A field study on characteristics and diversity of gene expression in the liver of dairy cows during the transition period

Metabolic and endocrine adaptations to support milk production during the transition period vary between individual cows. This variation between cows to adapt to lactation may have a genetic basis. The present field study was carried out to determine hepatic adaptations occurring from late pregnancy through early lactation by measuring mRNA abundance of candidate genes in dairy cows on-farm. Additionally, the objective was to observe the diversity in inter-individual variation for the candidate genes that may give indications where individual adaptations at a molecular level can be found. This study was carried out on-farm including 232 dairy cows (parity >3) from 64 farms in Switzerland. Blood and liver samples were collected on d 20+/-7 before parturition, on d 24+/-2, and on d 89+/-4 after parturition. Blood plasma was assayed for concentrations of glucose, nonesterified fatty acids, beta-hydroxybutyrate, cholesterol, triglycerides, urea, albumin, protein, insulin, insulin-like growth factor-1, leptin, 3,5,3'-triiodothyronine, and thyroxine. Liver samples were obtained at the same time points and were measured for mRNA abundance of 26 candidate genes encoding enzymes and nuclear receptors involved in gluconeogenesis, fatty acid beta-oxidation, fatty acid and triglyceride synthesis, ketogenesis, citric acid cycle, cholesterol synthesis, and the urea cycle. The cows in the present study experienced a marked metabolic load in early lactation, as presented by changes in plasma metabolites and hormones, and responded accordingly with upregulation and downregulation of almost all candidate genes involved in metabolic processes in the liver. The observed inter-individual variation for the candidate genes, which was highest for acetyl-CoA-carboxylase and glycerol-3-phosphate dehydrogenase 2, should be further investigated to unravel the regulation at molecular level for optimal adaptive performance in dairy cows.

Gene expression of tumour necrosis factor and insulin signalling-related factors in subcutaneous adipose tissue during the dry period and in early lactation in dairy cows

Gene expression of adipose factors, which may be part of the mechanisms that underlie insulin sensitivity, were studied in dairy cows around parturition. Subcutaneous fat biopsies and blood samples were taken from 27 dairy cows in week 8 antepartum (a.p.), on day 1 postpartum (p.p.) and in week 5 p.p. In the adipose tissue samples, mRNA was quantified by real-time reverse transcription polymerase chain reaction for tumour necrosis factor alpha (TNFalpha), insulin-independent glucose transporter (GLUT1), insulin-responsive glucose transporter (GLUT4), insulin receptor, insulin receptor substrate 1 (IRS1), insulin receptor substrate 2 (IRS2), regulatory subunit of phosphatidylinositol-3 kinase (p85) and catalytic subunit of phosphatidylinositol-3 kinase. Blood plasma was assayed for concentrations of glucose, beta-hydroxybutyric acid, non-esterified fatty acids (NEFA) and insulin. Plasma parameters followed a pattern typically observed in dairy cows. Gene expression changes were observed, but there were no changes in TNFalpha concentrations, which may indicate its local involvement in catabolic adaptation of adipose tissue. Changes in GLUT4 and GLUT1 mRNA abundance may reflect their involvement in reduced insulin sensitivity and in sparing glucose for milk synthesis in early lactation. Unchanged gene expression of IRS1, IRS2 and p85 over time may imply a lack of their involvement in terms of insulin sensitivity dynamics. Alternatively, it may indicate that post-transcriptional modifications of these factors came into play and may have concealed an involvement.

THE RESONATE-AND-FIRE NEURON: TIME DEPENDENT AND FREQUENCY SELECTIVE NEURONS IN NEURAL NETWORKS

The means through which the nervous system perceives its environment is one of the most fascinating questions in contemporary science. Our endeavors to comprehend the principles of neural science provide an instance of how biological processes may inspire novel methods in mathematical modeling and engineering. The application ofmathematical models towards understanding neural signals and systems represents a vibrant field of research that has spanned over half a century. During this period, multiple approaches to neuronal modeling have been adopted, and each approach is adept at elucidating a specific aspect of nervous system function. Thus while bio-physical models have strived to comprehend the dynamics of actual physical processes occurring within a nerve cell, the phenomenological approach has conceived models that relate the ionic properties of nerve cells to transitions in neural activity. Further-more, the field of neural networks has endeavored to explore how distributed parallel processing systems may become capable of storing memory. Through this project, we strive to explore how some of the insights gained from biophysical neuronal modeling may be incorporated within the field of neural net-works. We specifically study the capabilities of a simple neural model, the Resonate-and-Fire (RAF) neuron, whose derivation is inspired by biophysical neural modeling. While reflecting further biological plausibility, the RAF neuron is also analytically tractable, and thus may be implemented within neural networks. In the following thesis, we provide a brief overview of the different approaches that have been adopted towards comprehending the properties of nerve cells, along with the framework under which our specific neuron model relates to the field of neuronal modeling. Subsequently, we explore some of the time-dependent neurocomputational capabilities of the RAF neuron, and we utilize the model to classify logic gates, and solve the classic XOR problem. Finally we explore how the resonate-and-fire neuron may be implemented within neural networks, and how such a network could be adapted through the temporal backpropagation algorithm.

National Identity in Lithuania: Processes During the Period of Changes

Under the conditions of rapid and total change in the social, political, economic and legal environment in Lithuania, a re-orientation process is going on in all groups of society. In this process, not only younger but also middle-aged and old people become adherents to what Ms. Liubiniene calls the new, "post-materialist" values, strongly reinforced by powerful agents of socialisation originating in the West, like the media, advertising agencies and lifestyle-consumption models. As a result, the national identity of Lithuania and its inhabitants is being reconstructed. Ms. Liubiniene set out to examine the details of this evolving identity by conducting a survey of 1218 university staff and students. Her conclusions are set out in a 74 page manuscript, written in Lithuanian and available on disc. Change is most noticeable among the young. Indeed, time and time again, Ms. Liubiniene was to find that the age of 36 marks a natural watershed, with, for instance, the younger group valuing individualism highly and the older, collectivism. Ms. Liubiniene ventures to suggest that traditional values are deeply rooted amongst elderly people, women and people with an education in the humanities. Young people on the other hand, and especially those with a professional orientation towards business are more open to change and ready to adapt to new values. Turning to the evaluation of national symbols, Ms. Liubinie finds that those with an education in the humanities might be considered to be the most traditional, placing greater value on the symbols of nature, ethnic culture and religion. Folk songs and the crucifix are also in their top ten. Respondents with a technical education favour symbols of statehood and nature, and respondents with a business orientation assign greater value to the symbols of nature, history, sports and statehood. Ms. Liubinie concludes that the group of respondents most active and ready to adapt to new things is composed of young males of a business orientation. Generally the national identity of the young is weaker compared to that of the old. In the future, the combination of the evolution of values and the process of inter-generational replacement allows us to predict a weakening of the sense of national identity, or at least its transformation into something radically different to what it is today.

Civil Society and Political Parties in the Period of Transition

The major aim of Mr. Marada's project was to investigate the role of political parties on the one hand, and various institutional forms of civil society on the other, in the process of establishing mechanisms of political decision-making and policy-formation in Czechoslovakia and the Czech Republic, after November 1989. Mr. Marada wanted to examine what consequences the interplay and tensions between political parties and institutions of civil society had on the status and practical understanding of citizenship and civil society. At the beginning of his research Mr. Marada found that, while the sphere of the political was relatively clearly defined, the phenomenon of civil society required a conceptual clarification. He devoted a great deal of time to analysing the emergence, development, and disintegration of Civic Forum as the major agent of the regime change and subsequent political reforms. Alongside this analysis is a commentary on Czech society in general, drawing on established research to show how, as yet, a kind of civic incompetence reigns within the country, and how this situation has its roots in the belief, promoted by politicians themselves, that politics is an activity for experts only. The final outcome of his research took the form of a series of articles, in English, totalling 40 pages.

The Monumental Barrows of the Period 700-1100 AD at the Russian North-West

Nicholas Petrov. The Monumental Barrows of the Period 700-11 AD in the Russian North-West The research deals with the monumental barrows erected in the Russian north-west in the period of 700-1100 AD, which Russian archaeological literature has traditionally named sopka-barrows. These sopka-barrows were analysed as original sacral and funeral structures and considered in the context of cultural processes under way in that region at the time. The position occupied by the sopka-barrows in the culture of the people who erected them was reconstructed on the basis of a synthesis of various kinds of sources - archaeological, written, folklore. The high barrows are not in fact a determining type of the sites of the so-called "culture of the sopka-barrows" in modern literature, which focuses rather on settlements near to which sopka-barrows are absent. Recent excavations have revealed the presence of "surface" burial places (cremation located on the top of the barrow repeatedly rather than only once) in the majority of the sopka-barrows. The materials only provide evidence about the sacrificial nature of the graves in the "body" of the sopka-barrows. They thus offer an embodiment of one element of the widespread views about the dead man's path to the world of the dead (mountain) which is traced in folklore texts. Special attention was paid to the question of the disappearance of the tradition of erecting sopka-barrows and to the nature of their role in the culture of the region during the period 1000-1200 AD. The functioning of the sopka-barrows as funeral monuments in the second millennium AD is also traced on the inlet inhumatios found in them.

Changing Values in a Transitional Period

This project examined the change in values in the still unfinished transitional period in Serbia during the 1990s and compared it with Greece in the same period. During this period the social and political transition affected the ruling value system primarily through changes in the modes of the production and representation of reality. The most remarkable trait of this period in Serbia is the parallel and interweaving existence of different value systems. The very perception of reality has been blurred by the emergence of a very complex technical and ideological structure. Reality is presented by and through extensions and additions, the models of which are language and media. With the development of media technology and global communication and information systems, representation has become the only available reality. This enables the media to overtly and unlimitedly intervene in reality, to manage and change it without constraint and thus have a direct impact on values. The difference between public and private is abolished, so the media start promoting exclusive collective values. However, since the collective thus loses its counterpart, it itself needs to be redefined. This confusion of values make the possible results of their change uncertain. It will either open up a space for multiculturalism and social pluralism and thus completely replace the old systems of values, or result in an indefinite survival of different, often contradictory, value systems and conceptions of reality, which often lead to all forms of exclusivity and intolerance.

The origin of the European Medieval Warm Period"

Proxy records and results of a three dimensional climate model show that European summer temperatures roughly a millennium ago were comparable to those of the last 25 years of the 20th century, supporting the existence of a summer "Medieval Warm Period" in Europe. Those two relatively mild periods were separated by a rather cold era, often referred to as the "Little Ice Age". Our modelling results suggest that the warm summer conditions during the early second millennium compared to the climate background state of the 13th–18th century are due to a large extent to the long term cooling induced by changes in land-use in Europe. During the last 200 years, the effect of increasing greenhouse gas concentrations, which was partly levelled off by that of sulphate aerosols, has dominated the climate history over Europe in summer. This induces a clear warming during the last 200 years, allowing summer temperature during the last 25 years to reach back the values simulated for the early second millennium. Volcanic and solar forcing plays a weaker role in this comparison between the last 25 years of the 20th century and the early second millennium. Our hypothesis appears consistent with proxy records but modelling results have to be weighted against the existing uncertainties in the external forcing factors, in particular related to land-use changes, and against the uncertainty of the regional climate sensitivity. Evidence for winter is more equivocal than for summer. The forced response in the model displays a clear temperature maximum at the end of the 20th century. However, the uncertainties are too large to state that this period is the warmest of the past millennium in Europe during winter.

The Impact of Uncertainty in the AIDS Incubation Period on Reconstructions of the HIV Epidemic

Backcalculation is the primary method used to reconstruct past human immunodeficiency virus (HIV) infection rates, to estimate current prevalence of HIV infection, and to project future incidence of acquired immunodeficiency syndrome (AIDS). The method is very sensitive to uncertainty about the incubation period. We estimate incubation distributions from three sets of cohort data and find that the estimates for the cohorts are substantially different. Backcalculations employing the different estimates produce equally good fits to reported AIDS counts but quite different estimates of cumulative infections. These results suggest that the incubation distribution is likely to differ for different populations and that the differences are large enough to have a big impact on the resulting estimates of HIV infection rates. This seriously limits the usefulness of backcalculation for populations (such as intravenous drug users, heterosexuals, and women) that lack precise information on incubation times.

Uncertainty About the Incubation Period of AIDS and its Impact on Backcalculation

We analyze three sets of doubly-censored cohort data on incubation times, estimating incubation distributions using semi-parametric methods and assessing the comparability of the estimates. Weibull models appear to be inappropriate for at least one of the cohorts, and the estimates for the different cohorts are substantially different. We use these estimates as inputs for backcalculation, using a nonparametric method based on maximum penalized likelihood. The different incubations all produce fits to the reported AIDS counts that are as good as the fit from a nonstationary incubation distribution that models treatment effects, but the estimated infection curves are very different. We also develop a method for estimating nonstationarity as part of the backcalculation procedure and find that such estimates also depend very heavily on the assumed incubation distribution. We conclude that incubation distributions are so uncertain that meaningful error bounds are difficult to place on backcalculated estimates and that backcalculation may be too unreliable to be used without being supplemented by other sources of information in HIV prevalence and incidence.

Local targeting of malignant gliomas by the diffusible peptidic vector 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid-substance p

PURPOSE: Malignant glial brain tumors consistently overexpress neurokinin type 1 receptors. In classic seed-based brachytherapy, one to several rigid (125)I seeds are inserted, mainly for the treatment of small low-grade gliomas. The complex geometry of rapidly proliferating high-grade gliomas requires a diffusible system targeting tumor-associated surface structures to saturate the tumor, including its margins. EXPERIMENTAL DESIGN: We developed a new targeting vector by conjugating the chelator 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid to Arg(1) of substance P, generating a radiopharmaceutical with a molecular weight of 1,806 Da and an IC(50) of 0.88 +/- 0.34 nmol/L. Cell biological studies were done with glioblastoma cell lines. neurokinin type-1 receptor (NK1R) autoradiography was done with 58 tumor biopsies. For labeling, (90)Y was mostly used. To reduce the "cross-fire effect" in critically located tumors, (177)Lut and (213)Bi were used instead. In a pilot study, we assessed feasibility, biodistribution, and early and long-term toxicity following i.t. injection of radiolabeled 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid substance P in 14 glioblastoma and six glioma patients of WHO grades 2 to 3. RESULTS: Autoradiography disclosed overexpression of NK1R in 55 of 58 gliomas of WHO grades 2 to 4. Internalization of the peptidic vector was found to be specific. Clinically, the radiopharmeutical was distributed according to tumor geometry. Only transient toxicity was seen as symptomatic radiogenic edema in one patient (observation period, 7-66 months). Disease stabilization and/or improved neurologic status was observed in 13 of 20 patients. Secondary resection disclosed widespread radiation necrosis with improved demarcation. CONCLUSIONS: Targeted radiotherapy using diffusible peptidic vectors represents an innovative strategy for local control of malignant gliomas, which will be further assessed as a neoadjuvant approach.