesity, metabolic dysfunction-associated fatty liver disease (MAFLD), and NASH. Clinical evidence is supportive of TLR9 overactivation as a driver of disease. The role of TLR9 in metabolism and energy regulation may have an underappreciated contribution in the pathogenesis of NASH. Antagonism of TLR9 in NASH and NASH-associated fibrosis could be an effective therapeutic strategy to target both the inflammatory and metabolic components of such a complex disease.

Trajectories of self-reported sleep disturbance across inpatient psychiatric treatment predict clinical outcome in comorbid major depressive disorder and generalized anxiety disorder.

BACKGROUND: As there has been a demonstrated link between sleep disturbance and suicide, the present study investigated the relationship between self-reported sleep disturbance during inpatient psychiatric treatment and clinical outcomes at discharge and six months post-discharge. METHODS: Participants were 2,970 adults receiving care in a long-term inpatient psychiatric hospital. Greater than 90% of inpatients reported at least mild sleep disturbance throughout treatment. Group-based trajectory modeling was used to determine patterns of sleep disturbance changes over time. RESULTS: Participants fit into distinct categories based on their trajectories of sleep problems across treatment: No Sleep Problems (10.3% of participants, no sleep problems endorsed over the course of inpatient psychiatric treatment), Resolvers (sleep problems completely resolved over the course of inpatient psychiatric treatment; 10.6%), Non-Responders (did not respond to inpatient psychiatric treatment; 35.7%) and Responders (sleep problems decreased but did not fully resolve over the course of inpatient psychiatric treatment; 43.4%). Individuals with comorbid major depressive disorder and generalized anxiety disorder were significantly more likely to demonstrate higher rates of sleep disturbance throughout inpatient psychiatric treatment and their sleep problems did not respond to treatment as usual (Non-Responders). Further, patients in the Non-Responder group had significantly more suicidal ideation and worse clinical outcomes (higher anxiety, more disability, and lower well-being) at discharge and six months post-discharge, as well as were on more medication including hypnotics throughout treatment. CONCLUSIONS: Findings indicate the urgent need to design and implement inpatient psychiatry sleep protocols to not only improve sleep and clinical outcomes, but also reduce the risk for suicide post-discharge.

Emotional rigidity negatively impacts remission from anxiety and recovery of well-being.

OBJECTIVES: Emotional rigidity is described in clinical literature as a significant barrier to recovery; however, few there are few empirical measures of the construct. The current study had two aims: Study 1 aimed to identify latent factors that may bear on the construct of emotional rigidity while Study 2 assessed the potential impact of the latent factor(s) on anxiety remission rates and well-being. METHOD: This study utilized data from 2472 adult inpatients (1176 females and 1296 males) with severe psychopathology. Study 1 utilized exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) to identify latent factors of emotional rigidity. Study 2 utilized hierarchical logistic regression analyses to assess the relationships among emotional rigidity factors and anxiety remission and well-being recovery at discharge. RESULTS: Study 1 yielded a two-factor solution identified in EFA was confirmed with CFA. Factor 1 consisted of neuroticism, experiential avoidance, non-acceptance of emotions, impaired goal-directed behavior, impulse control difficulties and limited access to emotion regulation strategies when experiencing negative emotions. Factor 2 consisted of lack of emotional awareness and lack of emotional clarity when experiencing negative emotions. Results of Study 2 indicated higher scores on Factor 1 was associated with lower remission rates from anxiety and poorer well-being upon discharge. Factor 2 was not predictive of outcome. CONCLUSIONS: Emotional rigidity appears to be a latent construct that negatively impacts remission rates from anxiety. Limitations of the present study include its retrospective design, and inefficient methods of assessing emotional rigidity.

Treatment outcomes for inpatients with obsessive-compulsive personality disorder: An open comparison trial.

BACKGROUND: The current case-control study compared rates of clinically significant and reliable change in psychopathology and global functioning, prevalence of clinical deterioration, and rates of symptom remission among adult patients with obsessive compulsive personality disorder OCPD (n=52) and well-matched inpatients with any other personality disorder (n=56) and no personality disorder (n=53). METHODS: Propensity score matching (PSM) was utilized to select patients matched on specific criteria present in the OCPD group. Multivariate analysis of variance models measured differences in admission functioning and RCI change across depression and anxiety severity, emotion dysregulation and suicidal ideation. RESULTS: Patients diagnosed with OCPD admit to treatment with higher rates of depression, anxiety, difficulty with emotion regulation and non-acceptance of emotional experience than inpatient controls. Furthermore, OCPD patients respond to treatment at a similar rate to inpatient controls, but experience lower rates of anxiety remission upon discharge. Post-hoc analyses indicate individuals meeting stubbornness and rigidity (OCPD Criteria 8) were nine times more likely to report moderate to severe anxiety at point of discharge. LIMITATIONS: Limitations include a predominantly Caucasian, inpatient sample, use of self-report measures and a non-manualized treatment approach. CONCLUSIONS: Overall, OCPD inpatients benefit from an intensive multimodal psychiatric treatment, but experience more anxiety than non-PD patients upon discharge.

Leaf processing behaviour in Atta leafcutter ants: 90% of leaf cutting takes place inside the nest, and ants select pieces that require less cutting.

Leafcutter ants cut trimmings from plants, carry them to their underground nests and cut them into smaller pieces before inoculating them with a fungus that serves as a primary food source for the colony. Cutting is energetically costly, so the amount of cutting is important in understanding foraging energetics. Estimates of the cutting density, metres of cutting per square metre of leaf, were made from samples of transported leaf cuttings and of fungal substrate from field colonies of Atta cephalotes and Atta colombica. To investigate cutting inside the nest, we made leaf-processing observations of our laboratory colony, A. cephalotes. We did not observe the commonly reported reduction of the leaf fragments into a pulp, which would greatly increase the energy cost of processing. Video clips of processing behaviours, including behaviours that have not previously been described, are linked. An estimated 2.9 (±0.3) km of cutting with mandibles was required to reduce a square metre of leaf to fungal substrate. Only about 12% (±1%) of this cutting took place outside of the nest. The cutting density and energy cost is lower for leaf material with higher ratios of perimeter to area, so we tested for, and found that the laboratory ants had a preference for leaves that were pre-cut into smaller pieces. Estimates suggest that the energy required to transport and cut up the leaf material is comparable to the metabolic energy available from the fungus grown on the leaves, and so conservation of energy is likely to be a particularly strong selective pressure for leafcutter ants.

Attachment insecurity and obsessive-compulsive personality disorder among inpatients with serious mental illness.

BACKGROUND: Obsessive-compulsive personality disorder (OCPD) is characterized by traits such as extreme rigidity, perfectionism, and controlling behavior, all of which have a negative impact on interpersonal functioning. Attachment theory provides a useful framework to elucidate the interpersonal dysfunction characteristic of OCPD; yet, there is a dearth of attachment research on OCPD in the context of severe mental illness. METHODS: Attachment security and personality disorders were assessed in adult inpatients with severe mental illness. Propensity Score Matching (PSM) was used to match OCPD and control subjects on age, gender, number of psychiatric disorders, and number of criteria endorsed for borderline personality disorder. RESULTS: Consistent with hypotheses, the OCPD group (n=61) showed greater attachment avoidance than controls (n=61), and the avoidance was manifested in a predominance of the most insecure attachment style, fearful attachment. Correlations between attachment anxiety/avoidance with specific OCPD diagnostic criteria revealed that attachment avoidance was correlated with four of eight OCPD criteria across the full sample. Within the subset of OCPD patients, attachment avoidance was significantly correlated with OCPD criterion 3 (is excessively devoted to work and productivity to the exclusion of leisure activities and friendships). LIMITATIONS: The use of self-report measure of attachment and the high burden of illness in the SMI population may not generalize to interview based assessment or outpatients, respectively. CONCLUSIONS: Findings attest to the severity of impairment in interpersonal functioning and attachment avoidance, in particular, is characteristic of OCPD patients. These results suggest that viable treatment targets include interpersonal functioning along with more classical features of OCPD such as perfectionism and obsessiveness in task performance.

Hepatocyte induced re-expression of E-cadherin in breast and prostate cancer cells increases chemoresistance.

Post-extravasation survival is a key rate-limiting step of metastasis; however, not much is known about the factors that enable survival of the metastatic cancer cell at the secondary site. Furthermore, metastatic nodules are often refractory to current therapies, necessitating the elucidation of molecular changes that affect the chemosensitivity of metastases. Drug resistance exhibited by tumor spheroids has been shown to be mediated by cell adhesion and can be abrogated by addition of E-cadherin blocking antibody. We have previously shown that hepatocyte coculture induces the re-expression of E-cadherin in breast and prostate cancer cells. In this study, we show that this E-cadherin re-expression confers a survival advantage, particularly in the liver microenvironment. E-cadherin re-expression in MDA-MB-231 breast cancer cells resulted in increased attachment to hepatocytes. This heterotypic adhesion between cancer cells and secondary organ parenchymal cells activated ERK MAP kinase, suggesting a functional pro-survival role for E-cadherin during metastatic colonization of the liver. In addition, breast cancer cells that re-expressed E-cadherin in hepatocyte coculture were more chemoresistant compared to 231-shEcad cells unable to re-express E-cadherin. Similar results were obtained in DU-145 prostate cancer cells induced to re-express E-cadherin in hepatocyte coculture or following chemical induction by the GnRH agonist buserelin or the EGFR inhibitor PD153035. These results suggest that E-cadherin re-expression and other molecular changes imparted by a partial mesenchymal to epithelial reverting transition at the secondary site increase post-extravasation survival of the metastatic cancer cell and may help to elucidate why chemotherapy commonly fails to treat metastatic breast cancer.

Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition.

BACKGROUND: Epithelial to mesenchymal transition (EMT), implicated as a mechanism for tumor dissemination, is marked by loss of E-cadherin, disruption of cell adhesion, and induction of cell motility and invasion. In most intraductal breast carcinomas E-cadherin is regulated epigenetically via methylation of the promoter. E-cadherin expression is therefore dynamic and open to modulation by the microenvironment. In addition, it has been observed that metastatic foci commonly appear more differentiated than the primary tumor, suggesting that cancer cells may further undergo a mesenchymal to epithelial reverting transition (MErT) in the secondary organ environment following the EMT that allows for escape. RESULTS: We first examined E-cadherin expression in primary breast tumors and their corresponding metastases to liver, lung and brain and discovered that 62% (10/16) of cases showed increased E-cadherin expression in the metastases compared to the primaries. These observations led to the question of whether the positive metastatic foci arose from expansion of E-cadherin-positive cells or from MErT of originally E-cadherin-negative disseminated cells. Thus, we aimed to determine whether it was possible for the mesenchymal-like MDA-MB-231 breast cancer cells to undergo an MErT through the re-expression of E-cadherin, either through exogenous introduction or induction by the microenvironment. Ectopic expression of full-length E-cadherin in MDA-MB-231 cells resulted in a morphological and functional reversion of the epithelial phenotype, with even just the cytosolic domain of E-cadherin yielding a partial phenotype. Introduction of MDA-MB-231 cells or primary explants into a secondary organ environment simulated by a hepatocyte coculture system induced E-cadherin re-expression through passive loss of methylation of the promoter. Furthermore, detection of E-cadherin-positive metastatic foci following the spontaneous metastasis of MDA-MB-231 cells injected into the mammary fat pad of mice suggests that this re-expression is functional. CONCLUSIONS: Our clinical observations and experimental data indicate that the secondary organ microenvironment can induce the re-expression of E-cadherin and consequently MErT. This phenotypic change is reflected in altered cell behavior and thus may be a critical step in cell survival at metastatic sites.

E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas.

Cancer metastasis follows a sequential series of events, and many of the critical steps are distinctly similar to EMT-like transformations that occur during normal embryonic development. A current area of focus is the similarities between how cancer cells interact with the ectopic parenchyma after metastatic spread, and secondary developmental MET events that occur in epithelial tissues that have re-assembled within the embryo from mesenchymal cells. Accumulating evidence suggests a critical role for these secondary events, termed mesenchymal-epithelial transitions (MET) in development and mesenchymal-epithelial reverting transitions (MErT) in cancer. In this situation, metastatic seed cancer cells may inertly become part of the ectopic tissue and therefore surmount the metastatic inefficiencies to which most disseminated cancer cells succumb. Just as a critical EMT event is the downregulation or silencing of E-cadherin, we discuss the role of E-cadherin in cancer-associated MErT at distant metastatic sites and speculate on the implications for the fate of micrometastases that undergo a transition to being E-cadherin positive.

Influence, information overload, and information technology in health care.

We investigate whether information technology (IT) can help physicians more efficiently acquire new knowledge in a clinical environment characterized by information overload. We combine analysis of data from a randomized trial with a theoretical model of the influence that IT has on the acquisition of new medical knowledge. Although the theoretical framework we develop is conventionally microeconomic, the model highlights the non-market and non-pecuniary influence activities that have been emphasized in the sociological literature on technology diffusion. We report three findings. First, empirical evidence and theoretical reasoning suggests that computer-based decision support will speed the diffusion of new medical knowledge when physicians are coping with information overload. Second, spillover effects will likely lead to "underinvestment" in this decision support technology. Third, alternative financing strategies common to new IT, such as the use of marketing dollars to pay for the decision support systems, may lead to undesirable outcomes if physician information overload is sufficiently severe and if there is significant ambiguity in how best to respond to the clinical issues identified by the computer. This is the first paper to analyze empirically and theoretically how computer-based decision support influences the acquisition of new knowledge by physicians.