Computer assisted synthesis and in-vitro cytotoxic evaluation of new pyrazole-fused isoquinolinoquinones derivatives as PI3K receptor antagonist with promising antitumoral activity

The importance of pyrazole and isoquinoline-5,8-dione scaffolds in medical chemistry is underlined by the high number of drugs currently on trading that contains these active ingredients. Due to their cytotoxic capability, the interest of medicinal chemists in these heterocyclic rings has grown exponentially especially, for cancer therapy. In this project, the first synthesis of pyrazole-fused isoquinoline-5,8-diones has been developed. 1,3-Dipolar cycloaddition followed by oxidative aromatization, established by our research group, has been employed. Screening of reaction conditions and characterization studies about the regioselectivity have been successfully performed. A remote control of regioselectivity, to achieve the two possible regioisomers has been accomplished. Through Molecular Docking studies, Structure-Activity relationship of differently substituted scaffolds containing our central core proved that a family of PI3K inhibitors have been discovered. Finally, in order to verify the promising antitumor activity, a first test of cell viability in vitro on T98G cell line of a solid brain tumor, the Glioblastoma Multiforme, showed cytotoxic inhibition comparable to currently trade anticancer drugs.

Temporal Coding of Volumetric Imagery

'Image volumes' refer to realizations of images in other dimensions such as time, spectrum, and focus. Recent advances in scientific, medical, and consumer applications demand improvements in image volume capture. Though image volume acquisition continues to advance, it maintains the same sampling mechanisms that have been used for decades; every voxel must be scanned and is presumed independent of its neighbors. Under these conditions, improving performance comes at the cost of increased system complexity, data rates, and power consumption.

This dissertation explores systems and methods capable of efficiently improving sensitivity and performance for image volume cameras, and specifically proposes several sampling strategies that utilize temporal coding to improve imaging system performance and enhance our awareness for a variety of dynamic applications.

Video cameras and camcorders sample the video volume (x,y,t) at fixed intervals to gain understanding of the volume's temporal evolution. Conventionally, one must reduce the spatial resolution to increase the framerate of such cameras. Using temporal coding via physical translation of an optical element known as a coded aperture, the compressive temporal imaging (CACTI) camera emonstrates a method which which to embed the temporal dimension of the video volume into spatial (x,y) measurements, thereby greatly improving temporal resolution with minimal loss of spatial resolution. This technique, which is among a family of compressive sampling strategies developed at Duke University, temporally codes the exposure readout functions at the pixel level.

Since video cameras nominally integrate the remaining image volume dimensions (e.g. spectrum and focus) at capture time, spectral (x,y,t,\lambda) and focal (x,y,t,z) image volumes are traditionally captured via sequential changes to the spectral and focal state of the system, respectively. The CACTI camera's ability to embed video volumes into images leads to exploration of other information within that video; namely, focal and spectral information. The next part of the thesis demonstrates derivative works of CACTI: compressive extended depth of field and compressive spectral-temporal imaging. These works successfully show the technique's extension of temporal coding to improve sensing performance in these other dimensions.

Geometrical optics-related tradeoffs, such as the classic challenges of wide-field-of-view and high resolution photography, have motivated the development of mulitscale camera arrays. The advent of such designs less than a decade ago heralds a new era of research- and engineering-related challenges. One significant challenge is that of managing the focal volume (x,y,z) over wide fields of view and resolutions. The fourth chapter shows advances on focus and image quality assessment for a class of multiscale gigapixel cameras developed at Duke.

Along the same line of work, we have explored methods for dynamic and adaptive addressing of focus via point spread function engineering. We demonstrate another form of temporal coding in the form of physical translation of the image plane from its nominal focal position. We demonstrate this technique's capability to generate arbitrary point spread functions.

The Land of the Savior: Óscar Romero and the Reform of Agriculture

This study approaches Óscar Romero by attending to his intimate involvement in and concern for the problematic surrounding the reform of Salvadoran agriculture and the conflict over property and possession underlying it. In this study, I situate Romero in relation to the concentration of landholding and the production of landlessness in El Salvador over the course of the twentieth century, and I examine his participation in the longstanding societal and ecclesial debate about agrarian reform provoked by these realities. I try to show how close attention to agrarian reform and what was at stake in it can illumine not only the conflict that occasioned Romero’s martyrdom but the meaning of the martyrdom itself.

Understanding Romero’s involvement in the debate about agrarian reform requires sustained attention to how it takes its bearings from the line of thinking about property and possession for which Pope Leo XIII’s 1891 encyclical Rerum novarum stands as a new beginning. The enclyclical tradition developing out of Leo’s pontificate is commonly referred to as Catholic social doctrine or Catholic social teaching. Romero’s and the Church’s participation in the debate about agrarian reform in El Salvador is unintelligible apart from it.

What Romero and the encyclical tradition share, I argue, is an understanding of creation as a common gift, from which follows a distinctive construal of property and the demands of justice with respect to possessing it. On this view, property does not name, as it is often taken to mean, the enclosure of what is common for the exclusive use of its possessors—something to be held by them over and against others. Rather, property and everything related to its holding derive from the claim that creation is a gift given to human creatures in common. The acknowledgement of creation as a common gift gives rise to what I describe in this study as a politics of common use, of which agrarian reform is one expression.

In Romero’s El Salvador, those who took the truth of creation as common gift seriously—those who spoke out against or opposed the ubiquity of the concentration of land and who clamored for agrarian reform so that the landless and land-poor could have access to land to cultivate for subsistence—suffered greatly as a consequence. I argue that, among other things, their suffering shows how, under the conditions of sin and violence, those who work to ensure that others have access to what is theirs in justice often risk laying down their lives in charity. In other words, they witness to the way that God’s work to restore creation has a cruciform shape. Therefore, while the advocacy for agrarian reform begins with the understanding of creation as common gift, the testimony to this truth in word and in deed points to the telos of the gift and the common life in the crucified and risen Lord in which it participates

The Barriers to the Integration of the Uterine Balloon Tamponade into South Africa and Ghana's Health Systems for the Management of Postpartum Hemorrhage

Background

Postpartum hemorrhage is the most significant contributor to maternal mortality globally, claiming 140,000 lives annually. Postpartum hemorrhage is a leading cause of maternal death in South Africa, with the literature indicating that 80 percent of the postpartum hemorrhage deaths in South Africa are avoidable. Ghana, as of 2010, witnesses 2700 maternal deaths annually, primarily because of poor quality of care in health facilities and services being difficult to access. As per WHO recommendations, uterotonics are integral to treating postpartum hemorrhage as soon as it is diagnosed. In case of persistent bleeding or limited availability of uterotonics, the uterine balloon tamponade (UBT) can be used as a second line of defense. If both these measures are unable to counter the bleeding, providers must perform surgical interventions. Literature on the UBT, as one tool in the protocol to address postpartum hemorrhage, has shown it to have success rates ranging from 60 to 100 percent. Despite the potential to lower the number of postpartum hemorrhage deaths in South Africa and Ghana, the UBT has not been incorporated widely in South Africa and Ghana. The aim of this study is to describe the barriers involved with integrating the UBT into South Africa and Ghana’s health systems to address postpartum hemorrhage.

Methods

The study took place in multiple sites in South Africa (Cape Town, Johannesburg, Durban and Mpumalanga) and in Accra, Ghana. South Africa and Ghana were selected because postpartum hemorrhage contributes greatly to their maternal mortality numbers and there is potential in both countries to lower those rates through greater use of the UBT. A total of 25 participants were interviewed through purposive sampling, snowball sampling and participant referrals, and included various categories of stakeholders integral to the integration process of a medical device. Individual in-depth interviews were used for data collection, with interview questions being tailored to each stakeholder category. The focus of the interviews was on the protocol used to counter postpartum hemorrhage, the frequency with which the UBT is used as part of the protocol, and the process of integrating it into the South Africa and Ghana’s health systems. The data collected were coded using NVivo and analyzed using content analysis.

Results

The barriers to integration of the uterine balloon tamponade to address postpartum hemorrhage in South Africa and Ghana were evident on the political, economic and health delivery levels. The results indicated that the barriers to integration in South Africa included the low recognition of postpartum hemorrhage as a problem, the lack of clarity surrounding the role of the Medicines Control Council as a regulatory body for medical devices, and low awareness of the UBT as an intervention to control postpartum hemorrhage. The barriers in Ghana were the cash constraints experienced by the Ghana Health Services to fund medical devices, a heavy reliance on donors for funding, and the lack of consistent knowledge on processes involving clinical trials for new medical devices in Ghana.

Conclusion

Existing literature on methods to counter postpartum hemorrhage to reduce maternal mortality has focused on and emphasized the efficacy of the UBT. Despite overwhelming evidence supporting the use of the UBT, many health systems across the world, particularly low-income countries, do not have access to the device owing to numerous barriers in integrating the device into obstetric care. This study illustrates the need to focus on incorporating the UBT into health systems for greater availability to health workers and its use as standard of care. Ultimately, this study can be used as a stepping-stone for more research on this subject, providing evidence to influence policymakers to integrate the UBT into their protocols for postpartum hemorrhage response.

Molecular Mechanisms of Airway Epithelial Progenitor Cell Maintenance and Repair.

The lungs are vital organs whose airways are lined with a continuous layer of epithelial cells. Epithelial cells in the distal most part of the lung, the alveolar space, are specialized to facilitate gas exchange. Proximal to the alveoli is the airway epithelium, which provides an essential barrier and is the first line of defense against inhaled toxicants, pollutants, and pathogens. Although the postnatal lung is a quiescent organ, it has an inherent ability to regenerate in response to injury. Proper balance between maintaining quiescence and undergoing repair is crucial, with imbalances in these processes leading to fibrosis or tumor development. Stem and progenitor cells are central to maintaining balance, given that they proliferate and renew both themselves and the various differentiated cells of the lung. However, the precise mechanisms regulating quiescence and repair in the lungs are largely unknown. In this dissertation, ionizing radiation is used as a physiologically relevant injury model to better understand the repair process of the airway epithelium. We use in vitro and in vivo mouse models to study the response of a secretory progenitor, the club cell, to various doses and qualities of ionizing radiation. Exposure to radiation found in space environments and in some types of radiotherapy caused clonal expansion of club cells specifically in the most distal branches of the airway epithelium, indicating that the progenitors residing in the terminal bronchioles are radiosensitive. This clonal expansion is due to an increase in p53-dependent apoptosis, senescence, and mitotic defects. Through the course of this work, we discovered that p53 is not only involved in radiation response, but is also a novel regulator of airway epithelial homeostasis. p53 acts in a gene dose-dependent manner to regulate the composition of airway epithelium by maintaining quiescence and regulating differentiation of club progenitor cells in the steady-state lung. The work presented in this dissertation represents an advance in our understanding of the molecular mechanisms underlying maintenance of airway epithelial progenitor cells as well as their repair following ionizing radiation exposure.

Neural mechanisms of negative reinforcement in children and adolescents with autism spectrum disorders.

BACKGROUND: Previous research has found accumulating evidence for atypical reward processing in autism spectrum disorders (ASD), particularly in the context of social rewards. Yet, this line of research has focused largely on positive social reinforcement, while little is known about the processing of negative reinforcement in individuals with ASD. METHODS: The present study examined neural responses to social negative reinforcement (a face displaying negative affect) and non-social negative reinforcement (monetary loss) in children with ASD relative to typically developing children, using functional magnetic resonance imaging (fMRI). RESULTS: We found that children with ASD demonstrated hypoactivation of the right caudate nucleus while anticipating non-social negative reinforcement and hypoactivation of a network of frontostriatal regions (including the nucleus accumbens, caudate nucleus, and putamen) while anticipating social negative reinforcement. In addition, activation of the right caudate nucleus during non-social negative reinforcement was associated with individual differences in social motivation. CONCLUSIONS: These results suggest that atypical responding to negative reinforcement in children with ASD may contribute to social motivational deficits in this population.

A molecular analysis of the interactions of escherichia coli and macrophages

Escherichia coli (E.coli) is a diverse bacterial species that primarily forms a beneficial symbiotic relationship with the host in the human lower gastrointestinal track (GIT), however it can also be pathogenic in this environment. Furthermore, some strains can diverge from the GIT and occupy niches such as the urinary tract. In all these environments, E. coli interacts with the immune system and macrophages represent the front line of the innate immune system. In this study we characterise the immune response by macrophages to E. coli infection. It was shown that E. coli broadly provoke a similar cytokine response during macrophages infection and furthermore are degraded primarily by the phagocytosis pathway. Recently a new group of E. coli called Adherent Invasive Escherichia coli (AIEC) has been described. AIEC are present in the guts of Crohn’s disease (CD) patients at a higher frequency than in healthy patients. AIEC can replicate in macrophages but the mechanism for this is not fully understood. The processing of AIEC by macrophages was investigated and it was shown that AIEC only replicated in permissive macrophages. Furthermore, even in a permissive macrophages AIEC are trafficked through macrophages in a similar manner to commensal E. coli. This supports the hypothesis that AIEC are highly similar to commensal E. coli and only cause pathogenicity when present in the permissive environment of the gut of CD patients. Replication in macrophages requires functioning metabolic pathways and it was identified that glycolysis is important for AIEC survival in macrophages. AIEC mutants without a fully functioning glycolysis pathway induced less IL-1β cytokine release from macrophages than wild type strain suggesting that metabolism plays a role in inflammasome activation. Furthermore, AIEC mutants that could not produce the glycolytic end product acetate induced significantly reduced IL-1β release during infection. This suggest that the acetate molecule or a phenotypic effect of its production may be a driver of IL-1β release from AIEC infected macrophages. The interaction of uropathogenic E. coli (UPEC) with macrophages was also investigated. UPEC induced very high levels of cytotoxicity in human macrophages which was shown to be dependent on the production of the pore forming toxin α-hemolysin. However, UPEC did not induced high levels of cytotoxicity in murine macrophages suggesting there are species specific sensitivity to α-hemolysin that should be considered when studying UPEC pathogenicity in murine models.

Lead isotope ratios of basalts from DSDP Leg 37 (Table 1)

Analyses of Pb from mid-ocean ridge basalts obtained from DSDP Leg 37 lie on a line of near-zero-age slope. The data seem consistent with an evolutionary model of three stages, the beginning of the second stage being at about 600 m.y. - the model age obtained for the least radiogenic Pb. The beginning of the third stage of evolution at the time of formation of the rocks apparently did not change the average Th/U ratio since measured values are consistent with the ratio deduced from Pb isotope ratios. Ratios of U/Pb are not consistent with Pb isotope ratios, however, thus ruling out a simple two-stage evolutionary model.

Project SCORE! Coaches’ Perceptions of an Online Tool to Promote Positive Youth Development in Sport

Research points to the potential of youth sport as an avenue to support the growth of particular assets and outcomes. A recurring theme in this line of research is the need to train coaches to deliberately deliver themes relating to positive youth development (PYD) consistently in youth sport programs. The purpose of the study was to design and deliver a technology-based PYD program. Project SCORE! (www.projectscore.ca) is a series of 10 lessons to help coaches integrate PYD into sport. Four youth sport coaches completed the program in this first phase of this research and were interviewed. The goal of this study was to gain some insights from coaches as they completed the program. Positive comments about the program (i.e. ease of use, success of particular lessons, coach’s personal growth) and challenges regarding teaching positive skills to youth are discussed. These results helped to shape the program and make necessary changes so that it may be used for a larger research study. Other implications and future research directions are discussed.

Travel, back and forth, to the myth. Cinema´s contribution to the formation of the tourist iconography of Mallorca

Mallorca, the largest of the Balearic Islands, is a well-known summer holidays destination; an ideal place to relax and enjoy the sun and the sea. That tourist gaze reflected on postcards results from advertising campaigns, where cinema played an important role with documentaries and fiction films. The origins of that iconography started in the decades of the 1920’s and 1930’s, reflecting the so-called myth of the “island of calm”. On the other hand, the films of the 1950’s and 1960’s created new stereotypes related to the mass tourism boom. Busy beaches and the white bodies of tourists replaced white sandy beaches, mountains and landscapes shown up in the movies of the early decades of the 20th century. Besides, hotels and nightclubs also replaced monuments, rural landscapes and folk exhibitions. These tourist images mirror the social and spatial transformations of Mallorca, under standardization processes like other seaside mass tourist destinations. The identity was rebuilt on the foundations of "modernity". Although "balearization" has not ceased, nowadays filmmaking about Mallorca is advertising again a stereotype close to that one of the 1920s and 1930s, glorifying the myth of the "island of calm". This singular identity makes the island more profitable for capital that searches socio-spatial differentiation in post-fordist times.

Los primeros testimonios sobre Martin Seidel, autor de Origo et fundamenta religionis christianae

El tratado clandestino Origo et fundamenta religionis christianae ataca los fundamentos del cristianismo y propone una religión natural. Pese a que todas las copias manuscritas que lo conservan datan del siglo xVIII, se encuentran suficientes indicios que señalan al silesio Martin Seidel como su autor y documentan la existencia del texto a finales del siglo xVI o principios del xVII. Las primeras fuentes sobre Seidel lo vinculan con los antitrinitarios de Heidelberg (1570), los unitarios polacos (1580) y los “cripto-socinianos” de Altdorf (1610). En este artículo valoro dichas fuentes y corrijo a la luz de las mismas algunas afirmaciones de la crítica reciente sobre Seidel y su Origo.

Hans Blumenberg and Feminism

The German philosopher Hans Blumenberg [1920-1996] was interested in feminist issues during the last two decades of his life as shown their dedication and effort in compiling selected cuts in the media related to the topic of women and their development of multiple short essays inspired by the latter and countless curious anecdotes. Hans Blumenberg and feminism seeks to inform the reader about the existence of a blumenberguian thought line of research totally unexplored so far. It can only be revealed through the study of the philosopher ‘Nachlaβ’ found in the Deutsches literaturarchiv Marbach (Stuttgart) which I personally had a chance to dig through the award of a research grant from the DAAD (Deutscher Akademischer Dienst Austage).

Los orígenes de la industria española de los forasteros

La llegada de forasteros a nuestro país no era una empresa fácil de acometer en una España en crisis después de 1898, dividida políticamente entre conservadores y liberales, y con serias carencias en sus infraestructuras y transportes. La actividad comercial española necesitaba nuevos frentes y el turismo podría convertirse en un importante factor y motor mercantil.La búsqueda y la construcción en torno a ese objetivo comenzó a partir de 1905, cuando la iniciativa pública y privada realizaron las primeras gestiones encaminadas a este fin, y se constituyen se constituyeron sociedades-sindicatos, según el modelo francés, para fomentar la afición por los viajes y la recepción de viajeros.

Of Marx and Makers: an Historical Perspective on Generative Justice

In Marxist frameworks “distributive justice” depends on extracting value through a centralized state. Many new social movements—peer to peer economy, maker activism, community agriculture, queer ecology, etc.—take the opposite approach, keeping value in its unalienated form and allowing it to freely circulate from the bottom up. Unlike Marxism, there is no general theory for bottom-up, unalienated value circulation. This paper examines the concept of “generative justice” through an historical contrast between Marx’s writings and the indigenous cultures that he drew upon. Marx erroneously concluded that while indigenous cultures had unalienated forms of production, only centralized value extraction could allow the productivity needed for a high quality of life. To the contrary, indigenous cultures now provide a robust model for the “gift economy” that underpins open source technological production, agroecology, and restorative approaches to civil rights. Expanding Marx’s concept of unalienated labor value to include unalienated ecological (nonhuman) value, as well as the domain of freedom in speech, sexual orientation, spirituality and other forms of “expressive” value, we arrive at an historically informed perspective for generative justice. 

Robust indoor speaker recognition in a network of audio and video sensors

Situational awareness is achieved naturally by the human senses of sight and hearing in combination. Automatic scene understanding aims at replicating this human ability using microphones and cameras in cooperation. In this paper, audio and video signals are fused and integrated at different levels of semantic abstractions. We detect and track a speaker who is relatively unconstrained, i.e., free to move indoors within an area larger than the comparable reported work, which is usually limited to round table meetings. The system is relatively simple: consisting of just 4 microphone pairs and a single camera. Results show that the overall multimodal tracker is more reliable than single modality systems, tolerating large occlusions and cross-talk. System evaluation is performed on both single and multi-modality tracking. The performance improvement given by the audio–video integration and fusion is quantified in terms of tracking precision and accuracy as well as speaker diarisation error rate and precision–recall (recognition). Improvements vs. the closest works are evaluated: 56% sound source localisation computational cost over an audio only system, 8% speaker diarisation error rate over an audio only speaker recognition unit and 36% on the precision–recall metric over an audio–video dominant speaker recognition method.