Molecular mechanisms of shikonin and its derivatives in cancer therapy

The identification of molecular processes involved in cancer development and prognosis opened avenues for targeted therapies, which made treatment more tumor-specific and less toxic than conventional therapies. One important example is the epidermal growth factor receptor (EGFR) and EGFR-specific inhibitors (i.e. erlotinib). However, challenges such as drug resistance still remain in targeted therapies. Therefore, novel candidate compounds and new strategies are needed for improvement of therapy efficacy. Shikonin and its derivatives are cytotoxic constituents in traditional Chinese herbal medicine Zicao (Lithospermum erythrorhizin). In this study, we investigated the molecular mechanisms underlying the anti-cancer effects of shikonin and its derivatives in glioblastoma cells and leukemia cells. Most of shikonin derivatives showed strong cytotoxicity towards erlotinib-resistant glioblastoma cells, especially U87MG.ΔEGFR cells which overexpressed a deletion-activated EGFR (ΔEGFR). Moreover, shikonin and some derivatives worked synergistically with erlotinib in killing EGFR-overexpressing cells. Combination treatment with shikonin and erlotinib overcame the drug resistance of these cells to erlotinib. Western blotting analysis revealed that shikonin inhibited ΔEGFR phosphorylation and led to corresponding decreases in phosphorylation of EGFR downstream molecules. By means of Loewe additivity and Bliss independence drug interaction models, we found erlotinb and shikonin or its derivatives corporately suppressed ΔEGFR phosphorylation. We believed this to be a main mechanism responsible for their synergism in U87MG.ΔEGFR cells. In leukemia cells, which did not express EGFR, shikonin and its derivatives exhibited even greater cytotoxicity, suggesting the existence of other mechanisms. Microarray-based gene expression analysis uncovered the transcription factor c-MYC as the commonly deregulated molecule by shikonin and its derivatives. As validated by Western blotting analysis, DNA-binding assays and molecular docking, shikonin and its derivatives bound and inhibited c-MYC. Furthermore, the deregulation of ERK, JNK MAPK and AKT activity was closely associated with the reduction of c-MYC, indicating the involvement of these signaling molecules in shikonin-triggered c-MYC inactivation. In conclusion, the inhibition of EGFR signaling, synergism with erlotinib and targeting of c-MYC illustrate the multi-targeted feature of natural naphthoquinones such as shikonin and derivatives. This may open attractive possibilities for their use in a molecular targeted cancer therapy.

On the experimental behaviour of a silty sand and its modelling through Generalized Plasticity.

La tesi contiene uno studio sperimentale sul comportamento di una sabbia limosa del sottosuolo della laguna veneta e propone un'interpretazione dei risultati sperimentali ottenuti alla luce dei presupposti teorici di un approccio costitutivo avanzato noto come "Plasticità Generalizzata". Il programma sperimentale è consistito nella realizzazione di prove edometriche e prove triassiali su campioni di sabbia provenienti dal sito di Treporti, situato in prossimità della bocca di Lido. La risposta sperimentale, in termini di modulo volumetrico, è stata messa a confronto con i risultati di alcuni studi di letteratura, con particolare riferimento a quelli condotti da Jefferies & Been (2000). La disponibilità di prove di compressione edometrica realizzate nella cella K0 e la conseguente possibilità di valutare il coefficiente di spinta a riposo ha permesso di interpretare le prove in termini di tensione media efficace p' e di verificare l'applicabilità al caso in esame degli approcci di letteratura disponibili, spesso sviluppati a partire da prove di compressione isotropa effettuate in cella triassiale. Il comportamento tenso-deformativo osservato è stato successivamente simulato con un modello costitutivo per sabbie sviluppato nell'ambito della Plasticità Generalizzata. In particolare sono state utilizzate tre diverse formulazioni, che costituiscono un avanzamento dell'iniziale modello costitutivo proposto da Pastor, Zienkiewicz e Chan (1990), basate sull'uso di un parametro di stato del materiale definito rispetto alle condizioni di Stato Critico. Dal confronto tra previsioni del modello e risposta sperimentale è stato possibile individuare la formulazione che meglio simula il comportamento meccanico osservato sia in compressione edometrica sia in prove di taglio ed è stato proposto un set di parametri costitutivi ritenuti rappresentativi del terreno studiato.

Characterization of harmonic tremor at Santiaguito volcano and its implications for eruption mechanisms

We observed Santiaguito volcano in southwestern Guatemala from March 2008 - March 2010. Seismic and infrasound data collected between January and March of 2009 contain records of many diverse processes occurring at the dacitic dome complex, including the recurrence of short lived (30-200 seconds in duration) harmonic tremor concurrent with ash poor gas emissions from the volcano. We employ several different analytical techniques to examine different portions of the tremor and source mechanisms. We use the parameters derived by this analysis to compare the feasibility of several suggested models of eruption mechanisms, and determine that this type of harmonic tremor is most justifiably generated by the flow of gas through crack networks generated by shear fracture along the magma conduit margin.

Design of a lab scale direct-filtration system and its application in process lab

The Environmental Process and Simulation Center (EPSC) at Michigan Technological University started accommodating laboratories for an Environmental Engineering senior level class CEE 4509 Environmental Process and Simulation Laboratory since 2004. Even though the five units that exist in EPSC provide the students opportunities to have hands-on experiences with a wide range of water/wastewater treatment technologies, a key module was still missing for the student to experience a full cycle of treatment. This project fabricated a direct-filtration pilot system in EPSC and generated a laboratory manual for education purpose. Engineering applications such as clean bed head loss calculation, backwash flowrate determination, multimedia density calculation and run length prediction are included in the laboratory manual. The system was tested for one semester and modifications have been made both to the direct filtration unit and the laboratory manual. Future work is also proposed to further refine the module.

Development of a high performance parallel computing platform and its use in the study of nanostructures : clusters, sheets and tubes .

Small clusters of gallium oxide, technologically important high temperature ceramic, together with interaction of nucleic acid bases with graphene and small-diameter carbon nanotube are focus of first principles calculations in this work. A high performance parallel computing platform is also developed to perform these calculations at Michigan Tech. First principles calculations are based on density functional theory employing either local density or gradient-corrected approximation together with plane wave and gaussian basis sets. The bulk Ga2O3 is known to be a very good candidate for fabricating electronic devices that operate at high temperatures. To explore the properties of Ga2O3 at nonoscale, we have performed a systematic theoretical study on the small polyatomic gallium oxide clusters. The calculated results find that all lowest energy isomers of GamOn clusters are dominated by the Ga-O bonds over the metal-metal or the oxygen-oxygen bonds. Analysis of atomic charges suggest the clusters to be highly ionic similar to the case of bulk Ga2O3. In the study of sequential oxidation of these slusters starting from Ga2O, it is found that the most stable isomers display up to four different backbones of constituent atoms. Furthermore, the predicted configuration of the ground state of Ga2O is recently confirmed by the experimental result of Neumark's group. Guided by the results of calculations the study of gallium oxide clusters, performance related challenge of computational simulations, of producing high performance computers/platforms, has been addressed. Several engineering aspects were thoroughly studied during the design, development and implementation of the high performance parallel computing platform, rama, at Michigan Tech. In an attempt to stay true to the principles of Beowulf revolutioni, the rama cluster was extensively customized to make it easy to understand, and use - for administrators as well as end-users. Following the results of benchmark calculations and to keep up with the complexity of systems under study, rama has been expanded to a total of sixty four processors. Interest in the non-covalent intereaction of DNA with carbon nanotubes has steadily increased during past several years. This hybrid system, at the junction of the biological regime and the nanomaterials world, possesses features which make it very attractive for a wide range of applicatioins. Using the in-house computational power available, we have studied details of the interaction between nucleic acid bases with graphene sheet as well as high-curvature small-diameter carbon nanotube. The calculated trend in the binding energies strongly suggests that the polarizability of the base molecules determines the interaction strength of the nucleic acid bases with graphene. When comparing the results obtained here for physisorption on the small diameter nanotube considered with those from the study on graphene, it is observed that the interaction strength of nucleic acid bases is smaller for the tube. Thus, these results show that the effect of introducing curvature is to reduce the binding energy. The binding energies for the two extreme cases of negligible curvature (i.e. flat graphene sheet) and of very high curvature (i.e. small diameter nanotube) may be considered as upper and lower bounds. This finding represents an important step towards a better understanding of experimentally observed sequence-dependent interaction of DNA with Carbon nanotubes.

Determination of ajulemic acid and its glucuronide in human plasma by gas chromatography-mass spectrometry

A method using gas chromatography-mass spectrometry (GC-MS) and solid-phase extraction (SPE) was developed for the determination of ajulemic acid (AJA), a non-psychoactive synthetic cannabinoid with interesting therapeutic potential, in human plasma. When using two calibration graphs, the assay linearity ranged from 10 to 750 ng/ml, and 750 to 3000 ng/ml AJA. The intra- and inter-day precision (R.S.D., %), assessed across the linear ranges of the assay, was between 1.5 and 7.0, and 3.6 and 7.9, respectively. The limit of quantitation (LOQ) was 10 ng/ml. The amount of AJA glucuronide was determined by calculating the difference in the AJA concentration before ("free AJA") and after enzymatic hydrolysis ("total AJA"). The present method was used within a clinical study on 21 patients suffering from neuropathic pain with hyperalgesia and allodynia. For example, plasma levels of 599.4+/-37.2 ng/ml (mean+/-R.S.D., n=9) AJA were obtained for samples taken 2 h after the administration of an oral dose of 20 mg AJA. The mean AJA glucuronide concentration at 2h was 63.8+/-127.9 ng/ml.

Assessing the Influence of Brain-based Instructional Methods and Its Impact on Systemic Change for Learning Communities

Background: As scholars who prepare future school leaders to be innovative instructional leaders for their learning communities, we are on the verge of a curriculum design revolution. The application of brain research findings promotes educational reform efforts to systemically change the way in which children experience school. However, most educators, school leaders, board members, and policy makers are ill prepared to reconsider the implications for assessment, pedagogy, school climate, daily schedules, and use of technology. This qualitative study asked future school leaders to reconsider how school leadership preparedness programs prepared them to become instructional leaders for the 21st century. The findings from this study will enhance the field of school leadership, challenging the current emphasis placed on standardized testing, traditional school calendars, assessments, monocultural instructional methods, and meeting the needs of diverse learning communities. [See PDF for complete abstract]

The German business and information technologies project

The Business and Information Technologies (BIT) project strives to reveal new insights into how modern IT impacts organizational structures and business practices using empirical methods. Due to its international scope, it allows for inter-country comparison of empirical results. Germany — represented by the European School of Management and Technologies (ESMT) and the Institute of Information Systems at Humboldt-Universität zu Berlin — joined the BIT project in 2006. This report presents the result of the first survey conducted in Germany during November–December 2006. The key results are as follows: • The most widely adopted technologies and systems in Germany are websites, wireless hardware and software, groupware/productivity tools, and enterprise resource planning (ERP) systems. The biggest potential for growth exists for collaboration and portal tools, content management systems, business process modelling, and business intelligence applications. A number of technological solutions have not yet been adopted by many organizations but also bear some potential, in particular identity management solutions, Radio Frequency Identification (RFID), biometrics, and third-party authentication and verification. • IT security remains on the top of the agenda for most enterprises: budget spending was increasing in the last 3 years. • The workplace and work requirements are changing. IT is used to monitor employees' performance in Germany, but less heavily compared to the United States (Karmarkar and Mangal, 2007).1 The demand for IT skills is increasing at all corporate levels. Executives are asking for more and better structured information and this, in turn, triggers the appearance of new decision-making tools and online technologies on the market. • The internal organization of companies in Germany is underway: organizations are becoming flatter, even though the trend is not as pronounced as in the United States (Karmarkar and Mangal, 2007), and the geographical scope of their operations is increasing. Modern IT plays an important role in enabling this development, e.g. telecommuting, teleconferencing, and other web-based collaboration formats are becoming increasingly popular in the corporate context. • The degree to which outsourcing is being pursued is quite limited with little change expected. IT services, payroll, and market research are the most widely outsourced business functions. This corresponds to the results from other countries. • Up to now, the adoption of e-business technologies has had a rather limited effect on marketing functions. Companies tend to extract synergies from traditional printed media and on-line advertising. • The adoption of e-business has not had a major impact on marketing capabilities and strategy yet. Traditional methods of customer segmentation are still dominating. The corporate identity of most organizations does not change significantly when going online. • Online sales channel are mainly viewed as a complement to the traditional distribution means. • Technology adoption has caused production and organizational costs to decrease. However, the costs of technology acquisition and maintenance as well as consultancy and internal communication costs have increased.

Achievements of the FIGO Initiative for the Prevention of Unsafe Abortion and its Consequences in South-Southeast Asia.

Since 2008, the FIGO Initiative for the Prevention of Unsafe Abortion and its Consequences has contributed to ensuring the substitution of sharp curettage by manual vacuum aspiration (MVA) and medical abortion in selected hospitals in participating countries of South-Southeast Asia. This initiative facilitated the registration of misoprostol in Pakistan and Bangladesh, and the approval of mifepristone for "menstrual regulation" in Bangladesh. The Pakistan Nursing Council agreed to include MVA and medical abortion in the midwifery curriculum. The Bangladesh Government has approved the training of nurses and paramedics in the use of MVA to treat incomplete abortion in selected cases. The Sri Lanka College of Obstetricians and Gynaecologists, in collaboration with partners, has presented a draft petition to the relevant authorities appealing for them to liberalize the abortion law in cases of rape and incest or when lethal congenital abnormalities are present. Significantly, the initiative has introduced or strengthened the provision of postabortion contraception.

Participation in farmer's cooperatives and its effects on agricultural incomes : evidence from vegetable-producing areas in China

Chinese agricultural cooperatives, called Farmer's Professional Cooperatives (FPCs), are expected to become a major tool to facilitate agro-industrialization for small farmers through the diffusion of new technologies, the supply of high-quality agricultural inputs and the marketing of their products. This study compares FPC participants with vegetable-producing non-participants and grain farmers in vegetable-producing areas in rural China to investigate the treatment effect of participation in FPCs as well as implementation of vegetable cultivation. I adopt parametric and nonparametric approaches to precisely estimate the treatment effects. Estimated results indicate no significant difference between participants and non-participants of FPCs on agricultural net income in both parametric and non-parametric estimations. In contrast, the comparison between vegetable and grain farmers using propensity score matching (PSM) reveals that the treatment effect of vegetable cultivation is significantly positive for total and agricultural incomes, although vegetable cultivation involves more labor-intensive efforts. These results indicate that it is the implementation of vegetable cultivation rather than the participation in an FPC that enhances the economic welfare of farmers, due to the non-excludability of FPCs' services as well as the risks involved in vegetable cultivation.

Comparison of CO2 From Coal Capture Processes and Valorisation Technologies

Coal is the most plentiful and evenly distributed fossil fuel worldwide. Based on current production, it is estimated that the reserves will last approximately 130 years. Its use worldwide has been increasing, mainly due to consumption by emerging countries. CO2 emissions generated by combustion and the repercussions of such on climate change support the view that it could no longer be used. CO2 capture may be the solution to continue using it, which would cater for the growing energy demand worldwide. The aim of this study is to compare different processes concerning CO2 capture that may be economically viable, ultimately showing that coal, a fossil energy source widely distributed around the world, can, as a result of using different CO2 capture processes, be used as a clean source of electricity. Hence, in places where geological hurdles may render the costs of CO2 storage considerably higher, since it might have to travel far, coal may be used for other purposes, thus valorising CO2 within the industrial sector. This research is focused on the technical and economic comparison of the most relevant CO2 capture projects designed in Spain using different existing technologies. The oxyfuel project in Ciuden (Leon, Spain), the IGCC Elcogas, precombustion CO2-capture project (Puertollano, Spain) and the postcombustion project in Carboneras (Almeria, Spain) will be analyzed in order to assess the options available to valorise captured CO2. Valorising captured CO2 may be an adequate solution in areas where, although CO2 capture is still possible, storage is not equally so, thus generating a further benefit. The possible uses of CO2 will be assessed in vegetable growing greenhouses, harnessing CO2 in vegetable life cycles. This will also be used in growing algae for subsequent biodiesel production. Both CO2 capture and valorising will eventually lead to the clean use of coal, which will thus enhance the level of self-supply, aiding the development of electric vehicles, which require large amounts of electricity, as well as improve the level of energy autonomy in countries around the world. Another type of fuel, biodiesel, will also be obtained, without this affecting international food prices.

Comparison of CO2 from coal captureprocesses and valorisation technologies

Coal is the most plentiful and evenly distributed fossil fuel worldwide. Based on current production, it is estimated that the reserves will last approximately 130 years. Its use worldwide has been increasing, mainly due to consumption by emerging countries. CO2 emissions generated by combustion and the repercussions of such on climate change support the view that it could no longer be used. CO2 capture may be the solution to continue using it, which would cater for the growing energy demand worldwide. The aim of this study is to compare different processes concerning CO2 capture that may be economically viable, ultimately showing that coal, a fossil energy source widely distributed around the world, can, as a result of using different CO2 capture processes, be used as a clean source of electricity. Hence, in places where geological hurdles may render the costs of CO2 storage considerably higher, since it might have to travel far, coal may be used for other purposes, thus valorizing CO2 within the industrial sector. This research is focused on the technical and economic comparison of the most relevant CO2 capture projects designed in Spain using different existing technologies. The oxyfuel project in Ciuden (Leon, Spain), the IGCC Elcogas, precombustion CO2-capture project (Puertollano, Spain) and the postcombustion project in Carboneras (Almeria, Spain) will be analyzed in order to assess the options available to valorizecaptured CO2. Valorizing captured CO2 may be an adequate solution in areas where, although CO2 capture is still possible, storage is not equally so, thus generating a further benefit. The possible uses of CO2 will be assessed in vegetable growing greenhouses, harnessing CO2 in vegetable life cycles. This will also be used in growing algae for subsequent biodiesel production. Both CO2capture and valorizing will eventually lead to the clean use of coal, which will thus enhance the level of self-supply, aiding the development of electric vehicles, which require large amounts of electricity, as well as improve the level of energy autonomy in countries around the world. Another type of fuel, biodiesel, will also be obtained, without this affecting international food prices.

Interfacing prolog and VRML and its application to constraint visualization

A number of data description languages initially designed as standards for trie WWW are currently being used to implement user interfaces to programs. This is done independently of whether such programs are executed in the same or a different host as trie one running the user interface itself. The advantage of this approach is that it provides a portable, standardized, and easy to use solution for the application programmer, and a familiar behavior for the user, typically well versed in the use of WWW browsers. Among the proposed standard description languages, VRML is a aimed at representing three dimensional scenes including hyperlink capabilities. VRML is already used as an import/export format in many 3-D packages and tools, and has been shown effective in displaying complex objects and scenarios. We propose and describe a Prolog library which allows parsing and checking VRML code, transforming it, and writing it out as VRML again. The library converts such code to an internal representation based on first order terms which can then be arbitrarily manipulated. We also present as an example application the use of this library to implement a novel 3-D visualization for examining and understanding certain aspects of the behavior of CLP(FD) programs.