Higher-order molecular properties and excitation energies in single-reference and multireference coupled-cluster theory

Coupled-cluster (CC) theory is one of the most successful approaches in high-accuracy quantum chemistry. The present thesis makes a number of contributions to the determination of molecular properties and excitation energies within the CC framework. The multireference CC (MRCC) method proposed by Mukherjee and coworkers (Mk-MRCC) has been benchmarked within the singles and doubles approximation (Mk-MRCCSD) for molecular equilibrium structures. It is demonstrated that Mk-MRCCSD yields reliable results for multireference cases where single-reference CC methods fail. At the same time, the present work also illustrates that Mk-MRCC still suffers from a number of theoretical problems and sometimes gives rise to results of unsatisfactory accuracy. To determine polarizability tensors and excitation spectra in the MRCC framework, the Mk-MRCC linear-response function has been derived together with the corresponding linear-response equations. Pilot applications show that Mk-MRCC linear-response theory suffers from a severe problem when applied to the calculation of dynamic properties and excitation energies: The Mk-MRCC sufficiency conditions give rise to a redundancy in the Mk-MRCC Jacobian matrix, which entails an artificial splitting of certain excited states. This finding has established a new paradigm in MRCC theory, namely that a convincing method should not only yield accurate energies, but ought to allow for the reliable calculation of dynamic properties as well. In the context of single-reference CC theory, an analytic expression for the dipole Hessian matrix, a third-order quantity relevant to infrared spectroscopy, has been derived and implemented within the CC singles and doubles approximation. The advantages of analytic derivatives over numerical differentiation schemes are demonstrated in some pilot applications.

Functional, structural and molecular plasticity of mammalian skeletal muscle in response to exercise stimuli

Biological systems have acquired effective adaptive strategies to cope with physiological challenges and to maximize biochemical processes under imposed constraints. Striated muscle tissue demonstrates a remarkable malleability and can adjust its metabolic and contractile makeup in response to alterations in functional demands. Activity-dependent muscle plasticity therefore represents a unique model to investigate the regulatory machinery underlying phenotypic adaptations in a fully differentiated tissue. Adjustments in form and function of mammalian muscle have so far been characterized at a descriptive level, and several major themes have evolved. These imply that mechanical, metabolic and neuronal perturbations in recruited muscle groups relay to the specific processes being activated by the complex physiological stimulus of exercise. The important relationship between the phenotypic stimuli and consequent muscular modifications is reflected by coordinated differences at the transcript level that match structural and functional adjustments in the new training steady state. Permanent alterations of gene expression thus represent a major strategy for the integration of phenotypic stimuli into remodeling of muscle makeup. A unifying theory on the molecular mechanism that connects the single exercise stimulus to the multi-faceted adjustments made after the repeated impact of the muscular stress remains elusive. Recently, master switches have been recognized that sense and transduce the individual physical and chemical perturbations induced by physiological challenges via signaling cascades to downstream gene expression events. Molecular observations on signaling systems also extend the long-known evidence for desensitization of the muscle response to endurance exercise after the repeated impact of the stimulus that occurs with training. Integrative approaches involving the manipulation of single factors and the systematic monitoring of downstream effects at multiple levels would appear to be the ultimate method for pinpointing the mechanism of muscle remodeling. The identification of the basic relationships underlying the malleability of muscle tissue is likely to be of relevance for our understanding of compensatory processes in other tissues, species and organisms.

"The need obliged us" : culture as capacity during the Hurricane Stan emergency response. A case study from Tectitan, Huehuetenango, Guatemala

A major deficiency in disaster management plans is the assumption that pre-disaster civil-society does not have the capacity to respond effectively during crises. Following from this assumption a dominant emergency management strategy is to replace weak civil-society organizations with specialized disaster organizations that are often either military or Para-military and seek to centralize decision-making. Many criticisms have been made of this approach, but few specifically addresses disasters in the developing world. Disasters in the developing world present unique problems not seen in the developed world because they often occur in the context of compromised governments, and marginalized populations. In this context it is often community members themselves who possess the greatest capacity to respond to disasters. This paper focuses on the capacity of community groups to respond to disaster in a small town in rural Guatemala. Key informant interviews and ethnographic observations are used to reconstruct the community response to the disaster instigated by Hurricane Stan (2005) in the municipality of Tectitán in the Huehuetenango department. The interviews were analyzed using techniques adapted from grounded theory to construct a narrative of the events, and identify themes in the community’s disaster behavior. These themes are used to critique the emergency management plans advocated by the Guatemalan National Coordination for the Reduction of Disasters (CONRED). This paper argues that CONRED uncritically adopts emergency management strategies that do not account for the local realities in communities throughout Guatemala. The response in Tectitán was characterized by the formation of new organizations, whose actions and leadership structure were derived from “normal” or routine life. It was found that pre-existing social networks were resilient and easily re-oriented meet the novel needs of a crisis. New or emergent groups that formed during the disaster utilized social capital accrued by routine collective behavior, and employed organizational strategies derived from “normal” community relations. Based on the effectiveness of this response CONRED could improve its emergency planning on the local-level by utilizing the pre-existing community organizations rather than insisting that new disaster-specific organizations be formed.

Structural response and dynamics of fluid-structure-control interaction in wind turbine blades

Reducing the uncertainties related to blade dynamics by the improvement of the quality of numerical simulations of the fluid structure interaction process is a key for a breakthrough in wind-turbine technology. A fundamental step in that direction is the implementation of aeroelastic models capable of capturing the complex features of innovative prototype blades, so they can be tested at realistic full-scale conditions with a reasonable computational cost. We make use of a code based on a combination of two advanced numerical models implemented in a parallel HPC supercomputer platform: First, a model of the structural response of heterogeneous composite blades, based on a variation of the dimensional reduction technique proposed by Hodges and Yu. This technique has the capacity of reducing the geometrical complexity of the blade section into a stiffness matrix for an equivalent beam. The reduced 1-D strain energy is equivalent to the actual 3-D strain energy in an asymptotic sense, allowing accurate modeling of the blade structure as a 1-D finite-element problem. This substantially reduces the computational effort required to model the structural dynamics at each time step. Second, a novel aerodynamic model based on an advanced implementation of the BEM(Blade ElementMomentum) Theory; where all velocities and forces are re-projected through orthogonal matrices into the instantaneous deformed configuration to fully include the effects of large displacements and rotation of the airfoil sections into the computation of aerodynamic forces. This allows the aerodynamic model to take into account the effects of the complex flexo-torsional deformation that can be captured by the more sophisticated structural model mentioned above. In this thesis we have successfully developed a powerful computational tool for the aeroelastic analysis of wind-turbine blades. Due to the particular features mentioned above in terms of a full representation of the combined modes of deformation of the blade as a complex structural part and their effects on the aerodynamic loads, it constitutes a substantial advancement ahead the state-of-the-art aeroelastic models currently available, like the FAST-Aerodyn suite. In this thesis, we also include the results of several experiments on the NREL-5MW blade, which is widely accepted today as a benchmark blade, together with some modifications intended to explore the capacities of the new code in terms of capturing features on blade-dynamic behavior, which are normally overlooked by the existing aeroelastic models.

The self-administered 24-item geriatric pain measure (GPM-24-SA): psychometric properties in three European populations of community-dwelling older adults

OBJECTIVE: To explore the feasibility and psychometric properties of a self-administered version of the 24-item Geriatric Pain Measure (GPM-24-SA). DESIGN: Secondary analysis of baseline data from the Prevention in Older People-Assessment in Generalists' practices trial, an international multi-center study of a health-risk appraisal system. PARTICIPANTS: One thousand seventy-two community dwelling nondisabled older adults self-reporting pain from London, UK; Hamburg, Germany; and Solothurn, Switzerland. OUTCOME MEASURES: GPM-24-SA as part of a multidimensional Health Risk Appraisal Questionnaire including self-reported demographic and health-related information. RESULTS: Among the 1,072 subjects, 655 had complete GPM-24-SA data, 404 had 30% missing GPM-24-SA data. In psychometric analyses across the three European populations with complete GPM-24-SA data, the measure exhibited stable internal consistency, good convergent, divergent and discriminant validity, and produced stable pain measurements. However, factor analysis indicated differences in the GPM-24-SA across sites with discrepancies mainly related to items of a single subscale that failed to load appropriately. Analyses including imputation for subjects with response and uncertainty in factor structure, further refinement and psychometric evaluation of the GPM-24-SA is needed before it could be recommended for widespread use.

Dynamics of settling charged particles in turbulence : theory and experiments

It has been proposed that inertial clustering may lead to an increased collision rate of water droplets in clouds. Atmospheric clouds and electrosprays contain electrically charged particles embedded in turbulent flows, often under the influence of an externally imposed, approximately uniform gravitational or electric force. In this thesis, we present the investigation of charged inertial particles embedded in turbulence. We have developed a theoretical description for the dynamics of such systems of charged, sedimenting particles in turbulence, allowing radial distribution functions to be predicted for both monodisperse and bidisperse particle size distributions. The governing parameters are the particle Stokes number (particle inertial time scale relative to turbulence dissipation time scale), the Coulomb-turbulence parameter (ratio of Coulomb ’terminalar speed to turbulence dissipation velocity scale), and the settling parameter (the ratio of the gravitational terminal speed to turbulence dissipation velocity scale). For the monodispersion particles, The peak in the radial distribution function is well predicted by the balance between the particle terminal velocity under Coulomb repulsion and a time-averaged ’drift’ velocity obtained from the nonuniform sampling of fluid strain and rotation due to finite particle inertia. The theory is compared to measured radial distribution functions for water particles in homogeneous, isotropic air turbulence. The radial distribution functions are obtained from particle positions measured in three dimensions using digital holography. The measurements support the general theoretical expression, consisting of a power law increase in particle clustering due to particle response to dissipative turbulent eddies, modulated by an exponential electrostatic interaction term. Both terms are modified as a result of the gravitational diffusion-like term, and the role of ’gravity’ is explored by imposing a macroscopic uniform electric field to create an enhanced, effective gravity. The relation between the radial distribution functions and inward mean radial relative velocity is established for charged particles.

The STEREO/PLASTIC response to solar wind ions (Flight measurements and models)

The Plasma and Supra-Thermal Ion Composition (PLASTIC) instrument is one of four experiment packages on board of the two identical STEREO spacecraft A and B, which were successfully launched from Cape Canaveral on 26 October 2006. During the two years of the nominal STEREO mission, PLASTIC is providing us with the plasma characteristics of protons, alpha particles, and heavy ions. PLASTIC will also provide key diagnostic measurements in the form of the mass and charge state composition of heavy ions. Three measurements (E/qk, time of flight, ESSD) from the pulse height raw data are used to characterize the solar wind ions from the solar wind sector, and part of the suprathermal particles from the wide-angle partition with respect to mass, atomic number and charge state. In this paper, we present a new method for flight data analysis based on simulations of the PLASTIC response to solar wind ions. We present the response of the entrance system / energy analyzer in an analytical form. Based on stopping power theory, we use an analytical expression for the energy loss of the ions when they pass through a thin carbon foil. This allows us to model analytically the response of the time of flight mass spectrometer to solar wind ions. Thus we present a new version of the analytical response of the solid state detectors to solar wind ions. Various important parameters needed for our models were derived, based on calibration data and on the first flight measurements obtained from STEREO-A. We used information from each measured event that is registered in full resolution in the Pulse Height Analysis words and we derived a new algorithm for the analysis of both existing and future data sets of a similar nature which was tested and works well. This algorithm allows us to obtain, for each measured event, the mass, atomic number and charge state in the correct physical units. Finally, an important criterion was developed for filtering our Fe raw flight data set from the pulse height data without discriminating charge states.

Beyond Kantianism - Response to Critiques

I am flattered and privileged to have received four such astute critiques of my work from an international cast. I will reflect at length about many of their points in future work but to respond fully would require a very long article and so I will highlight some of the more salient issues. The authors share misgivings about my commitment to a realist version of governmentality theory so I will try to articulate a bit more clearly how it is different from two major alternative perspectives highlighted by the authors: what I term a `discursive` governmentality perspective (Stenson 2005), and the neo-Marxist regulationist school of political economy. However, deeper normative questions are raised, for example by Wendy Larner, about what it means to be progressive or critical within the broad terrain of liberalism (which can include neo-liberals and neo-conservatives) in the wake of the collapse of communism and much of the power of western labour movements, the rise of the new emancipatory and environmental social movements and varieties of religious fundamentalism. As social scientists and university intellectuals we usually argue that our work differs from journalistic reportage or ideological polemics that gather supportive evidence through selective fact gathering. This is because we dig beneath the flux of events and surface appearances and debates to uncover the deeper structures of thought and social relations that shape our experiences and the flow of events. And we also engage with contrary evidence that troubles our truth claims. This is the work of theory. I accept that theory plays a vital role but argue for a more grounded approach rooted in empirical research using a variety of methods and data sources. Hence I adopt a more cautious approach to conceptions of the `deeper structures` we uncover. At best we can only know them through provisional heuristic modelling and it is best not to reify them.

Exploring the validity and reliability of a questionnaire for evaluating virtual patient design with a special emphasis on fostering clinical reasoning

Background: The design of Virtual Patients (VPs) is essential. So far there are no validated evaluation instruments for VP design published. Summary of work: We examined three sources of validity evidence of an instrument to be filled out by students aimed at measuring the quality of VPs with a special emphasis on fostering clinical reasoning: (1) Content was examined based on theory of clinical reasoning and an international VP expert team. (2) Response process was explored in think aloud pilot studies with students and content analysis of free text questions accompanying each item of the instrument. (3) Internal structure was assessed by confirmatory factor analysis (CFA) using 2547 student evaluations and reliability was examined utilizing generalizability analysis. Summary of results: Content analysis was supported by theory underlying Gruppen and Frohna’s clinical reasoning model on which the instrument is based and an international VP expert team. The pilot study and analysis of free text comments supported the validity of the instrument. The CFA indicated that a three factor model comprising 6 items showed a good fit with the data. Alpha coefficients per factor were 0,74 - 0,82. The findings of the generalizability studies indicated that 40-200 student responses are needed in order to obtain reliable data on one VP. Conclusions: The described instrument has the potential to provide faculty with reliable and valid information about VP design. Take-home messages: We present a short instrument which can be of help in evaluating the design of VPs.

Progenitor cells as remote "bioreactors": Neuroprotection via modulation of the systemic inflammatory response.

Acute central nervous system (CNS) injuries such as spinal cord injury, traumatic brain injury, autoimmune encephalomyelitis, and ischemic stroke are associated with significant morbidity, mortality, and health care costs worldwide. Preliminary research has shown potential neuroprotection associated with adult tissue derived stem/progenitor cell based therapies. While initial research indicated that engraftment and transdifferentiation into neural cells could explain the observed benefit, the exact mechanism remains controversial. A second hypothesis details localized stem/progenitor cell engraftment with alteration of the loco-regional milieu; however, the limited rate of cell engraftment makes this theory less likely. There is a growing amount of preclinical data supporting the idea that, after intravenous injection, stem/progenitor cells interact with immunologic cells located in organ systems distant to the CNS, thereby altering the systemic immunologic/inflammatory response. Such distant cell "bioreactors" could modulate the observed post-injury pro-inflammatory environment and lead to neuroprotection. In this review, we discuss the current literature detailing the above mechanisms of action for adult stem/progenitor cell based therapies in the CNS.

THE ASSOCIATION BETWEEN CANCER-RELATED-FATIGUE, RESPONSE TO FATIGUE TREATMENT, AND CYTOKINES AND THEIR RECEPTORS, IN PATIENTS WITH ADVANCED CANCER

Background: Inflammation is implicated in the development of cancer related fatigue (CRF). However there is limited literature on the mediators of inflammation (namely), cytokines and their receptors, associated with clinically significant fatigue and response to treatment. Methods: We reviewed 37 advanced cancer patients with fatigue (≥4/10), who participated in two Randomized Controlled Trials, of anti-inflammatory agents (Thalidomide and Dexamethasone) for CRF. Responders showed improvement in FACIT-F subscale at the end of study (Day 15). Baseline patient characteristics and symptoms were assessed by FACIT-F, ESAS; serum cytokines [IL-1β and receptor antagonist (IL-1RA), IL-6, IL-6R, TNF-α and sTNF-R1 and R2, IL-8, IL-10, IL-17] levels measured by Luminex. Data were analyzed using principal component analysis (PCA) [reporting cumulative variance (variance) for the first four components] to determine their association with fatigue and response to treatment. Results: Females were 54%. Mean (SD) was as follows for age, 61(14); baseline FACIT (F) scores, 21.4(8.6); ESAS Fatigue item, 6.5(1.9); and FACIT-F change, 6.4(9.7); ESAS (fatigue) change, -2 (2.41). Baseline median in pg/mL for IL-6, TNF-α, IL-1β were 31.9; 18.9; 0.55, respectively. Change in IL-6 negatively correlated with change in FACIT-F scores (p=0.02). Baseline CRF (FACIT-F score) was associated with IL-6, IL-6R and IL-17, Variance = 78% whereas IL-10, IL-1RA, TNF-α and IL-1β were associated with improvement of CRF, Variance=74%. Conversely, IL-6 and IL-8 were associated with no improvement or worsening of CRF, Variance= 93%. Conclusions: Change in IL-6 negatively correlated with change in FACIT-F scores. IL-6, IL-6R and IL-17 are associated with CRF while IL-6 and IL-8 were associated with no improvement of CRF. Further studies are warranted confirm our findings.

The adolescent response to pregnancy: Accepting the reality

The research literature on adolescent pregnancy indicates a relationship between early prenatal care and positive pregnancy outcomes, yet fewer than half of pregnant teenagers seek prenatal care in the first trimester of pregnancy. Although social support theory speculates that there should be a relationship between support and health outcomes, available studies do not reflect the processes by which pregnant adolescents use their social resources in making decisions about their pregnancies. This study describes the processes by which the adolescent comes to accept the reality of her pregnancy.^ Drawing from the social-psychological theories of illness behavior and symbolic interactionism, this study examines the symptom diagnosis and help seeking behavior of the pregnant adolescent. This approach describes how the adolescent interprets events and draws conclusions based on her social reality.^ Interviews were conducted with ten young women, aged 15-17, who had recently delivered a first child. Onset of prenatal care ranged from the third month to the seventh month. None were married, and all but two lived with a parent. All but one were currently in school. Initial unstructured interviews were attempted to construe the modes of expression of the young women regarding the event of pregnancy. Subsequent interviews elicited the processes of recognition and explanation of symptoms of pregnancy.^ Analysis revealed a consistent natural history in the subjects' experiences as they come to accept the reality of pregnancy. Symptom appraisal and definition involves noticing changes in themselves, and evaluating and attempting to find suitable explanations for these symptoms. Lay consultation from friends and family aids in identifying the symptoms and to receive suggestions for treatment. It is at this point that prenatal care is usually initiated. Finally the young women describe the integration of pregnancy into their belief systems. ^

Effects of variable Gs expression on $\beta\sb2$-adrenergic receptor stimulated adenylyl cyclase response

An exact knowledge of the kinetic nature of the interaction between the stimulatory G protein (G$\sb{\rm s}$) and the adenylyl cyclase catalytic unit (C) is essential for interpreting the effects of Gs mutations and expression levels on cellular response to a wide variety of hormones, drugs, and neurotransmitters. In particular, insight as to the association of these proteins could lead to progress in tumor biology where single spontaneous mutations in G proteins have been associated with the formation of tumors (118). The question this work attempts to answer is whether the adenylyl cyclase activation by epinephrine stimulated $\beta\sb2$-adrenergic receptors occurs via G$\sb{\rm s}$ proteins by a G$\sb{\rm s}$ to C shuttle or G$\sb{\rm s}$-C precoupled mechanism. The two forms of activation are distinguishable by the effect of G$\sb{\rm s}$ levels on epinephrine stimulated EC50 values for cyclase activation.^ We have made stable transfectants of S49 cyc$\sp-$ cells with the gene for the $\alpha$ protein of G$\sb{\rm s}$ $(\alpha\sb{\rm s})$ which is under the control of the mouse mammary tumor virus LTR promoter (110). Expression of G$\sb{\rm s}\alpha$ was then controlled by incubation of the cells for various times with 5 $\mu$M dexamethasone. Expression of G$\sb{\rm s}\alpha$ led to the appearance of GTP shifts in the competitive binding of epinephrine with $\sp{125}$ICYP to the $\beta$-adrenergic receptors and to agonist dependent adenylyl cyclase activity. High expression of G$\sb{\rm s}\alpha$ resulted in lower EC50's for the adenylyl cyclase activity in response to epinephrine than did low expression. By kinetic modelling, this result is consistent with the existence of a shuttle mechanism for adenylyl cyclase activation by hormones.^ One item of concern that remains to be addressed is the extent to which activation of adenylyl cyclase occurs by a "pure" shuttle mechanism. Kinetic and biochemical experiments by other investigators have revealed that adenylyl cyclase activation, by hormones, may occur via a Gs-C precoupled mechanism (80, 94, 97). Activation of adenylyl cyclase, therefore, probably does not occur by either a pure "'Shuttle" or "Gs-C Precoupled" mechanism, but rather by a "Hybrid" mechanism. The extent to which either the shuttle or precoupled mechanism contributes to hormone stimulated adenylyl cyclase activity is the subject of on-going research. ^

A quality of life subscale for terminally ill cancer patients

A subscale was developed to assess the quality of life of cancer patients with a life expectancy of six months or less. Phase I of this study identified the major concerns of 74 terminally ill cancer patients (19 with breast cancer, 19 with lung cancer, 18 with colorectal cancer, 9 with renal cell cancer, 9 with prostate cancer), 39 family caregivers, and 20 health care professionals. Patients interviewed were being treated at the University of Texas M. D. Anderson Cancer Center or at the Hospice at the Texas Medical Center in Houston. In Phase II, 120 patients (30 with breast cancer, 30 with lung cancer, 30 with colorectal cancer, 15 with prostate cancer, and 15 with renal cell cancer) rated the importance of these concerns for quality of life. Items retained for the subscale were rated as "extremely important" or "very important" by at least 60% of the sample and were reported as being applicable by at least two-thirds of the sample. The 61 concerns that were identified were formatted as a questionnaire for Phase III. In Phase III, 356 patients (89 with breast cancer, 88 with lung cancer, 88 with colorectal cancer, 44 with prostate cancer, and 47 with renal cell cancer) were interviewed to determine the subscale's reliability and sensitivity to change in clinical status. Both factor analysis and item response theory supported the inclusion of the same 35 items for the subscale. Internal consistency reliability was moderate to high for the subscale's domains: spiritual (0.87), existential (0.76), medical care (0.68), symptoms (0.67), social/family (0.66), and emotional (0.61). Test-retest correlation coefficients also were high for the domains: social/family (0.86), emotional (0.83), medical care (0.83), spiritual (0.75), existential (0.75), and symptoms (0.81).^ In addition, concurrent validity was supported by the high correlation between the subscale's symptom domain and symptom items from the European Organization for Research and Treatment of Cancer (EORTC) scale (r = 0.74). Patients' functional status was assessed with the Eastern Cooperative Oncology Group (ECOG) Performance status rating. When ECOG categories were compared to subscale domains, patients who scored lower in functional status had lower scores in the spiritual, existential, social/family, and emotional domains. Patients who scored lower in physical well-being had higher scores in the symptom domain. Patient scores in the medical care domain were similar for each ECOG category. The results of this study support the subscale's use in assessing quality of life and the outcomes of palliative treatment for cancer patients in their last six months of life. ^