Characterisation of the role of canonical BMP-Smad 1/5/8 signalling in the development of ventral midbrain dopaminergic neurons

Ventral midbrain (VM) dopaminergic (DA) neurons, which project to the dorsal striatum via the nigrostriatal pathway, are progressively degenerated in Parkinson’s disease (PD). The identification of the instructive factors that regulate midbrain DA neuron development, and the subsequent elucidation of the molecular bases of their effects, is vital. Such an understanding would facilitate the generation of transplantable DA neurons from stem cells and the identification of developmentally-relevant neurotrophic factors, the two most promising therapeutic approaches for PD. Two related members of the bone morphogenetic protein (BMP) family, BMP2 and growth/differentiation factor (GDF) 5, which signal via a canonical Smad 1/5/8 signalling pathway, have been shown to have neurotrophic effects on midbrain DA neurons both in vitro and in vivo, and may function to regulate VM DA neuronal development. However, the molecular (signalling pathway(s)) and cellular (direct neuronal or indirect via glial cells) mechanisms of their effects remain to be elucidated. The present thesis hypothesised that canonical Smad signalling mediates the direct effects of BMP2 and GDF5 on the development of VM DA neurons. By activating, modulating and/or inhibiting various components of the BMP-Smad signalling pathway, this research demonstrated that GDF5- and BMP2-induced neurite outgrowth from midbrain DA neurons is dependent on BMP type I receptor activation of the Smad signalling pathway. The role of glial cell-line derived neurotrophic factor (GDNF)-signalling, dynamin-dependent endocytosis and Smad interacting protein-1 (Sip1) regulation, in the neurotrophic effects of BMP2 and GDF5 were determined. Finally, the in vitro development of VM neural stem cells (NSCs) was characterised, and the ability of GDF5 and BMP2 to induce these VM NSCs towards DA neuronal differentiation was investigated. Taken together, these experiments identify GDF5 and BMP2 as novel regulators of midbrain DA neuronal induction and differentiation, and demonstrate that their effects on DA neurons are mediated by canonical BMPR-Smad signalling.

The role of transformative thinking and practice in a property entrepreneur's response to the funding crisis since 2008

This portfolio of exploration explores the role of transformative thinking and practice in a property entrepreneur’s response to the financial crisis which swept over Ireland from 2008. The complexity of this challenge and the mental capacity to meet its demands is at the core of the exploration. This inquiry emerged from the challenges the financial crisis presented to my values, beliefs, assumptions, and theories, i.e. the interpretive lens through which I make meaning of my experiences. Given the issue identified, this inquiry is grounded in aspects of theories of constructive developmental psychology, applied developmental science, and philosophy. Integrating and linking these elements to business practice is the applied element of the Portfolio. As the 2008 crisis unfolded I realised I was at the limits of my way of knowing. I came to understand that the underlying structure of a way of knowing is the ‘subject-object relationship’ i.e. what a way of knowing can reflect upon, look at, have perspective on, in other words, make object, as against what is it embedded in, attached to, identified within, or subject to. My goal became enhancing my awareness of how I made meaning and how new insights, which would transform a way of knowing, are created. The focus was on enhancing my practice. This Portfolio is structured into three essays. Essay One reported on my self-reflection and external evaluation out of which emerged my developmental goals. In Essay Two I undertake a reading for change programme in which different meaning making systems were confronted in order to challenge me as a meaning maker. Essay Three reported on my experiment which concerned the question whether it was possible for me as a property entrepreneur, and for others alike, to retain bank finance in the face of the overwhelming objective of the bank to deleverage their balance sheet of property loans. The output of my research can be grouped into General Developmental and Specific Business Implications. Firstly I address those who are interested in a transformational-based response to the challenges of operating in the property sector in Ireland during a crisis. I outline the apparatus of thought that I used to create insight, and thus transform how I thought, these are Awareness, Subject-object separation, Exploring other’s perspectives from the position of incompleteness, Dialectical thinking and Collingwood’s Questioning activity. Secondly I set out my learnings from the crisis and their impact on entrepreneurial behaviour and the business of property development. I identify ten key insights that have emerged from leading a property company through the crisis. Many of these are grounded in common sense, however, in my experience these were, to borrow Shakespeare’s words, “More honor'd in the breach than the observance” in pre Crisis Ireland. Finally I set out a four-step approach for forging a strategy. This requires my peer practitioners to identify (i) what they are subject to, (ii) Assess the Opportunity or challenge in a Systemic Context, (iii) Explore Multiple Perspectives on the opportunity or Challenge with an Orientation to change how you know and (iv) Using the Questioning Activity to create Knowledge. Based on my experience I conclude that transformative thinking and practice is a key enabler for a property entrepreneur, in responding to a major collapse of traditional (bank debt) funding.

Survival expectations of the obese: Is excess mortality reflected in perceptions?

OBJECTIVE: This study compared self-reported subjective life expectancy (i.e., probability of living to age 75) for normal-weight, overweight, and obese weight groups to examine whether individuals are internalizing information about the health risks due to excessive weight. RESEARCH METHODS AND PROCEDURES: Using data from the Health and Retirement Study, a total of 9035 individuals 51 to 61 years old were analyzed by BMI category. The primary outcome measure was individuals' reports about their own expectations of survival to age 75. Absolute and relative risks of survival were compared with published estimates of survival to age 75. RESULTS: Consistently, higher levels of BMI were associated with lower self-estimated survival probabilities. Differences relative to normal weight ranged from 4.9% (p < 0.01) for male nonsmokers to 8.8% (p < 0.001) for female nonsmokers. However, these differences were substantially less than those obtained from published survival curve estimates, suggesting that obese individuals tended to underestimate mortality risks. DISCUSSION: Individuals appeared to underestimate the mortality risks of excessive weight; thus, knowledge campaigns about the risks of obesity should remain a top priority.

ION, OPERA IN SEVEN SCENES, BASED ON EURIPIDES ORIGINAL PLAY

The opera ION serves as my Doctoral Dissertation at the University of Maryland School of Music. The librettist of the opera is Nick Olcott, Opera Assistant Director at the University. My interest in this little-known play of Euripides began with my work with Professor Lillian Doherty of the University's Classics Department. Since I am fluent in Greek, I was able to read the play in original, becoming aware of nuances of meaning absent in the standard English translations. Professor Leon Major, Artistic Director of the University's Opera Studio, was enthusiastic about the choice of this play as the basis for an opera, and has been very generous of his time in showing me what must be done to turn a play into an opera. ION is my first complete stage work for voices and constitutes an ambitious project. The opera is scored for a small chamber orchestra, consisting of Saxophone, Percussion (many types), Piano, a Small Chorus of six singers, as well as five Soloists. An orchestra of this size is adequate for the plot, and also provides support for various new vocal techniques, alternating between singing and speaking, as well as traditional arias. In ION, I incorporate Greek folk elements, which I know first-hand from my Balkan background, as well as contemporary techniques which I have absorbed during my graduate work at Boston University and the University of Maryland. Euripides' ION has fascinated me for two reasons in particular: its connection with founding myth of Athens, and the suggestiveness of its plot, which turns on the relationship of parents to children. In my interpretation, the leading character Ion is seen as emblematic for today's teenagers. Using the setting of the classic play, I hope to create a modern transformation of a myth, not to simply retell it. To this end, hopefully a new opera form will rise, as valid for our times as Verdi and Wagner were for theirs.

The distribution of sales revenues from pharmaceutical innovation.

OBJECTIVE: This report updates our earlier work on the returns to pharmaceutical research and development (R&D) in the US (1980 to 1984), which showed that the returns distributions are highly skewed. It evaluates a more recent cohort of new drug introductions in the US (1988 to 1992) and examines how the returns distribution is emerging for drugs with life cycles concentrated in the 1990s versus the 1980s. DESIGN AND SETTING: Methods were described in detail in our earlier reports. The current sample included 110 new drug entities (including 28 orphan drugs), and sales data were obtained for the period 1988 to 1998, which represented between 7 and 11 years of sales for the drugs included. 20 years was chosen as the expected market life for this cohort, and a 2-step procedure was used to project future sales for the drugs--during the period until patent expiry and then beyond patent expiry until the 20-year time-horizon was completed. Thus, the values in the first half of the life cycle are essentially based on realised sales, while those in the second half are projected using information on patent expiry and other inputs. MAIN OUTCOME MEASURES AND RESULTS: Peak annual sales for the top decile of drugs introduced between 1988 and 1992 in the US amounted to almost $US1.1 billion compared with peak sales of less than $US175 million (1992 values) for the mean compound. In particular, the top decile accounted for 56% of overall sales revenue. Although the sales distributions were skewed in both our earlier and current analysis, the top decile in the later time-period exhibited more rapid rates of growth after launch, a peak that was more than 50% greater in real terms than for the 1980 to 1984 cohort, and a faster rate of expected decline in sales after patent expiry. One factor contributing to the distribution of sales revenues becoming more skewed over time is the orphan drug phenomenon (i.e. most of the orphan drugs are concentrated at the bottom of the distribution). CONCLUSION: The distribution of sales revenues for new drug compounds is highly skewed in nature. In this regard, the top decile of new drugs accounts for more than half of the total sales generated by the 1988 to 1992 cohort analysed. Furthermore, the distribution of sales revenues for this cohort is more skewed than that of the 1980 to 1984 cohort we analysed in previous research.

The Evolution of the Russian Romance Through the Nineteenth and Twentieth centuries

This performance dissertation traced the evolution of the Russian romance from 1800 to the present. The Russian romance is a relatively unknown and greatly neglected genre of classical art songs. It is commonly believed that the Russian romance began with Dargomizhsky and Glinka proceeding directly to Tchaikovsky and Rachmaninoff. Forgotten are the composers before Dargornizhsky and Glinka, the bridge composers, and the post-Tchaikovsky and post-Rachmaninoff composers. This may be, in part, because of the difficulties in obtaining Russian vocal scores. While most of the musical world is acquainted with the magnificent Russian instrumental music, the "true soul" of the Russian people lies in its romances. I presented examples of the two different schools of composition, reflecting their philosophical differences in thinking that came about in the 1860s: (1) Russian National school, (2) Western European school. Each school's influence on generations of Russian composers and their pupils have been represented in the recital programs. Also represented was the effect of the October Revolution on music and the voice of the Russian people, Anna Akhmatova. The amount of music that could be included in this dissertation greatly exceeds the amount of available performance time and represents a selected portion of the repertoire. The first recital included repertoire from the beginning of the romance in the early nineteenth century to the beginning of the twentieth century and the second recital focused on the music of the twentieth century, pre and post, the October Revolution. Finally, given the status of Anna Akhmatova and her contributions, the third recital was devoted entirely to her poetry. The "Russian soul" is one of deep, heartfelt emotions and sorrow. Happiness and joy are also present, but always with a touch of melancholy. The audience did not simply go through a musical journey, but took a journey through the "Russian soul". With the strong response of the audience to these recitals, my belief that this repertoire deserves a prominent place in recital programming was confirmed.

Evaluation of Altered Kras Codon Bias and NOS Inhibition During Lung Tumorigenesis

The small GTPases <italic>HRAS, <italic>NRAS and <italic>KRAS are mutated in approximately one-third of all human cancers, rendering the proteins constitutively active and oncogenic. Lung cancer is the leading cause of cancer deaths worldwide, and more than 20% of human lung cancers harbor mutations in <italic>RAS, with 98% of those occurring in the <italic>KRAS isoform. While there have been many advances in the understanding of <italic>KRAS–driven lung tumorigenesis, it remains a therapeutic challenge. To further this understanding and assess novel approaches for treatment, I have investigated two aspects of <italic>Kras–driven tumorigenesis in the lung:

(<italic>I) Despite nearly identical protein sequences, the three <italic>RAS proto-oncogenes exhibit divergent codon usage. Of the three isoforms, <italic>KRAS contains the most rare codons resulting in lower levels of KRAS protein expression relative to <italic>HRAS and <italic>NRAS. To determine the consequences of rare codon bias during <italic>de <italic>novo tumorigenesis, we created a knock-in <italic>Krasex3op mouse in which synonymous mutations in exon 3 converted codons from rare to common. These mice had reduced tumor burden and fewer oncogenic mutations in the <italic>Krasex3op allele following carcinogen exposure. The reduction in tumorigenesis appeared to be a product of rare codons affecting both the oncogenic and non–oncogenic alleles. Converting rare codons to common codons yielded a more potent oncogenic allele that promoted growth arrest and enhanced tumor suppression by the non-oncogenic allele. Thus, rare codons play an integral role in <italic>Kras tumorigenesis.

(<italic>II) Lung cancer patients exhale higher levels of NO and <italic>iNOS-/- mice are resistant to chemically induced lung tumorigenesis. I hypothesize that NO promotes <italic>Kras–driven lung adenocarcinoma, and NOS inhibition may decrease <italic>Kras–driven lung tumorigenesis. To test this hypothesis, I assessed efficacy of the NOS inhibitor L–NAME in a genetically engineered mouse model of <italic>Kras-driven lung adenocarcinoma. Adenoviral Cre recombinase was delivered into the lungs intranasally, resulting in expression of oncogenic <italic>KrasG12D and dominant-negative <italic>Trp53R172H in lung epithelial cells. L–NAME treatment was provided in the water and continued until survival endpoints. In this model, L–NAME treatment decreased tumor growth and prolonged survival. These data establish a potential clinical role for NOS inhibition in lung cancer treatment.

THE COMPLETE PRELUDES OF ALEXANDER SCRIABIN: THE EVOLUTION OF HIS REVOLUTIONARY COMPOSITIONAL STYLE

During the second half of the nineteenth century, a series of remarkable advances in musical composition emerged in the works of such innovative spirits as Franz Liszt, Hector Berlioz and Richard Wagner. Their pioneering works exerted an extraordinary impact on the music of the subsequent generation of composers--of disparate nationalities-who were active at the dawn of the 20th century: Including most notably Claude-Achille Debussy, Gustav Mahler, Richard Strauss, and Alexander Nikolayevich Scriabin. These important musical figures, each one leaving an indelible and formative imprint on late-nineteenth century Romantic style, together launched the modern era in music. Scriabin stands alone as a transcendental visionary: His music, initiated in the fashion of Chopin and Liszt, wanders through the realms of Debussy and Wagner, and, ultimately abandoning late Romantic tradition, unlocks the heretofore unforeseen power of atonality, bitonality, polyrhythms and key-signature free compositions. Arguably, Scriabin's compositions count among the most innovative, idiosyncratic and bewitching of all time. The development of Scriabin's groundbreaking compositional style is best understood by means of his piano works, which comprise the majority of his oeuvre. Beyond the larger works-his twelve sonatas, a concerto and a fantasy-Scriabin's piano explorations are also represented by miniature gems: The mazurkas, impromptus, waltzes, poems, a polonaise, etudes, nocturnes, morceaux and, in particular, the preludes. Scriabin's 90 preludes for piano, arranged in several opus numbers, richly exemplify the striking evolution of his ingenious music, his idiosyncratic philosophy and his provocative personality.

The effectiveness of low-level laser therapy for nonspecific chronic low back pain: a systematic review and meta-analysis.

BACKGROUND: In recent decades, low-level laser therapy (LLLT) has been widely used to relieve pain caused by different musculoskeletal disorders. Though widely used, its reported therapeutic outcomes are varied and conflicting. Results similarly conflict regarding its usage in patients with nonspecific chronic low back pain (NSCLBP). This study investigated the efficacy of low-level laser therapy (LLLT) for the treatment of NSCLBP by a systematic literature search with meta-analyses on selected studies. METHOD: MEDLINE, EMBASE, ISI Web of Science and Cochrane Library were systematically searched from January 2000 to November 2014. Included studies were randomized controlled trials (RCTs) written in English that compared LLLT with placebo treatment in NSCLBP patients. The efficacy effect size was estimated by the weighted mean difference (WMD). Standard random-effects meta-analysis was used, and inconsistency was evaluated by the I-squared index (I(2)). RESULTS: Of 221 studies, seven RCTs (one triple-blind, four double-blind, one single-blind, one not mentioning blinding, totaling 394 patients) met the criteria for inclusion. Based on five studies, the WMD in visual analog scale (VAS) pain outcome score after treatment was significantly lower in the LLLT group compared with placebo (WMD = -13.57 [95 % CI = -17.42, -9.72], I(2) = 0 %). No significant treatment effect was identified for disability scores or spinal range of motion outcomes. CONCLUSIONS: Our findings indicate that LLLT is an effective method for relieving pain in NSCLBP patients. However, there is still a lack of evidence supporting its effect on function.

Dinámica de la población de semillas de Sorghum halepense (L) Pers. en un suelo arable : I-efecto de la germinación (in situ)

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Utilising computational fluid dynamics (CFD) for the modelling of granular material in large-scale engineering processes

In this paper, the framework is described for the modelling of granular material by employing Computational Fluid Dynamics (CFD). This is achieved through the use and implementation in the continuum theory of constitutive relations, which are derived in a granular dynamics framework and parametrise particle interactions that occur at the micro-scale level. The simulation of a process often met in bulk solids handling industrial plants involving granular matter, (i.e. filling of a flat-bottomed bin with a binary material mixture through pneumatic conveying-emptying of the bin in core flow mode-pneumatic conveying of the material coming out of a the bin) is presented. The results of the presented simulation demonstrate the capability of the numerical model to represent successfully key granular processes (i.e. segregation/degradation), the prediction of which is of great importance in the process engineering industry.

Research in statistical education — planning of an international survey

As announced in the November 2000 issue of MathStats&OR [1], one of the projects supported by the Maths, Stats & OR Network funds is an international survey of research into pedagogic issues in statistics and OR. I am taking the lead on this and report here on the progress that has been made during the first year. A paper giving some background to the project and describing initial thinking on how it might be implemented was presented at the 53rd session of the International Statistical Institute in Seoul, Korea, in August 2001 in a session on The future of statistics education research [2]. It sounded easy. I considered that I was something of an expert on surveys having lectured on the topic for many years and having helped students and others who were doing surveys, particularly with the design of their questionnaires. Surely all I had to do was to draft a few questions, send them electronically to colleagues in statistical education who would be only to happy to respond, and summarise their responses? I should have learnt from my experience of advising all those students who thought that doing a survey was easy and to whom I had to explain that their ideas were too ambitious. There are several inter-related stages in survey research and it is important to think about these before rushing into the collection of data. In the case of the survey in question, this planning stage revealed several challenges. Surveys are usually done for a purpose so even before planning how to do them, it is advisable to think about the final product and the dissemination of results. This is the route I followed.

Modelling the behavior of solder joints for wafer level SiP

Design for manufacture of system-in-package (SiP) structures is dependent on a number of physical processes that affect the final quality of the package in terms of its performance and reliability. Solder joints are key structures in a SiP and their behavior can be the critical factor in terms of reliability. This paper discusses the results from a research programme on design for manufacturing of system in package (SiP) technologies. The focus of the paper is on thermo-mechanical modelling of solder joints. This includes the behavior of the joints during testing plus some important insights into the reflow process and how physical phenomena taking place at the assembly stage can affect solder joint behavior. Finite element analysis of a numerical model of an SiP structure with various design parameters is discussed. The goal of this analysis is to identify the most promising combination of design parameters which guarantee longer lifetime of the solder joints and hence the SiP component. The parameters that were studied are the size of the package (i.e. number of solder joints per row), the presence of the underfill and/or the reinforcement as well as the thickness of the passive die. Discussion was also provided on phenomena that take place during the reflow process where the solder joints are formed. In particular, the formation of intermetallics at the solder-pad interfaces

A regional chemostratigraphically-defined correlation framework for the late Triassic TAG-I Formation in Blocks 402 and 405a, Algeria

The Triassic Argilo-Gréseux Inférieur Formation (TAG-I) is one of the principal hydrocarbon reservoirs in the Berkine Basin of Algeria. Sedimentological studies have shown that it exhibits marked spatial and temporal facies variations on both a local field scale and a regional basinal scale. This variability, combined with a lack of diagnostic flora and fauna, makes regional correlation within the unit difficult. In turn, the lack of a consistent regional stratigraphic framework hampers the comparison of the various correlation schemes devised by operators in the basin. Contrasting the TAG-I in Blocks 402 and 405a exemplifies the problems encountered when attempting regionally to define a correlation framework for the interval. Between these two blocks, a distance of approximately 200 km, there are marked changes in the style of deposition from sand-dominated, proximal fluvial systems in the SW (Block 405a, MLN, MLC, KMD and MLNW fields) to a more distal, more clay-prone system in the NE (Block 402, ROD/BRSE/BSFN, SFNE and BSF fields). A chemostratigraphic study of the TAG-I in these two blocks has allowed a four-fold correlation framework to be defined, where each chemostratigraphic package has distinctive geochemical features. Chemostratigraphic Package 10, the oldest unit, lies above the Hercynian Unconformity, but beneath a geochemically identifiable hiatal surface. Chemostratigraphic Package 20 lies above the hiatal surface but is separated from the overlying packages by a mineralogical change identifiable in both claystone and sandstone geochemistry. Chemostratigraphic Packages 30 and 40 are chemically somewhat similar, but are separated by a regional event interpreted as a period of dolocrete and lacustrine development. By combining the geochemical differentiation of the units and recognition of their stratal boundaries, it is possible to define a correlation for the TAG-I between Blocks 402 and 405a. The proposed correlation between the two blocks suggests that the northern parts of Block 405a may have been occupied by a spur or subsidiary channel from the main SW–NE-trending fluvial system, resulting in one of the chemically defined packages being demonstrably absent in the MLNW, MLN, KMD and MLC fields when compared with the other areas of the study.

Leucine Aminopeptidase (Aminopeptidase-I) N-Acetyl-Beta-Hexosaminidase And Lysosomes In The Mussel Mytilus-Edulis-L In Response To Salinity Changes

The intracellular distribution of aminopeptidase-I in the intestinal and digestive cells of Mytilus edulishas been shown to be the same as the lysosomal marker enzymes β-glucuronidase and N-acetyl-β-hexosaminidase. Activity for these enzymes was also associated with the intestinal apical cytoplasm and microvillous border where there was pronounced staining for aminopeptidase-I. Experimental alterations of salinity induced changes in both microdensitometrically and spectrophotometrically determined aminopeptidase-I activity, as an increase with raised salinity and a decrease with lowered salinity. Lysosomal hexosaminidase showed similar changes in activity with altered salinity. Cytochemically determined lysosomal stability was also responsive to salinity changes, indicative of alterations in lysosomal functional capability. The lysosomal distribution of aminopeptidase-I is discussed in terms of the function of lysosomes in intracellular protein turnover, their high concentrations of free amino acids, and the possible roles which these might play in intracellular osmoregulation in response to salinity change.