Bioconductor: Open software development for computational biology and bioinformatics

The Bioconductor project is an initiative for the collaborative creation of extensible software for computational biology and bioinformatics. We detail some of the design decisions, software paradigms and operational strategies that have allowed a small number of researchers to provide a wide variety of innovative, extensible, software solutions in a relatively short time. The use of an object oriented programming paradigm, the adoption and development of a software package system, designing by contract, distributed development and collaboration with other projects are elements of this project's success. Individually, each of these concepts are useful and important but when combined they have provided a strong basis for rapid development and deployment of innovative and flexible research software for scientific computation. A primary objective of this initiative is achievement of total remote reproducibility of novel algorithmic research results.

Heparin-induced thrombocytopenia: some working hypotheses on pathogenesis, diagnostic strategies and treatment

PURPOSE OF REVIEW: The present contribution will illustrate some evolving concepts on the pathogenesis and clinical management of heparin-induced thrombocytopenia (HIT) and describe how we approach patients with suspected HIT at our institution. RECENT FINDINGS: HIT is caused by an autoimmune reaction leading to the formation of antibodies directed against platelet factor 4. Conditions favoring the development of anti-platelet factor 4/heparin antibodies differ from those required for the formation of macromolecular ternary complexes (HIT antibody/platelet factor 4/heparin), which are able to activate platelets and induce clinical HIT. HIT can be diagnosed by combining its pretest probability with the quantitative result of rapid HIT-antibody assays. Treatment of acute HIT requires inhibition of in-vivo thrombin generation by means of alternative nonheparin anticoagulant drugs, whose effective dosage appears to be significantly lower than the official recommendations. As HIT antibodies are transient, HIT patients can be re-exposed to heparin, provided that previous heparin treatment is remote and that anti-platelet factor 4/heparin antibodies are undetectable. SUMMARY: In recent years, there has been a continuing elucidation of pathogenic and clinically relevant issues, which are intellectually rewarding to follow and should enable us to offer a steadily improving treatment to the HIT patients we are in charge of.

Cardiovascular risk factors impair native collateral development and may impair efficacy of therapeutic interventions

Animal and early clinical studies of gene therapy for tissue ischaemia suggested that this approach might provide benefit to patients with coronary artery disease not amenable to traditional revascularization. This enthusiasm was then tempered by the subsequent disappointing results of randomized clinical trials and led researchers to develop strategies using progenitor cells as an alternative to improve collateral function. However, the recent publication of several randomized clinical trials reporting either negative or weakly positive results using this approach have led to questions regarding its effectiveness. There are several factors that need to be considered in explaining the discordance between the positive studies of such treatments in animals and the disappointing results seen in randomized patient trials. Aside from the practical issues of arteriogenic therapies, such as effective delivery, vascular remodelling is an extraordinarily complex process, and the administration of a single agent or cell in the hope that it would lead to lasting physiological effects may be far too simplistic an approach. In addition, however, evidence now suggests that many of the traditional cardiovascular risk factors-such as age and hypercholesterolemia-may impair the host response not only to ischaemia but, critically, also to treatment as well. This review discusses the evidence and mechanisms for these observations and highlights future directions that might be taken in an effort to provide more effective therapies.

Assessing Decision Making Strategies In Construction Management By Using A Schedule-Based Simulation Framework

During the project, managers encounter numerous contingencies and are faced with the challenging task of making decisions that will effectively keep the project on track. This task is very challenging because construction projects are non-prototypical and the processes are irreversible. Therefore, it is critical to apply a methodological approach to develop a few alternative management decision strategies during the planning phase, which can be deployed to manage alternative scenarios resulting from expected and unexpected disruptions in the as-planned schedule. Such a methodology should have the following features but are missing in the existing research: (1) looking at the effects of local decisions on the global project outcomes, (2) studying how a schedule responds to decisions and disruptive events because the risk in a schedule is a function of the decisions made, (3) establishing a method to assess and improve the management decision strategies, and (4) developing project specific decision strategies because each construction project is unique and the lessons from a particular project cannot be easily applied to projects that have different contexts. The objective of this dissertation is to develop a schedule-based simulation framework to design, assess, and improve sequences of decisions for the execution stage. The contribution of this research is the introduction of applying decision strategies to manage a project and the establishment of iterative methodology to continuously assess and improve decision strategies and schedules. The project managers or schedulers can implement the methodology to develop and identify schedules accompanied by suitable decision strategies to manage a project at the planning stage. The developed methodology also lays the foundation for an algorithm towards continuously automatically generating satisfactory schedule and strategies through the construction life of a project. Different from studying isolated daily decisions, the proposed framework introduces the notion of {em decision strategies} to manage construction process. A decision strategy is a sequence of interdependent decisions determined by resource allocation policies such as labor, material, equipment, and space policies. The schedule-based simulation framework consists of two parts, experiment design and result assessment. The core of the experiment design is the establishment of an iterative method to test and improve decision strategies and schedules, which is based on the introduction of decision strategies and the development of a schedule-based simulation testbed. The simulation testbed used is Interactive Construction Decision Making Aid (ICDMA). ICDMA has an emulator to duplicate the construction process that has been previously developed and a random event generator that allows the decision-maker to respond to disruptions in the emulation. It is used to study how the schedule responds to these disruptions and the corresponding decisions made over the duration of the project while accounting for cascading impacts and dependencies between activities. The dissertation is organized into two parts. The first part presents the existing research, identifies the departure points of this work, and develops a schedule-based simulation framework to design, assess, and improve decision strategies. In the second part, the proposed schedule-based simulation framework is applied to investigate specific research problems.

The potential effect of population development, smoking and antioxidant supplementation on the future epidemiology of age-related macular degeneration in Switzerland

BACKGROUND: Due to the predicted age shift of the population an increase in the number of patients with late AMD is expected. At present smoking represents the only modifiable risk factor. Supplementation of antioxidants in patients at risk is the sole effective pharmacological prevention. The aim of this study is to estimate the future epidemiological development of late AMD in Switzerland and to quantify the potential effects of smoking and antioxidants supplementation. METHODS: The modelling of the future development of late AMD cases in Switzerland was based on a meta-analysis of the published data on AMD-prevalence and on published Swiss population development scenarios until 2050. Three different scenarios were compared: low, mean and high. The late AMD cases caused by smoking were calculated using the "population attributable fraction" formula and data on the current smoking habits of the Swiss population. The number of potentially preventable cases was estimated using the data of the Age-Related Eye Disease Study (AREDS). RESULTS: According to the mean population development scenario, late AMD cases in Switzerland will rise from 37 200 cases in 2005 to 52 500 cases in 2020 and to 93 200 cases in 2050. Using the "low" and the "high" scenarios the late AMD cases may range from 49 500 to 56 000 in 2020 and from 73 700 to 118 400 in 2050, respectively. Smoking is responsible for approximately 7 % of all late AMD cases, i. e., 2600 cases in 2005, 3800 cases in 2020, 6600 cases in 2050 ("mean scenario"). With future antioxidant supplementation to all patients at risk another 3100 cases would be preventable until 2020 and possibly 23 500 cases until 2050. CONCLUSION: Due to age shift in the population a 2.5-fold increase in late AMD cases until 2050 is expected, representing a socioeconomic challenge. Cessation of smoking and supplementation of antioxidants to all patients at risk has the potential to reduce this number. Unfortunately, public awareness is low. These data may support health-care providers and public opinion leaders when developing public education and prevention strategies.

Strategies to determine the biological function of microRNAs

MicroRNAs (miRNAs) are regulators of gene expression that control many biological processes in development, differentiation, growth and metabolism. Their expression levels, small size, abundance of repetitive copies in the genome and mode of action pose unique challenges in studies elucidating the function of miRNAs. New technologies for identification, expression profiling and target gene validation, as well as manipulation of miRNA expression in vivo, will facilitate the study of their contribution to biological processes and disease. Such information will be crucial to exploit the emerging knowledge of miRNAs for the development of new human therapeutic applications.

THE EXPERIENCE OF RESEARCH, GROWTH, DEVELOPMENT AND LEADERSHIP OF THE MiTEP PROGRAM

Chapter 1. The Action Research in this report was to focus on improving the reading comprehension of students with expository text in relation to identifying the main idea and supporting details. Students were given an expository text to read and identify main idea and 2 -3 supporting details as a pre assessment. Students were provided instruction and support in DRTA (Directed Reading Thinking Activity) and SQ3R (Survey, Question, Read, Recite, Review) methodology to identify the Main Idea and supporting details of a selected expository text for both pre & posttest. Results were compiled and analyzed on the effectiveness of the strategies by overall student growth in accurately identifying the Main Idea and being able to state at least 2 supporting details. Analysis of the data will show that the methods were effective in middle school students’ ability to read and extrapolate the necessary information from expository text. Chapter 2 is a reflective essay on the MiTEP Michigan Teacher Excellence Program and its impact on my teaching practices, lesson delivery and leadership development.

On producing and sharing knowledge across boundaries: experiences from the interfaces of an international development research network

The number of large research networks and programmes engaging in knowledge production for development has grown over the past years. One of these programmes devoted to generating knowledge about and for development is National Centre of Competence in Research (NCCR) North–South, a cross-disciplinary, international development research network funded by the Swiss Agency for Development and Cooperation and the Swiss National Science Foundation. Producing relevant knowledge for development is a core goal of the programme and an important motivation for many of the participating researchers. Over the years, the researchers have made use of various spaces for exchange and instruments for co-production of knowledge by academic and non-academic development actors. In this article we explore the characteristics of co-producing and sharing knowledge in interfaces between development research, policy and NCCR North–South practice. We draw on empirical material of the NCCR North–South programme and its specific programme element of the Partnership Actions. Our goal is to make use of the concept of the interface to reflect critically about the pursued strategies and instruments applied in producing and sharing knowledge for development across boundaries.

Challenges and strategies in the repair of ruptured annulus fibrosus

Lumbar discectomy is the surgical procedure most frequently performed for patients suffering from low back pain and sciatica. Disc herniation as a consequence of degenerative or traumatic processes is commonly encountered as the underlying cause for the painful condition. While discectomy provides favourable outcome in a majority of cases, there are conditions where unmet requirements exist in terms of treatment, such as large disc protrusions with minimal disc degeneration; in these cases, the high rate of recurrent disc herniation after discectomy is a prevalent problem. An effective biological annular repair could improve the surgical outcome in patients with contained disc herniations but otherwise minor degenerative changes. An attractive approach is a tissue-engineered implant that will enable/stimulate the repair of the ruptured annulus. The strategy is to develop three-dimensional scaffolds and activate them by seeding cells or by incorporating molecular signals that enable new matrix synthesis at the defect site, while the biomaterial provides immediate closure of the defect and maintains the mechanical properties of the disc. This review is structured into (1) introduction, (2) clinical problems, current treatment options and needs, (3) biomechanical demands, (4) cellular and extracellular components, (5) biomaterials for delivery, scaffolding and support, (6) pre-clinical models for evaluation of newly developed cell- and material-based therapies, and (7) conclusions. This article highlights that an interdisciplinary approach is necessary for successful development of new clinical methods for annulus fibrosus repair. This will benefit from a close collaboration between research groups with expertise in all areas addressed in this review.

Equine parasite control under prescription-only conditions in Denmark - Awareness, knowledge, perception, and strategies applied.

Due to widespread development of anthelmintic resistance in equine parasites, recommendations for their control are currently undergoing marked changes with a shift of emphasis toward more coprological surveillance and reduced treatment intensity. Denmark was the first nation to introduce prescription-only restrictions of anthelmintic drugs in 1999, but other European countries have implemented similar legislations over recent years. A questionnaire survey was performed in 2008 among Danish horse owners to provide a current status of practices and perceptions with relation to parasite control. Questions aimed at describing the current use of coprological surveillance and resulting anthelmintic treatment intensities, evaluating knowledge and perceptions about the importance of various attributes of parasite control, and assessing respondents' willingness to pay for advice and parasite surveillance services from their veterinarians. A total of 1060 respondents completed the questionnaire. A large majority of respondents (71.9%) were familiar with the concept of selective therapy. Results illustrated that the respondents' self-evaluation of their knowledge about parasites and their control associated significantly with their level of interest in the topic and their type of education (P<0.0001). The large majority of respondents either dewormed their horses twice a year and/or performed two fecal egg counts per horse per year. This approach was almost equally pronounced in foals, horses aged 1-3 years old, and adult horses. The respondents rated prevention of parasitic disease and prevention of drug resistance as the most important attributes, while cost and frequent fecal testing were rated least important. Respondents' actual spending on parasite control per horse in the previous year correlated significantly with the amount they declared themselves willing to spend (P<0.0001). However, 44.4% declared themselves willing to pay more than what they were spending. Altogether, results indicate that respondents were generally familiar with equine parasites and the concept of selective therapy, although there was some confusion over the terms small and large strongyles. They used a large degree of fecal surveillance in all age groups, with a majority of respondents sampling and/or treating around twice a year. Finally, respondents appeared willing to spend money on parasite control for their horses. It is of concern that the survey suggested that foals and young horses are treated in a manner very similar to adult horses, which is against current recommendations. Thus, the survey illustrates the importance of clear communication of guidelines for equine parasite control.

Language and executive functioning: Children’s benefit from induced verbal strategies in different tasks

The interplay of language and cognition in children’s development has been subject to research for a long time. The present study followed up on recently reported deleterious effects of articulatory suppression on children’s executive functioning (Fatzer & Roebers, 2012), aiming to provide more empirical evidence on the differential influence of language on executive functioning. In the present study, verbal strategies were induced in three executive functioning tasks. The tasks were linked to the three central executive functioning dimensions of updating (Complex Span task), shifting (Cognitive Flexibility task) and inhibition (Flanker task). It was expected that the effects of the verbal strategy instruction would counter the results of articulatory suppression and thus be strong in the Complex Span task, weak but present in the Cognitive Flexibility task and small or nonexistent in the Flanker task. N = 117 children participated in the study, with n = 39 four-year-olds, n = 38 six-year-olds, and n = 40 nine-year-olds. As expected, results revealed a benefit from induced verbal strategies in the Complex Span and the Cognitive Flexibility task, but not in the Flanker task. The positive effect of strategy instruction declined with increasing age, pointing to more frequent spontaneous and self-initiated use of verbal strategies over the course of development. The effect of strategy instruction in the Cognitive Flexibility task was unexpectedly strong in the light of the only small detrimental effect of articulatory suppression in the preceding study. Implications for language’s involvement in the different executive functioning dimensions and for practice are discussed.

Potentials and constraints of modeling for transdisciplinary co-producing strategies for sustainable water governance

Both climate change and socio-economic development will significantly modify the supply and consumption of water in future. Consequently, regional development has to face aggravation of existing or emergence of new conflicts of interest. In this context, transdisciplinary co-production of knowledge is considered as an important means for coping with these challenges. Accordingly, the MontanAqua project aims at developing strategies for more sustainable water management in the study area Crans-Montana-Sierre (Switzerland) in a transdisciplinary way. It strives for co-producing system, target and transformation knowledge among researchers, policy makers, public administration and civil society organizations. The research process basically consisted of the following steps: First, the current water situation in the study region was investigated. How much water is available? How much water is being used? How are decisions on water distribution and use taken? Second, participatory scenario workshops were conducted in order to identify the stakeholders’ visions of regional development. Third, the water situation in 2050 was simulated by modeling the evolution of water resources and water use and by reflecting on the institutional aspects. These steps laid ground for jointly assessing the consequences of the stakeholders’ visions of development in view of scientific data regarding governance, availability and use of water in the region as well as developing necessary transformation knowledge. During all of these steps researchers have collaborated with stakeholders in the support group RegiEau. The RegiEau group consists of key representatives of owners, managers, users, and pressure groups related to water and landscape: representatives of the communes (mostly the presidents), the canton (administration and parliament), water management associations, agriculture, viticulture, hydropower, tourism, and landscape protection. The aim of the talk is to explore potentials and constraints of scientific modeling of water availability and use within the process of transdisciplinary co-producing strategies for more sustainable water governance.

THE ROLE OF TAK1 IN PANCREATIC CANCER DEVELOPMENT

Pancreatic cancer is the fourth leading cause of cancer-related mortality in the United States and the fifth leading cause of cancer-related mortality worldwide. Pancreatic cancer is a big challenge in large due to the lack of early symptoms. In addition, drug resistance is a major obstacle to the success of chemotherapy in pancreatic cancer. The underlying mechanism of drug resistance in human pancreatic cancers is not well understood. Better understanding of the mechanism of molecular pathways in human pancreatic cancers can help to identify the novel therapeutic target candidates, and develop the new preventive and clinic strategies to improve patient survival. We discovered that TAK1 is overexpressed in pancreatic cancer cell lines and patient tumor tissues. We demonstrated that the elevated activity of TAK1 is caused by its binding partner TAB1. Knocking down of TAK1 in pancreatic cancer cells with RNAi technique resulted in cell apoptosis and significantly reduces the size of tumors in mice and made a chemotherapy drug more potent. Targeting the kinase activity of TAK1 with the selective inhibitor LY2610956 strongly synergized in vitro with the antitumor activity of gemcitabine, oxaliplatin, or irinotecan on pancreatic cancer cells. These findings highlighted that TAK1 could be a potential therapeutic target for pancreatic cancer. We also demonstrated that TAK activity is regulated by its binding protein TAB1. We defined a minimum TAB1 sequence which is required and sufficient for TAK1 kinase activity. We created a recombinant TAK1-TAB1 C68 fusion form which has highly kinase activity. This active form could is used for screening TAK1 inhibitors. In addition, several posttranslational modifications were identified in our study. The acetylation of lysine 158 on TAK1 is required for kinase activity. This site is conserved throughout all of kinase. Our findings may reveal a new mechanism by which kinase activity is regulated.

Development of prostate cancer gene therapy

Osseous metastases account for most of the morbidity and mortality associated with prostate cancer, for which there are currently no effective therapies. In the skeletal metastatic environment, neoplastic prostatic epithelial cells interact in a bidirectional stimulatory manner with osteoblastic stromal cells. Similarly, the presence of osteoblastic cells is essential for the survival and maintenance of intraosseous prostate cancer cells. In this thesis, I have developed novel gene therapy strategies for the treatment of androgen-independent human prostate cancers in experimental animal models. First, Ad-CMV-p53, a recombinant adenovirus (Ad) containing p53 tumor suppressor gene driven by the universal cytomegalovirus promoter, was effective in inhibiting prostate cancer cell growth, and direct intratumoral injections of Ad-CMV-p53 resulted in tumor regression. Second, because prostate cancer cells as well as osteoblastic cells produce osteocalcin (OC), OC promoter mediated tissue/tumor specific toxic gene therapy is developed to interrupt stromal-epithelial communications by targeting both cell types. Ad-OC-TK, a recombinant Ad containing the herpes simplex virus thymidine kinase (TK) gene driven by the OC promoter, was generated to inhibit the growth of osteoblastic osteosarcoma with prodrug acyclovir (ACV). Ad-OC-TK/ACV also inhibited the growth of prostate cancer cells and suppressed the growth of subcutaneous and intraosseous prostate tumor. In order to combine treatment modalities to maximize tumor cell-kill with minimized host toxicities, Ad-OC-TK/ACV was applied in combination with low dose methotrexate to eradicate osteoblastic osteosarcoma. In targeting of micrometastatic disease, intravenous Ad-OC-TK/ACV treatment resulted in significant tumor nodule reduction and prolonged the survival of animals harboring osteosarcoma lung metastases without significant host toxicity. Ad-OC-TK is a rational choice for the treatment of prostate cancer skeletal metastasis because OC is uniformly detected in both primary and metastatic human prostate cancer specimens by immunohistochemistry. Ad-OC-TK/ACV inhibits the growth not only of prostate cancer cells but also of their supporting bone stromal cells. Targeting both prostate cancer epithelium and its supporting stroma may be most efficacious for the treatment of prostate cancer osseous metastases. ^

Stage-dependent strategies of host invasion in the egg-larval parasitoid Chelonus inanitus.

Chelonus inanitus (Braconidae) is a solitary egg-larval parasitoid which lays its eggs into eggs of Spodoptera littoralis (Noctuidae); the parasitoid larva then develops in the haemocoel of the host larva. Host embryonic development lasts approx. 3.5 days while parasitoid embryonic development lasts approx. 16 h. All stages of host eggs can be successfully parasitized, and we show here that either the parasitoid larva or the wasp assures that the larva eventually is located in the host's haemocoel. (1) When freshly laid eggs, up to almost 1-day-old, are parasitized, the parasitoid hatches while still in the yolk and enters the host either after waiting or immediately through the dorsal opening. (2) When 1-2-day-old eggs are parasitized, the host embryo has accomplished final dorsal closure and is covered by an embryonic cuticle when the parasitoid hatches; in this case the parasitoid larva bores with its moving abdominal tip into the host. (3) When 2.5-3.5-day-old eggs are parasitized, the wasp oviposits directly into the haemocoel of the host embryo; from day 2 to 2.5 the embryo is still very small and the wasps, after probing, often restrain from oviposition for a few hours.