Single-conformation spectroscopy of hydrogen bonding networks: Solvation, synthetic foldamers, and neurodegenerative diseases

The hydrogen bond is one of the most important interactions in natural processes ranging from protein folding to chemical reactions. Two complementary methodologies are applied to understanding this important interaction: top-down and bottom-up. Top-down methods use large molecules, such as proteins, revealing secondary structure information. Bottom-up experiments are performed on small molecules, utilizing high-resolution spectroscopy to reveal underlying quantum mechanical effects. The complexity gap is formed between these two experimental regimes; between large and small molecules; between bulk and individual solvent molecules; between classical mechanics calculations and quantum chemical calculations. This dissertation will focus on the application of gas phase, single-conformation ultraviolet (UV) and infrared (IR) spectroscopies to the study of molecules and clusters in the size and solvation complexity gap, with the goal of bridging the gulf between the two experimental approaches. Single-conformation spectroscopy is perfectly suited to study solvation. Solvent molecules, in many instances water, can be frozen onto the solute in a stepwise manner. Here, we solvate a prototypical flexible bichromophore—1,2-diphenoxyethane (DPOE)—by stepwise addition of water molecules. Single-conformation spectroscopy reveals both the structural perturbations associated with water molecule addition and their effect on DPOE’s pair of closely spaced excited electronic states. These experimental studies provide excellent insight into solvent effects on vibronic and excitonic coupling, and can be used to further develop the models used to describe such processes. Similarly, single-conformation spectroscopy can reveal the effects of conformational flexibility on the innate conformational preferences and hydrogen bonding motifs in peptides. Results obtained from a study of a cyclically constrained γ peptide, γACHC, reveal that increased conformational flexibility can be controlled by synthetic chemists in order to direct folding into pre-programmed secondary structures and that these structures are stabilized with intramolecular rather than intermolecular hydrogen bonds. This theme of conformational flexibility is continued in studies of glutamine containing peptides. Glutamine—with its flexible, hydrogen bond forming sidechain—is intimately involved with neurodegenerative diseases such as Huntington’s disease. Single-conformation studies help reveal the delicate interplay between three different types of hydrogen bonds within the molecule: backbone-backbone, sidechain-backbone, and sidechain-sidechain hydrogen bonds. The importance of these competing hydrogen bonds on the conformational preferences will be discussed both locally and within the larger context of disease pathogenesis

Dark Matter and the CACTUS Gamma-Ray Excess from Draco

The CACTUS atmospheric Cherenkov telescope collaboration recently reported a gamma-ray excess from the Draco dwarf spheroidal galaxy. Draco features a very low gas content and a large mass-to-light ratio, suggesting as a possible explanation annihilation of weakly interacting massive particles (WIMPs) in the Draco dark-matter halo. We show that with improved angular resolution, future measurements can determine whether the halo is cored or cuspy, as well as its scale radius. We find the relevant WIMP masses and annihilation cross sections and show that supersymmetric models can account for the required gamma-ray flux. The annihilation cross section range is found to be not compatible with a standard thermal relic dark-matter production. We compute for these supersymmetric models the resulting Draco gamma-ray flux in the GLAST energy range and the rates for direct neutralino detection and for the flux of neutrinos from neutralino annihilation in the Sun. We also discuss the possibility that the bulk of the signal detected by CACTUS comes from direct WIMP annihilation to two photons and point out that a decaying-dark-matter scenario for Draco is not compatible with the gamma-ray flux from the Galactic center and in the diffuse gamma-ray background.Comment: 24 pages, 10 figures; version accepted for publication in JCA

The European Photon Imaging Camera on XMM-Newton: The MOS Cameras

The EPIC focal plane imaging spectrometers on XMM-Newton use CCDs to record the images and spectra of celestial X-ray sources focused by the three X-ray mirrors. There is one camera at the focus of each mirror; two of the cameras contain seven MOS CCDs, while the third uses twelve PN CCDs, defining a circular field of view of 30 arcmin diameter in each case. The CCDs were specially developed for EPIC, and combine high quality imaging with spectral resolution close to the Fano limit. A filter wheel carrying three kinds of X-ray transparent light blocking filter, a fully closed, and a fully open position, is fitted to each EPIC instrument. The CCDs are cooled passively and are under full closed loop thermal control. A radio-active source is fitted for internal calibration. Data are processed on-board to save telemetry by removing cosmic ray tracks, and generating X-ray event files; a variety of different instrument modes are available to increase the dynamic range of the instrument and to enable fast timing. The instruments were calibrated using laboratory X-ray beams, and synchrotron generated monochromatic X-ray beams before launch; in-orbit calibration makes use of a variety of celestial X-ray targets. The current calibration is better than 10% over the entire energy range of 0.2 to 10 keV. All three instruments survived launch and are performing nominally in orbit. In particular full field-of-view coverage is available, all electronic modes work, and the energy resolution is close to pre-launch values. Radiation damage is well within pre-launch predictions and does not yet impact on the energy resolution. The scientific results from EPIC amply fulfil pre-launch expectations.Comment: 9 pages, 11 figures, accepted for publication in the A&A Special Issue on XMM-Newto

Optical study of orbital excitations in transition-metal oxides

The orbital excitations of a series of transition-metal compounds are studied by means of optical spectroscopy. Our aim was to identify signatures of collective orbital excitations by comparison with experimental and theoretical results for predominantly local crystal-field excitations. To this end, we have studied TiOCl, RTiO3 (R=La, Sm, Y), LaMnO3, Y2BaNiO5, CaCu2O3, and K4Cu4OCl10, ranging from early to late transition-metal ions, from t_2g to e_g systems, and including systems in which the exchange coupling is predominantly three-dimensional, one-dimensional or zero-dimensional. With the exception of LaMnO3, we find orbital excitations in all compounds. We discuss the competition between orbital fluctuations (for dominant exchange coupling) and crystal-field splitting (for dominant coupling to the lattice). Comparison of our experimental results with configuration-interaction cluster calculations in general yield good agreement, demonstrating that the coupling to the lattice is important for a quantitative description of the orbital excitations in these compounds. However, detailed theoretical predictions for the contribution of collective orbital modes to the optical conductivity (e.g., the line shape or the polarization dependence) are required to decide on a possible contribution of orbital fluctuations at low energies, in particular in case of the orbital excitations at about 0.25 eV in RTiO3. Further calculations are called for which take into account the exchange interactions between the orbitals and the coupling to the lattice on an equal footing.Comment: published version, discussion of TiOCl extended to low T, improved calculation of orbital excitation energies in TiOCl, figure 16 improved, references updated, 33 pages, 20 figure

Sex-specific aspects of phospholamban cardiomyopathy:The importance and prognostic value of low-voltage electrocardiograms

Background: A pathogenic variant in the gene encoding phospholamban (PLN), a protein that regulates calcium homeostasis of cardiomyocytes, causes PLN cardiomyopathy. It is characterized by a high arrhythmic burden and can progress to severe cardiomyopathy. Risk assessment guides implantable cardioverter-defibrillator therapy and benefits from personalization. Whether sex-specific differences in PLN cardiomyopathy exist is unknown. Objective: The purpose of this study was to improve the accuracy of PLN cardiomyopathy diagnosis and risk assessment by investigating sex-specific aspects. Methods: We analyzed a multicenter cohort of 933 patients (412 male, 521 female) with the PLN p.(Arg14del) pathogenic variant following up on a recently developed PLN risk model. Sex-specific differences in the incidence of risk model components were investigated: low-voltage electrocardiogram (ECG), premature ventricular contractions, negative T waves, and left ventricular ejection fraction. Results: Sustained ventricular arrhythmias (VAs) occurred in 77 males (18.7%) and 61 females (11.7%) (P =.004). Of the 933 cohort members, 287 (31%) had ≥1 low-voltage ECG during follow-up (180 females [63%], 107 males [37%]; P =.006). Female sex, age, age at clinical presentation, and proband status predicted low-voltage ECG during follow-up (area under the curve: 0.78). Sustained VA-free survival was lowest in males with low-voltage ECG (P <.001). Conclusion: Low-voltage ECGs predict sustained VA and are a component of the PLN risk model. Low-voltage ECGs are more common in females, yet prognostic value is greater in males. Future studies should determine the impact of this difference on the risk prediction of PLN cardiomyopathy and possibly other cardiomyopathies

PIN71 QUALITY OF LIFE (QOL) AND OTHER ENDPOINTS COMPARISON IN THE TREATMENT OF FACIAL LIPOATROPHY WITH INJECTION OF POLY-L-LACTIC ACID

Context: Longitudinal data on bone mineral density(BMD) in children and adolescents with Prader-Willi Syndrome (PWS) during long-term GH treatment are not available. Objective: This study aimed to determine effects of long-term GH treatment and puberty on BMD of total body (BMDTB), lumbar spine (BMDLS), and bone mineral apparent density of the lumbar spine (BMAD(LS)) in children with PWS. Design and Setting: This was a prospective longitudinal study of a Dutch PWS cohort. Participants: Seventy-seven children with PWS who remained prepubertal during GH treatment for 4 years and 64 children with PWS who received GH treatment for 9 years participated in the study. Intervention: The children received GH treatment, 1 mg/m(2)/day (congruent to 0.035 mg/kg/d). Main Outcome Measures: BMDTB, BMDLS, and BMAD(LS) was measured by using the same dual-energy x-ray absorptiometry machine for all annual measurements. Results: In the prepubertal group, BMDTB standard deviation score (SDS) and BMDLSSDS significantly increased during 4 years of GH treatment whereas BMAD(LS)SDS remained stable. During adolescence, BMDTBSDS and BMAD(LS)SDS decreased significantly, in girls from the age of 11 years and in boys from the ages of 14 and 16 years, respectively, but all BMD parameters remained within the normal range. Higher Tanner stages tended to be associated with lower BMDTBSDS (P = .083) and a significantly lowerBMAD(LS)SDS (P = .016). After 9 years of GH treatment, lean body mass SDS was the most powerful predictor of BMDTBSDS and BMDLSSDS in adolescents with PWS. Conclusions: This long-term GH study demonstrates that BMDTB, BMDLS, and BMAD(LS) remain stable in prepubertal children with PWS but decreases during adolescence, parallel to incomplete pubertal development. Based on our findings, clinicians should start sex hormone therapy from the age of 11 years in girls and 14 years in boys unless there is a normal progression of puberty

Analysing the European Union's responses to organized crime through different securitization lenses

In the past 30 years, organized crime (OC) has shifted from being an issue of little, or no concern, to being considered one of the key security threats facing the European Union (EU), the economic and political fabric of its society and its citizens. The purpose of this article is to understand how OC has come to be understood as one of the major security threats in the EU, by applying different lenses of Securitization Theory (ST). More specifically, the research question guiding this article is whether applying different ST approaches can lead us to draw differing conclusions as to whether OC has been successfully securitized in the EU. Building on the recent literature that argues that this theoretical framework has branched out into different approaches, this article wishes to contrast two alternative views of how a security problem comes into being, in order to verify whether different approaches can lead to diverging conclusions regarding the same phenomenon. The purpose of this exercise is to contribute to the further development of ST by pointing out that the choice in approach bears direct consequences on reaching a conclusion regarding the successful character of a securitization process. Starting from a reflection on ST, the article proceeds with applying a “linguistic approach” to the case study, which it then contrasts with a “sociological approach”. The article proposes that although the application of a “linguistic approach” seems to indicate that OC has become securitized in the EU, it also overlooks a number of elements, which the “sociological approach” renders visible and which lead us to refute the initial conclusion

Rationale and design of the PHOspholamban RElated CArdiomyopathy intervention STudy (i-PHORECAST)

Background: The p.Arg14del (c.40_42delAGA) phospholamban (PLN) pathogenic variant is a founder mutation that causes dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Carriers are at increased risk of malignant ventricular arrhythmias and heart failure, which has been ascribed to cardiac fibrosis. Importantly, cardiac fibrosis appears to be an early feature of the disease, occurring in many presymptomatic carriers before the onset of overt disease. As with most monogenic cardiomyopathies, no evidence-based treatment is available for presymptomatic carriers. Aims: The PHOspholamban RElated CArdiomyopathy intervention STudy (iPHORECAST) is designed to demonstrate that pre-emptive treatment of presymptomatic PLN p.Arg14del carriers using eplerenone, a mineralocorticoid receptor antagonist with established antifibrotic effects, can reduce disease progression and postpone the onset of overt disease. Methods: iPHORECAST has a multicentre, prospective, randomised, open-label, blinded endpoint (PROBE) design. Presymptomatic PLN p.Arg14del carriers are randomised to receive either 50 mg eplerenone once daily or no treatment. The primary endpoint of the study is a multiparametric assessment of disease progression including cardiac magnetic resonance parameters (left and right ventricular volumes, systolic function and fibrosis), electrocardiographic parameters (QRS voltage, ventricular ectopy), signs and/or symptoms related to DCM and ACM, and cardiovascular death. The follow-up duration is set at 3 years. Baseline results: A total of 84 presymptomatic PLN p.Arg14del carriers (n = 42 per group) were included. By design, at baseline, all participants were in New York Heart Association (NHYA) class I and had a left ventricular ejection fraction > 45% and < 2500 ventricular premature contractions during 24-hour Holter monitoring. There were no statistically significant differences between the two groups in any of the baseline characteristics. The study is currently well underway, with the last participants expected to finish in 2021. Conclusion: iPHORECAST is a multicentre, prospective randomised controlled trial designed to address whether pre-emptive treatment of PLN p.Arg14del carriers with eplerenone can prevent or delay the onset of cardiomyopathy. iPHORECAST has been registered in the clinicaltrials.gov-register (number: NCT01857856)