Two roads to planet detection

One of the most exciting discoveries in astrophysics of the last last decade is of the sheer diversity of planetary systems. These include "hot Jupiters", giant planets so close to their host stars that they orbit once every few days; "Super-Earths", planets with sizes intermediate to those of Earth and Neptune, of which no analogs exist in our own solar system; multi-planet systems with planets smaller than Mars to larger than Jupiter; planets orbiting binary stars; free-floating planets flying through the emptiness of space without any star; even planets orbiting pulsars. Despite these remarkable discoveries, the field is still young, and there are many areas about which precious little is known. In particular, we don't know the planets orbiting Sun-like stars nearest to our own solar system, and we know very little about the compositions of extrasolar planets. This thesis provides developments in those directions, through two instrumentation projects.

The first chapter of this thesis concerns detecting planets in the Solar neighborhood using precision stellar radial velocities, also known as the Doppler technique. We present an analysis determining the most efficient way to detect planets considering factors such as spectral type, wavelengths of observation, spectrograph resolution, observing time, and instrumental sensitivity. We show that G and K dwarfs observed at 400-600 nm are the best targets for surveys complete down to a given planet mass and out to a specified orbital period. Overall we find that M dwarfs observed at 700-800 nm are the best targets for habitable-zone planets, particularly when including the effects of systematic noise floors caused by instrumental imperfections. Somewhat surprisingly, we demonstrate that a modestly sized observatory, with a dedicated observing program, is up to the task of discovering such planets.

We present just such an observatory in the second chapter, called the "MINiature Exoplanet Radial Velocity Array," or MINERVA. We describe the design, which uses a novel multi-aperture approach to increase stability and performance through lower system etendue, as well as keeping costs and time to deployment down. We present calculations of the expected planet yield, and data showing the system performance from our testing and development of the system at Caltech's campus. We also present the motivation, design, and performance of a fiber coupling system for the array, critical for efficiently and reliably bringing light from the telescopes to the spectrograph. We finish by presenting the current status of MINERVA, operational at Mt. Hopkins observatory in Arizona.

The second part of this thesis concerns a very different method of planet detection, direct imaging, which involves discovery and characterization of planets by collecting and analyzing their light. Directly analyzing planetary light is the most promising way to study their atmospheres, formation histories, and compositions. Direct imaging is extremely challenging, as it requires a high performance adaptive optics system to unblur the point-spread function of the parent star through the atmosphere, a coronagraph to suppress stellar diffraction, and image post-processing to remove non-common path "speckle" aberrations that can overwhelm any planetary companions.

To this end, we present the "Stellar Double Coronagraph," or SDC, a flexible coronagraphic platform for use with the 200" Hale telescope. It has two focal and pupil planes, allowing for a number of different observing modes, including multiple vortex phase masks in series for improved contrast and inner working angle behind the obscured aperture of the telescope. We present the motivation, design, performance, and data reduction pipeline of the instrument. In the following chapter, we present some early science results, including the first image of a companion to the star delta Andromeda, which had been previously hypothesized but never seen.

A further chapter presents a wavefront control code developed for the instrument, using the technique of "speckle nulling," which can remove optical aberrations from the system using the deformable mirror of the adaptive optics system. This code allows for improved contrast and inner working angles, and was written in a modular style so as to be portable to other high contrast imaging platforms. We present its performance on optical, near-infrared, and thermal infrared instruments on the Palomar and Keck telescopes, showing how it can improve contrasts by a factor of a few in less than ten iterations.

One of the large challenges in direct imaging is sensing and correcting the electric field in the focal plane to remove scattered light that can be much brighter than any planets. In the last chapter, we present a new method of focal-plane wavefront sensing, combining a coronagraph with a simple phase-shifting interferometer. We present its design and implementation on the Stellar Double Coronagraph, demonstrating its ability to create regions of high contrast by measuring and correcting for optical aberrations in the focal plane. Finally, we derive how it is possible to use the same hardware to distinguish companions from speckle errors using the principles of optical coherence. We present results observing the brown dwarf HD 49197b, demonstrating the ability to detect it despite it being buried in the speckle noise floor. We believe this is the first detection of a substellar companion using the coherence properties of light.

Modern Computational Chemistry Methods for Prediction of Ground- and Excited-State Properties in Open-Shell Systems

The main goal of the research presented in this work is to provide some important insights about computational modeling of open-shell species. Such projects are: the investigation of the size-extensivity error in Equation-of-Motion Coupled Cluster methods, the analysis of the Long-Range corrected scheme in predicting UV-Vis spectra of Cu(II) complexes with the 4-imidazole acetate and its ethylated derivative, and the exploration of the importance of choosing a proper basis set for the description of systems such as the lithium monoxide anion. The most significant findings of this research are: (i) The contribution of the left operator to the size-extensivity error of the CR-EOMCC(2,3) approach, (ii) The cause of d-d shifts when varying the range-separation parameter and the amount of the exact exchange arising from the imbalanced treatment of localized vs. delocalized orbitals via the "tuned" CAM-B3LYP* functional, (iii) The proper acidity trend of the first-row hydrides and their lithiated analogs that may be reversed if the basis sets are not correctly selected.

Representaciones sociales del trasplante de médula ósea, la quimioterapia y la cirugía oncológica en población general colombiana

Las representaciones sociales son una construcción de significados que las personas otorgan a un objeto en este caso el tratamiento oncológico. En el mundo, el cáncer es una enfermedad de alta prevalencia y sus tratamientos suelen generar numerosos efectos secundarios, pero a la vez es el recurso médico disponible para controlar la enfermedad. Este estudio cualitativo tuvo como objetivo analizar las representaciones sociales del tratamiento oncológico en población colombiana. Participaron voluntariamente 20 personas seleccionadas por conveniencia. Se realizaron entrevistas abiertas y se analizaron los resultados a través del análisis temático y se interpretaron con base en la teoría de las representaciones sociales. Los resultados indicaron que las personas representan el tratamiento oncológico convencional, predominantemente como quimioterapia, generadores de sufrimiento, miedo, alto costo físico, emocional y económico; así como una apuesta en la que la ganancia puede ser la prolongación de la vida o la remisión. Se discuten los resultados y sus implicaciones.

Design and synthesis of E3 ligase RNF5 inhibitors as innovative strategy to trigger mutant CFTR rescue in Cystic Fibrosis

In Cystic Fibrosis (CF) the deletion of phenylalanine 508 (F508del) in the CFTR anion channel is associated to misfolding and defective gating of the mutant protein. Among the known proteins involved in CFTR processing, one of the most promising drug target is the ubiquitin ligase RNF5, which normally promotes F508del-CFTR degradation. In this context, a small molecule RNF5 inhibitor is expected to chemically mimic a condition of RNF5 silencing, thus preventing mutant CFTR degradation and causing its stabilization and plasma membrane trafficking. Hence, by exploiting a virtual screening (VS) campaign, the hit compound inh-2 was discovered as the first-in-class inhibitor of RNF5. Evaluation of inh-2 efficacy on CFTR rescue showed that it efficiently decreases ubiquitination of mutant CFTR and increases chloride current in human primary bronchial epithelia. Based on the promising biological results obtained with inh-2, this thesis reports the structure-based design of potential RNF5 inhibitors having improved potency and efficacy. The optimization of general synthetic strategies gave access to a library of analogues of the 1,2,4-thiadiazol-5-ylidene inh-2 for SAR investigation. The new analogues were tested for their corrector activity in CFBE41o- cells by using the microfluorimetric HS-YFP assay as a primary screen. Then, the effect of putative RNF5 inhibitors on proliferation, apoptosis and the formation of autophagic vacuoles was evaluated. Some of the new analogs significantly increased the basal level of autophagy, reproducing RNF5 silencing effect in cell. Among them, one compound also displayed a greater rescue of the F508del-CFTR trafficking defect than inh-2. Our preliminary results suggest that the 1,2,4-thiadiazolylidene could be a suitable scaffold for the discovery of potential RNF5 inhibitors able to rescue mutant CFTRs. Biological tests are still ongoing to acquire in-depth knowledge about the mechanism of action and therapeutic relevance of this unprecedented pharmacological strategy.

Strategies to hijack MTs dysfunction in neurodegenerative tauopathies: Design and synthesis of novel CNS-disease-modifying tools

Neuronal microtubules assembly and dynamics are regulated by several proteins including (MT)-associated protein tau, whose aberrant hyperphosphorylation promotes its dissociation from MTs and its abnormal deposition into neurofibrillary tangles, a common neurotoxic hallmarks of neurodegenerative tauopathies. To date, no disease-modifying drugs have been approved to combat CNS tau-related diseases. The multifactorial etiology of these conditions represents one of the major limits in the discovery of effective therapeutic options. In addition, tau protein functions are orchestrated by diverse post-translational modifications among which phosphorylation mediated by PKs plays a leading role. In this context, conventional single-target therapies are often inadequate in restoring perturbed networks and fraught with adverse side-effects. This thesis reports two distinct approaches to hijack MT defects in neurons. The first is focused on the rational design and synthesis of first-in-class triple inhibitors of GSK-3β, FYN, and DYRK1A, three close-related PKs, which act as master regulators of aberrant tau hyperphosphorylation. A merged multi-target pharmacophore strategy was applied to simultaneously modulate all three targets and achieve a disease-modifying effect. Optimization of ARN25068 by a computationally and crystallographic driven SAR exploration, allowed to rationalize the key structural modifications to maintain a balanced potency against all three targets and develop a new generation of quite well-balanced analogs exhibiting improved physicochemical properties, a good in vitro ADME profile, and promising cell-based anti-tau phosphorylation activity. In Part II, MT-stabilizing compounds have been developed to compensate MT defects in tau-related pathologies. Intensive chemical effort has been devoted to scaling up BL-0884, identified as a promising MT-normalizing TPD, which exhibited favorable ADME-PK, including brain penetration, oral bioavailability, and brain pharmacodynamic activity. A suitable functionalization of the exposed hydroxyl moiety of BL-0884 was carried out to generate corresponding esters and amides possessing a wide range of applications as prodrugs and active targeting for cancer chemotherapy.

Inhibition and characterization of two-metal ion enzymes to treat cancer: dna polymerase Ƞ and topoisomerase II α

Chemotherapeutic drugs can in many ways disrupt the replication machinery triggering apoptosis in cancer cells: some act directly on DNA and others block the enzymes involved in preparing DNA for replication. Cisplatin-based drugs are common as first-line cancer chemotherapics. Another example is etoposide, a molecule that blocks topoisomerase II α leading to the inhibition of dsDNA replication. Despite their efficacy, cancer cells can respond to these treatments over time by overtaking their effects, leading to drug resistance. Chemoresistance events can be triggered by the action of enzymes like DNA polymerase ƞ (Pol η). This polymerase helps also to bypass drug-induced damage in cancer cells, allowing DNA replication and cancer cells proliferation even when cisplatin-based chemotherapeutic drugs are in use. Pol ƞ is a promising drug discovery target, whose inhibition would help in overcoming of drug resistance. This study aims to identify a potent and selective Pol ƞ inhibitor able to improve the efficacy of platinum-based chemotherapeutic drugs. We report the discovery of compound 64 (ARN24964), after an extensive SAR reporting 35 analogs. We evaluated compound 64 on four different cell lines. Interestingly, the molecule is a Pol η inhibitor able to act synergistically with cisplatin. Moreover, we also synthesized a prodrug form that allowed us to improve its stability and the bioavailability. This compound represents an advanced scaffold featuring good potency and DMPK properties. In addition to this central theme, this thesis also describes our efforts in developing and characterize a novel hybrid inhibitor/poison for the human topoisomerase II α enzyme. In particular, we performed specific assays to study the inhibiton of Topoisomesare II α and we evaluated compounds effect on three cancer cell lines. These studies allowed us to identify a compound that is able to inhibit the enzyme with a good pK and a good potency.

Characterization of in-gap electronic states in two-dimensional single crystal PEA2PbBr4 perovskite for X-ray detection

Hybrid Organic-Inorganic Halide Perovskites (HOIPs) include a large class of materials described with the general formula ABX3, where A is an organic cation, B an inorganic cation and X an halide anion. HOIPs show excellent optoelectronic characteristics such as tunable band gap, high adsorption coefficient and great mobility life-time. A subclass of these materials, the so-called two- dimensional (2D) layered HOIPs, have emerged as potential alternatives to traditional 3D analogs to enhance the stability and increase performance of perovskite devices, with particular regard in the area of ionizing radiation detectors, where these materials have reached truly remarkable milestones. One of the key challenges for future development of efficient and stable 2D perovskite X-ray detector is a complete understanding of the nature of defects that lead to the formation of deep states. Deep states act as non-radiative recombination centers for charge carriers and are one of the factors that most hinder the development of efficient 2D HOIPs-based X-ray detectors. In this work, deep states in PEA2PbBr4 were studied through Photo-Induced Current Transient Spectroscopy (PICTS), a highly sensitive spectroscopic technique capable of detecting the presence of deep states in highly resistive ohmic materials, and characterizing their activation energy, capture cross section and, under stringent conditions, the concentration of these states. The evolution of deep states in PEA 2 PbBr 4 was evaluated after exposure of the material to high doses of ionizing radiation and during aging (one year). The data obtained allowed us to evaluate the contribution of ion migration in PEA2PbBr4. This work represents an important starting point for a better understanding of transport and recombination phenomena in 2D perovskites. To date, the PICTS technique applied to 2D perovskites has not yet been reported in the scientific literature.