Doctor en Farmacología / Diversos estudios clínicos han revelado que las tiazolidinedionas, fármacos para el tratamiento de la diabetes de tipo 2 y resistencia a insulina, podrían reducir la morbimortalidad cardiovascular. Su mecanismo de acción es a través de la activación de los Receptores Activados por Proliferadores Peroxisomales (PPARs), los cuales son factores transcripcionales activados por ligandos. En el sistema cardiovascular, los PPARs se expresan de forma variable y juegan un importante papel en la regulación del metabolismo energético y en la respuesta inflamatoria. Durante diversos estados patológicos como por ejemplo en el infarto al miocardio, el tratamiento con tiazolidinedionas ha mostrado efectos cardioprotectores ya que reducen la hipertrofia y el área infartada y atenúan la respuesta inflamatoria cardiaca. Estos antecedentes sugieren un importante papel de PPARγ durante el remodelado cardiaco, proceso fisiopatológico que consiste en un cambio estructural y funcional del tejido, caracterizado por fibrosis, hipertrofia y pérdida progresiva de los cardiomiocitos. Se ha sugerido que la apoptosis es el principal mecanismo de muerte celular en el corazón pero últimamente se ha avanzado en los estudios de la participación de la autofagia o “muerte programada de tipo II”. Sin embargo, la autofagia se describió inicialmente como un proceso fisiológico clave para la sobrevida celular durante la privación de aminoácidos, diferenciación celular y desarrollo. Consiste en un proceso dinámico y programado que procede con el secuestro de proteínas citoplasmáticas y organelos enteros dentro de vacuolas de doble membrana, que posteriormente se fusionan con los lisosomas formando los autolisosomas. Todos estos elementos capturados en las vacuolas son degradados por proteasas lisosomales y removidos de la célula por exocitosis. Evidencias recientes han mostrado que los agonistas de PPARγ podrían inducir la autofagia en algunas líneas celulares. Sin embargo, aún no queda claro si la autofagia es realmente un proceso de muerte o un mecanismo de sobrevida celular. Dado que prácticamente se desconoce si la activación de PPARγ regula la autofagia cardiaca, en esta tesis se postuló como hipótesis que “El agonista farmacológico de PPARγ rosiglitazona induce la autofagia del cardiomiocito, protegiéndolo de la muerte”. Los objetivos específicos propuestos fueron: • Estudiar in vitro el efecto de agonistas farmacológicos de PPARα y/o PPARγ en la viabilidad del cardiomiocito de rata. • Determinar si rosiglitazona induce autofagia en el cardiomiocito y si ésta se relaciona con sobrevida celular. • Investigar si la estimulación con rosiglitazona afecta la viabilidad de cardiomiocitos expuestos a estrés nutricional, estrés hiperosmótico o a isquemia/reperfusión simulada. El modelo experimental utilizado fue cultivo primario de cardiomiocitos de ratas neonatas tratados con rosigllitazona en un rango creciente de concentraciones y de tiempo. La autofagia se evaluó mediante procesamiento de la proteína LC3 endógena, cambio en la distribución y degradación de la proteína GFP-LC3 en cardiomiocitos transducidos con el adenovirus GFP-LC3. Los resultados mostraron que PPARγ está presente en cardiomiocitos de ratas y que es transcripcionalmente activo, lo cual se demostró mediante un plasmidio reportero que contiene el elemento de respuesta para este factor transcripcional. Además, rosiglitazona estimuló temprana y progresivamente la autofagia en los cultivos primarios de cardiomiocitos, determinada por el procesamiento de la proteína endógena LC3-I, efecto similar al observado en repuesta al tratamiento con rapamicina. Rosiglitazona también incrementó la distribución punteada de LC3-GFP, sin embargo no disminuyó la fluorescencia de la proteína LC3-GFP en los cardiomiocitos transducidos con el adenovirus LC3-GFP. Por otra parte, rosiglitazona no modificó de forma significativa los niveles intracelulares de ATP y ni afectó la viabilidad basal del cardiomiocito. El tratamiento con gemfibrozilo, tampoco modificó su viabilidad. Para determinar si la inducción de autofagia tiene un efecto en la viabilidad del cardiomiocito, los cultivos celulares se expusieron a estrés mecánico por hiperosmolaridad y se midió la viabilidad. El estrés hiperosmótico indujo de manera rápida y potente la muerte de las células cardiacas. Sin embargo, rosiglitazona y gemfibrozilo no previnieron este efecto. La muerte de las células cardiacas inducida por el estrés hiperosmótico es mediante apoptosis, lo que se demostró la evaluación por citometría de flujo de la subpoblación G1 en células permeabilizadas y tratadas con yoduro de propidio y determinación de potencial mitocondrial. Rosiglitazona y gemfibrozilo no previnieron la apoptosis del cardiomiocito inducida por estrés hiperosmótico. Rosiglitazona tampoco bloqueó la muerte celular inducida por isquemia y reperfusión simulada. Finalmente, los resultados obtenidos con el desarrollo de esta tesis permiten concluir que rosiglitazona induce la autofagia del cardiomiocito pero que ésta es insuficiente para modificar la viabilidad celular / Clinical studies showed that thiazolidinediones, drugs used for type 2 diabetes and insulin resistance treatment, can reduce cardiovascular morbid and mortality. These compounds are highly specific ligands of peroxisome proliferator-activator receptor gamma (PPARγ), a nuclear hormone receptor superfamily member. PPARs are variably expressed in the cardiovascular system and play an important role in both energetic metabolism regulation and inflammation response. In myocardial infarct, treatment with thiazolidinediones has cardioprotective effects reducing cardiac hypertrophy, infarcted area and inflammatory response. These data suggest an important role of PPARγ during cardiac remodeling. Remodeling is a physiopathological alteration in heart structure and function characterized by cardiomyocytes fibrosis, hypertrophy and death. Apoptosis has been described as the main cardiac cell death mechanism. However, recent studies have also described the participation of autophagy, also known as type II programmed cell death. Autophagy was first described as an adaptative physiological process during amino acids starvation. It has also been described its participation in cellular differentiation and development. Autophagy consists in the sequestration of cytoplasm portions and organelles within double membrane vesicles, named autophagosomes. These vesicles were subsequently fused with lysosomes forming the autofagosomes. All elements captured in these vesicles are degraded by lysosomal proteases and removed by exocytosis. Recent evidence has shown that PPARγ agonists could induce autophagy in some cells lines. However, is not clear whether autophagy is a mechanism for cell survival or death. Based on these antecedents we postulated the following hypothesis: “The pharmacological PPARγ agonist, rosiglitazone, induces cardiomyocyte autophagy protecting them from cell death”. The specific aims were: • To study in vitro the effects of PPARα and PPARγ pharmacological agonists on neonatal rat cardiomyocytes. • To determine whether rosiglitazone induces autophagy in cardiomyocyte and whether this process is related with cell viability. • To investigate if the stimulation with rosiglitazone affects cardiomyocyte viability when exposed to nutritional stress, hyperosmotic stress and simulated ischemia/reperfusion. The experimental models were primary cultures of neonatal rat cardiomyocytes treated with rosiglitazone at different concentrations and times. Autophagy was evaluated by endogenous LC3-I processing, and by change in adenoviral expressing GFP-LC3 distribution and degradation. Results showed that PPARγ is expressed and is transcriptionally active in neonatal rat cardiomyocytes as determined by western blot and activity of PPAR reporter plasmid. Furthermore, rosiglitazone stimulated early and progressively cardiac autophagy as determined by endogenous LC3-I processing. This effect was similar to that induced by rapamycin. Rosiglitazone also increased the GFP-LC3 punctuated pattern, but without decreasing GFP-LC3 fluorescence. On the other hand, rosiglitazone neither affects ATP levels nor viability of cardiomyocytes. Gemfibrozil treatment, also did not affect cardiomyocyte viability. To determine whether autophagy affects cardiomyocyte viability, cultured cells were exposed to hyperosmotic stress in the presence or absence of rosiglitazone or gemfobrozil, and viability was measured. Hyperosmotic stress induced a rapid decrease in cardiomyocyte viability. Cardiomyocyte death was also achieved by simulated ischemia/reperfusiom. Neither rosiglitazone nor gemfibrozil prevented cardiomyocyte death induced by both procedures. Hyperosmotic stress-induced cell death was characterized as apoptosis, as determined by mitochondrial potential decay and DNA fragmentation visualized by sub G1 population in propidium iodide-treated cells followed flow cytometry. Both rosiglitazone and gemfibrozil did not prevent the hyperosmotic stress-induced apoptosis. Finally, these results allow us to conclude that rosiglitazone induces cardiomyocyte autophagy but this process does not affect cardiomyocyte viability

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Protein-protein interactions play an important role in nearly all processes of the living cells and the function of many proteins is dependent on their specific interactions with other biomolecules. A reliable tool to modulate these interactions would be invaluable for the development of molecules suitable for diagnostics, medicine, and biotechnology. In this work, we aimed to study the specificity of interactions in the model system of Interferon gamma receptor 1 (IFNgR1) and its natural ligand Interferon gamma (IFNg), important in innate immunity. We searched for mutations within the interferon receptor molecule IFNgR1 to modulate (increase as well as decrease) its affinity to IFNg by in silico analysis of the existing crystal structures of the complex between IFNgR1 and IFNg. We modeled amino acid substitutions and gauged how they influenced the interaction using empirical force field implemented in software FoldX. All selected promising IFNgR1 variants were expressed in Escherichia coli, purified to homogeneity, characterized, and kinetics of their interactions with IFNg was measured by Surface Plasmon Resonance (SPR). The first set of IFNgR1 variants included mutations on the interface of the IFNg/IFNgR1 complex. According to our SPR measurements, the affinity of most of these receptor...

Two types of experiments involving the Mossbauer atom as a dilute impurity in a host lattice are discussed. For a zero-phonon experiment with Fe⁵⁷ in Pt¹⁹⁵ at room temperature, the expected shift of the central Mossbauer peak is [symbol omitted]/3000. The minimum time required to experimentally determine this shift to within 10% is found to be 16 weeks of counting with a 5 millicurie source. For a one-phonon experiment with Fe⁵⁷ in Pt¹⁹⁵, the count rate due to resonance scattering is found to be 3.14 x 10⁻⁴/sec., and the count rate due to Rayleigh scattering 2.2 x l0⁻²/sec. The case of Fe⁵⁷ in Be⁹ is also discussed. An air trough Mossbauer shift spectrometer constructed to perform the zero-phonon experiment is described. Vibrations present in this apparatus, making it inadequate for experimental work, are discussed. / Science, Faculty of / Physics and Astronomy, Department of / Graduate

The differential cross section for direct radiative capture of protons by 0¹⁶ has been measured using ice targets of known thickness and 800 kev. protons. The differential cross section for the gamma ray transition to the first excited state in F¹⁷ was found to be (10.4 ± 1.3) x 10⁻⁻³² cm² per steradian at 90° to the incident proton beam direction. At the same energy, the ratio of the differential cross section at 90° for transitions to the ground state to that for transitions to the first excited state in F¹⁷ was found to be o.14 ± 0.03. The energy of the first excited state in F¹⁷ was determined by measuring the energy of the gamma ray from this level to the ground state. This method is difficult because of the presence of positron annihilation radiation of the same energy, within experimental errors, from the decay of F¹⁷. The first excited state energy was also measured by noting the difference between the capture gamma rays to this state and to the ground state. The energy of this level was found to be 0.50 ± 0.01 Mev. in agreement with the results of Marion and Bonner (55) and with earlier results obtained in this laboratory (Warren et. al., (54), An attempt to confirm that the source of the 873 kev. radiation from proton bombardment of natural oxide targets above 1.8 Mev. bombarding energy was the 0¹⁷(p, p',૪)0¹⁷ reaction, was made using separated 0¹⁶ and 0¹⁷ targets. The results were inconclusive due to the small percentage of oxygen that stuck to the targets and to the presence of several contaminants. / Science, Faculty of / Physics and Astronomy, Department of / Graduate

The efficiency of a 4" x 5" Nal(Tl) scintillation counter for detecting gamma-rays has been measured by a number of experimental techniques, and the results compared with the efficiencies predicted from total absorption cross sections. The experimental techniques involve coincidence measurements of the cascade gamma-rays from a Co-60 source (1.173 MeV and 1.333 MeV), and from the reaction B¹¹(pγγ)C¹² (4.43 MeV and 11.68 MeV). The Co-60 measurements also lead to knowledge of the absolute strength of the sources. For both cascades it was necessary to know the angular correlations between the radiations; for the reaction B¹¹ (pγγ)C¹² a separate investigation of this correlation was made using a 180 KeV accelerator. Computer programs were written to analyze the experimental data, and to calculate the theoretical efficiency estimates, taking into account the collimator and shield geometry. The results of this work define the efficiency of the scintillation counters to better than 5% for a number of gamma-ray energies and a specific geometry. On the other hand, the efficiencies based on the total number of counts in the observed spectra were 20 percent to 40 percent higher than the theoretical efficiencies. The departures from theory depend on the gamma-ray energy and the geometry of the shielding and collimators in such a way that it is not possible to provide a simple basis for relating theoretical efficiencies to the experimental data. / Science, Faculty of / Physics and Astronomy, Department of / Graduate

Les sursauts gamma sont des événements fascinants de par leur origine longtemps restée mystérieuse, leur apparition imprévisible dans le ciel, et la formidable énergie qu'ils libèrent sous forme de bouffées de rayonnement gamma. Découverts fortuitement au début des années 1970, ils se traduisent par un intense flash de rayons gamma de brève durée (de quelques ms à quelques min), appelé émission prompte, suivi d'une émission longue, appelée rémanence, qui décroît rapidement, en émettant depuis les rayons X jusqu'au domaine radio. L'origine des sursauts gamma est encore largement discutée mais ces phénomènes extrêmes sont très vraisemblablement associés à la formation de nouveaux trous noirs stellaires. Mon sujet de thèse se situe au coeur de la mission sino-française SVOM dont le lancement du satellite est prévu en 2021, qui scrutera le ciel pour observer les sursauts avec une précision inégalée, associant observations spatiales et terrestres. Mon travail concerne l'instrument principal de la mission, le télescope spatial ECLAIRs. Il s'agit d'une caméra à masque codé sensible aux rayons X et gamma de basse énergie, en charge de la détection et de la localisation de l'émission prompte des sursauts. Durant mon travail de thèse, j'ai travaillé sur les performances scientifiques de l'instrument ECLAIRs et j'ai en particulier estimé le nombre de sursauts qui seront détectés et leurs caractéristiques. Pour cela, j'ai mis en place des simulations de performances utilisant les prototypes des algorithmes de détection embarqués combinés au modèle de l'instrument ECLAIRs. Les données en entrée des simulations comportent un bruit de fond simulé, et une population synthétique de sursauts gamma générée à partir de catalogues existants issus des observations des missions antérieures (CGRO, HETE-2, Swift et Fermi). Mon étude a permis d'estimer finement l'efficacité de détection d'ECLAIRs et prédit un taux de sursauts attendu par ECLAIRs entre 40 et 70 sursauts par an. Par ailleurs, mon travail a montré qu'ECLAIRs sera particulièrement sensible à une population de sursauts très riches en rayons X, population encore mal connue. Ma thèse présente plusieurs autres études complémentaires portant sur la performance de localisation, le taux de fausses alertes et les caractéristiques des déclenchements des algorithmes. Enfin, j'ai proposé deux nouvelles méthodes originales de détection de sursauts dont les résultats préliminaires présentés dans ma thèse sont très encourageants. Ils montrent que la sensibilité d'ECLAIRs aux sursauts courts (population d'intérêt particulier en raison de son lien attendu avec les ondes gravitationnelles) peut être encore améliorée. / Discovered in the early 1970s, gamma-ray bursts (GRBs) are amazing cosmic phenomena appearing randomly on the sky and releasing large amounts of energy mainly through gamma-ray emission. Although their origin is still under debate, they are believed to be produced by some of the most violent explosions in the Universe leading to the formation of stellar black-holes. GRBs are detected by their prompt emission, an intense short burst of gamma-rays (from a few millisecondes to few minutes), and are followed by a lived-afterglow emission observed on longer timescales from the X-ray to the radio domain. My thesis participates to the developement of the SVOM mission, which a Chinese-French mission to be launched in 2021, devoted to the study of GRBs and involving space and ground instruments. My work is focussed on the main instrument ECLAIRs, a hard X-ray coded mask imaging camera, in charge of the near real-time detection and localization of the prompt emission of GRBs. During my thesis, I studied the scientific performances of ECLAIRs and in particular the number of GRBs expected to be detected by ECLAIRs and their characteristics. For this purpose, I performed simulations using the prototypes of the embedded trigger algorithms combined with the model of the ECLAIRs instrument. The input data of the simulations include a background model and a synthetic population of gamma-ray bursts generated from existing catalogs (CGRO, HETE-2, Fermi and Swift). As a result, I estimated precisely the ECLAIRs detection efficiency of the algorithms and I predicted the number of GRBs to be detected by ECLAIRs : 40 to 70 GRBs per year. Moreover, the study highlighted that ECLAIRs will be particularly sensitive to the X-ray rich GRB population. My thesis provided additional studies about the localization performance, the rate of false alarm and the characteristics of the triggers of the algorithms. Finally, I also proposed two new methods for the detection of GRBs.The preliminary results were very promising and demonstrate that the sensitivity of ECLAIRs to the short GRBs (an interesting population due to the predicted association with gravitational waves) could be improved further.

Carbonic anhydrases catalyze a central reaction in life – the inter-conversion between carbon dioxide and water. Consequently, there is an increasing interest in research in using carbonic anhydrases for industrial applications such as biofuel production and carbon capture, since current approaches for CO2 capturing are expensive, harsh and energy demanding. The proof of principle for using carbonic anhydrase in these applications for carbon fixation has been validated. However, the current known and tested carbonic anhydrases are not tolerating the harsh industrial conditions. An ideal carbonic anhydrase should display thermo-, salt, and solvent stability and exhibit a decent reactivity. Herein we present the characterization and activity assessment of a halophilic γ-carbonic anhydrase from the Red Sea brine pool Discovery Deep. Protein X-ray structure exhibited the molecular structure and allowed the successful engineering of a small, active mutant library. Stopped-flow measurements gave insights into the activity and evaluated the engineering principles.

Depuis son émergence, la médecine nucléaire ne cesse d’évoluer. A la fois diagnostique et thérapeutique, elle occupe une place importante dans la stratégie médicale moderne. L’imagerie nucléaire consiste après injection au patient d’un radiotraceur, à détecter le rayonnement émis. Elle donne accès quantitativement à la fonctionnalité des organes ou à la localisation de structures cibles telles que des lésions tumorales. Cette imagerie a naturellement intégré les procédures chirurgicales en particulier en cancérologie (en pré et per opératoire). On parle de chirurgie radioguidée. Cette dernière permet de localiser lors du geste chirurgical les structures radiomarquées devant être retirées.Les avancées technologiques au niveau des radiopharmaceutiques et en instrumentation sont à l’origine de nouvelles stratégies de radioguidages pouvant cibler de petites structures. L’imagerie par rayonnement gamma reste la plus répandue et la mieux adaptée. On assiste au développement de dispositifs d’imagerie gamma portables miniaturisés permettant un contrôle visuel en per opératoire. Ces dispositifs sont prometteurs mais doivent être évalués.Un état des lieux des différentes procédures en chirurgie radioguidée et des imageurs utilisés en clinique est réalisé dans cette thèse.Le laboratoire Imagerie et Modélisation en Neurobiologie et Cancérologie (UMR 8165) développe de longue date de nouvelles approches de détection miniaturisée pour les différents types de rayonnement. Parmi celles-ci le prototype de deuxième génération appelé TReCam.Cette mini gamma caméra présente un champ de vue de 4,9 x 4,9 cm2 et intègre des technologies d’imagerie directement issues de la physique des particules. Elle est formée d’un collimateur à trous parallèles, d’un scintillateur continu LaBr3 (Ce) lu par un photomultiplicateur multi-anode et son électronique. Le système d’acquisition donne au chirurgien un affichage en temps réel de l’image radioactive.Ce travail de thèse a consisté également à évaluer la place des imageurs portables en chirurgie radioguidée, en particulier mammaire, à travers l’évaluation de la procédure SNOLL (repérage par marquage ɣ de la tumeur (T) et des ganglions sentinelles (GS)) avec TreCam. Il a reposé sur trois parties.Un premier volet a visé l’optimisation des performances de TReCam pour favoriser la localisation de structures peu radioactives dans des temps d’exposition de l’ordre de la dizaine de secondes. Pour ce faire, différentes stratégies d’optimisation des performances ont été mises en place au niveau du collimateur, de l’électronique et des algorithmes de traitement (dont réseaux de neurones) pour améliorer l’homogénéité de la détection.Le deuxième volet visait à objectiver les performances cliniques de TReCam pour la procédure SNOLL et situer les limites de son exploitation. A l’aide de simulations menées sur la plateforme GATE et modélisant la scène opératoire au plus près de la réalité clinique, nous avons montré que TreCam peut détecter des GS jusqu’à 4,5 cm de profondeur et situé à 4 cm de la T. L’impact du temps de pose n’est pas important. Par contre, le choix de la bonne fenêtre en énergie est primordial.Enfin, le troisième volet concrétise l’ambition interdisciplinaire de cette thèse. Il est consacré à l’évaluation clinique de TReCam à travers l’étude de son apport à la procédure SNOLL mammaire. Cette étude prospective interventionnelle incluant de 47 patientes (22 procédures SNOLL utilisant TReCam aux différents temps de la procédure et 25 procédures SNOLL standard). Les résultats ont montré un intérêt qualitatif à l’utilisation de TReCam en apportant un confort visuel lors de la procédure en complément de la sonde monopixel.Ce travail a montré l’intérêt de tels imageurs en chirurgie radioguidée mais aussi situé leurs limites actuelles. Des efforts de développement doivent être poursuivis tant au niveau des détecteurs qu’au niveau des radiopharmaceutiques utilisés pour le repérage. / Since its emergence in the middle of the twentieth century, nuclear medicine continues to evolve. At the same time diagnostic and therapeutic, it occupies an increasingly important place in the modern medical strategy. Nuclear imaging consists of injecting the patient with a radio-tracer to detect the radiation emitted. It provides quantitative access to the functionality of organs or the location of target structures such as tumor lesions. This imaging has been naturally integrated into surgical procedures, particularly in oncology (preoperatively and then intraoperatively). It is called radio-guided surgery. It makes possible to locate the radioactive target which will be removed during surgery.Technological advances in radiopharmaceutical instrumentation are driving new strategies that can target small structures. Gamma-ray imaging remains the most widespread and the most suitable. We are witnessing the development of miniaturized portable gamma imaging devices that allow visual control during surgery. These devices are promising but need to be evaluated.A short state-of-the-art of the various procedures in radioguided surgery and imagers used clinically is carried out in this thesis.For many years, the Imaging and Modeling in Neurobiology and Oncology Laboratory (UMR 8165) has been developing new miniaturized detection approaches for different types of radiation. Among them is the second-generation prototype called TReCam.This mini gamma camera has a field of view of 4.9 x 4.9 cm2 and integrates imaging technologies directly from particle physics. It consists of a collimator with parallel holes, a continuous scintillator LaBr3 (Ce) read by a multi-anode photomultiplier (PSPMT) and its electronics. The acquisition system gives the surgeon a real-time display of the radioactive image.This thesis work also consisted in evaluating the place of portable imagers in radioguided surgery, in particular mammary surgery, through the evaluation of the SNOLL procedure (identification of the tumor (T) and the sentinel lymph nodes (GS) by γ-labeling) with TreCam. It is based on three parts.The first part aimed at optimizing the performance of TReCam to improve the localization of lowradioactive structures with exposure times of around 10 seconds. To do this, different performance optimization strategies have been implemented in the collimator, electronics and processing algorithms (including neural networks) to improve the homogeneity of the detection. These performances were compared to those of a prototype developed at IMNC and integrating a new generation of photodetectors: the SiPM.The second part aimed to objectify the clinical performance of TReCam in the SNOLL procedure and to situate the limits of its exploitation. Using simulations conducted on the GATE platform and modeling the operating scene closer to clinical reality, we have shown that TreCam can detect GS up to 4.5 cm deep and located 4 cm from the T. Impact of the exposure time is not important. On the other hand, choosing the right energy window is essential.Finally, the third part concretizes the interdisciplinary ambition of this thesis. It is devoted to clinical evaluation of TReCam through the study of its contribution to the SNOLL breast procedure. This prospective interventional study included 47 patients (22 SNOLL procedures using TReCam at different times of the procedure and 25 standard SNOLL procedures). The results showed a qualitative interest in the use of TReCam by bringing a visual comfort during the procedure and must be used in addition to the monopixel probes.This work has shown the interest of such imagers in radioguided surgery but also set their current limits. Development efforts must be pursued at the level of both detectors and radiopharmaceuticals used for tracking.