90 Nb: potential radionuclide for application in immuno-PET : development of appropriate production strategy and first in vivo evaluation of 90 Nb-labeled monoclonal antibody

Die Nuklearmedizin ist ein modernes und effektives Werkzeug zur Erkennung und Behandlung von onkologischen Erkrankungen. Molekulare Bildgebung, die auf dem Einsatz von Radiopharmaka basiert, beinhaltet die Einzel-Photonen-Emissions-Tomographie (SPECT) und Positronenemissions¬tomographie (PET) und ermöglicht die nicht-invasive Visualisierung von Tumoren auf nano-und picomolarer Ebene.rnDerzeit werden viele neue Tracer für die genauere Lokalisierung von kleinen Tumoren und Metastasen eingeführt und hinsichtlich ihrer Eignung untersucht. Die meisten von ihnen sind Protein-basierte Biomoleküle, die die Natur selbst als Antigene für die Tumorzellen produziert. Dabei spielen Antikörper und Antikörper-Fragmente eine wichtige Rolle in der Tumor-Diagnostik und Behandlung. Die PET-Bildgebung mit Antikörpern und Antikörperfragmenten bezeichnet man als immuno-PET. Ein wichtiger Aspekt hierbei ist, dass entsprechende Radiopharmaka benötigt werden, deren Halbwertszeit mit der Halbwertszeit der Biomoleküle korreliert ist.rnIn neueren Arbeiten wird 90Nb als potenzieller Kandidat für die Anwendung in der immuno-PET vorgeschlagen. Seine Halbwertszeit von 14,6 Stunden ist geeignet für die Anwendung mit Antikörperfragmenten und einige intakten Antikörpern. 90Nb hat eine relativ hohen Anteil an Positronenemission von 53% und eine optimale Energie für die β+-Emission von 0,35 MeV, die sowohl eine hohe Qualität der Bildgebung als auch eine niedrige Aktivitätsmenge des Radionuklids ermöglicht.rnErsten grundlegende Untersuchungen zeigten: i) dass 90Nb in ausreichender Menge und Reinheit durch Protonen-Bombardierung des natürlichen Zirkonium Targets produziert, ii) aus dem Targetmaterial in entsprechender radiochemischer Reinheit isoliert und iii) zur Markierung des monoklonalen Antikörpers (Rituximab) verwendet werden kann und iv) dieser 90Nb-markierte mAb eine hohe in vitro Stabilität besitzt. Desweiteren wurde eine alternative und schnelle Abtrennungsmethode entwickelt, die es erlaubt 90Nb, mit einer geeigneten radiochemischen und radionuklidischen Reinheit für eine anschließende Markierung von Biomolekülen in einer Stunde zu aufzureinigen. Schließlich wurden erstmals 90Nb-markierte Biomolekülen in vivo untersucht. Desweiteren wurden auch Experimente durchgeführt, um den optimalen bifunktionellen Chelatbildner (BFC) für 90Niob zu finden. Mehrere BFC wurden hinsichtlich Komplexbildung mit NbV untersucht. Desferrioxamin (Df) erwies sich als geeignetster Chelator für 90Nb. Der monoklonale Antikörper Bevacizumab (Avastin®) wurde mit 90Nb markiert und eine Biodistributionsstudie und eine PET-Untersuchung durchgeführt. Alle diese Ergebnisse zeigten, dass 90Nb ein vielversprechendes Radionuklid für die Immuno-PET ist, welches sogar für weitere kommerzielle Anwendungen in der klinischen Routine geeignet zu sein scheint.rn

Industrial Restructuring in the Budapest agglomeration

The major 'motor' of the recent Hungarian industrial development has been foreign direct investment, particularly by multinational companies. This has stimulated the development process, as shown by the dynamism of production, exports and profitability of industry in Budapest. On the other hand, this has also led to a split of the industrial sphere into its foreign and domestic sections, or into foreign-owned companies and domestic SMEs. The major question asked in this project is where is Hungarian industry heading and will the gap between the contracting domestic part and the foreign multinationals continue to widen or will they be joined in a much more favourable scenario. Barta sees this as a question of whether Hungary can avoid the 'dead-end street' of South Asian industrialising countries, and instead move towards a new Eastern European or Hungarian model. He concludes that Budapest industry does not follow any given model and indeed its development probably cannot be seen as a 'model' proper in itself, but is, or will be, a mixture of different elements. This would be a welcome fusion of Hungary's rich human resources of accumulated knowledge with foreign direct investment. Budapest would play an exceptional role in such a process, as the gateway for foreign output to the rest of the country. The share of industry in the Budapest economy will continue to decrease, but it will become a more modern and profitable sector. It will also fulfil a technological transfer role between the developed world and the Hungarian countryside (or even a larger region of central and eastern Europe). Barta predicts that Budapest industry will develop a special structure, with a large subcontractor network supporting the large foreign enterprises, and alongside this industrial districts formed by SMEs.

Economic viability of shale gas production in the Marcellus Shale; indicated by production rates, costs and current natural gas prices

The U.S. natural gas industry has changed because of the recent ability to produce natural gas from unconventional shale deposits. One of the largest and most important deposits is the Marcellus Shale. Hydraulic fracturing and horizontal drilling have allowed for the technical feasibility of production, but concerns exist regarding the economics of shale gas production. These concerns are related to limited production and economic data for shale gas wells, declines in the rates of production, falling natural gas prices, oversupply issues coupled with slow growth in U.S. natural gas demand, and rising production costs. An attempt to determine profitability was done through the economic analysis of an average shale gas well using data that is representative of natural gas production from 2009 to 2011 in the Marcellus Shale. Despite the adverse conditions facing the shale gas industry it is concluded from the results of this analysis that a shale gas well in the Marcellus Shale is profitable based on NPV, IRR and breakeven price calculations.

A continuous-time MILP model for short-term scheduling of make-and-pack production processes

In process industries, make-and-pack production is used to produce food and beverages, chemicals, and metal products, among others. This type of production process allows the fabrication of a wide range of products in relatively small amounts using the same equipment. In this article, we consider a real-world production process (cf. Honkomp et al. 2000. The curse of reality – why process scheduling optimization problems are diffcult in practice. Computers & Chemical Engineering, 24, 323–328.) comprising sequence-dependent changeover times, multipurpose storage units with limited capacities, quarantine times, batch splitting, partial equipment connectivity, and transfer times. The planning problem consists of computing a production schedule such that a given demand of packed products is fulfilled, all technological constraints are satisfied, and the production makespan is minimised. None of the models in the literature covers all of the technological constraints that occur in such make-and-pack production processes. To close this gap, we develop an efficient mixed-integer linear programming model that is based on a continuous time domain and general-precedence variables. We propose novel types of symmetry-breaking constraints and a preprocessing procedure to improve the model performance. In an experimental analysis, we show that small- and moderate-sized instances can be solved to optimality within short CPU times.

Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC

Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H --> gamma-gamma, H --> ZZ* --> 4 leptons and H --> WW --> 2 leptons + 2 neutrinos. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of 7 TeV and 8 TeV, corresponding to an integrated luminosity of about 25/fb. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined fits probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson.

Scheduling the production of rolling ingots: Industrial context, model, and solution method

We study a real-world scheduling problem arising in the context of a rolling ingots production. First we review the production process and discuss peculiarities that have to be observed when scheduling a given set of production orders on the production facilities. We then show how to model this scheduling problem using prescribed time lags between operations, different kinds of resources, and sequence-dependent changeovers. A branch-and-bound solution procedure is presented in the second part. The basic principle is to relax the resource constraints by assuming infinite resource availability. Resulting resource conflicts are then stepwise resolved by introducing precedence relationships among operations competing for the same resources. The algorithm has been implemented as a beam search heuristic enumerating alternative sets of precedence relationships.

Analysis of the mechanisms that maintain coordinate production of $\alpha$- and $\beta$-tubulin in mammalian cells

Alpha and beta tubulin are essential proteins in all eukaryotic cells. To study how cells maintain coordinate levels of these two interacting proteins, we have used PCR to add a 9 amino acid epitope from influenza hemagglutinin protein onto the carboxyl terminus of $\alpha$1 and $\beta$1-tubulin. The chimeric tubulin genes (HA$\alpha$1 and HA$\beta$1) were transfected into CHO cells and cell lines that stably express each gene were selected. Cells transfected with HA-tubulin do not exhibit any gross changes in growth or morphology. Immunofluorescence analysis demonstrated that HA-tubulins incorporate into both cytoplasmic and spindle microtubules. A quantitative biochemical assay was used to show that HA-tubulins incorporate into microtubules to a normal extent and do not alter the steady state distribution of endogenous tubulin between monomer and polymer pools. Two-dimensional gel analysis of pulse-labeled cells indicated that when HA$\beta$1-tubulin is expressed at high levels, it slightly represses the synthesis of the endogenous $\beta$-tubulin but produces a small increase in the synthesis of $\alpha$-tubulin. Analysis of cells labeled to steady state showed that HA$\beta$1-tubulin accumulates to a similar level as the wild-type gene product, but together these polypeptides produce only a small increase in total tubulin content consistent with the increased synthesis of $\alpha$-tubulin. It thus appears that HA$\beta$1-tubulin successfully competes with endogenous $\beta$-tubulin for heterodimer formation and that free $\beta$-tubulin subunits (endogenous and HA$\beta$1) are selectively degraded to maintain coordinate amounts of $\alpha$- and $\beta$-tubulin. In addition, the increased synthesis of $\alpha$-tubulin suggested the existence of a mechanism to ensure coordinate synthesis of $\alpha$- and $\beta$-tubulin subunits. To analyze whether reciprocal changes in endogenous tubulin synthesis occur when $\alpha$-tubulin is overexpressed, stably transfected CHO cell lines were isolated in which HA$\alpha$1-tubulin represents 50% of the total $\alpha$-tubulin, and its relative abundance can be further increased to 85-90% by treatment with sodium butyrate. In contrast with results obtained using HA$\beta$1-tubulin, transfection of HA$\alpha$1-tubulin decreased the synthesis of endogenous $\alpha$-tubulin to 60% of normal with little or no change in $\beta$-tubulin synthesis. When the transfected cells were treated with sodium butyrate to further increase HA$\beta$1-tubulin production, a larger decrease in the synthesis of endogenous $\alpha$-tubulin (to 30% of normal) was observed. The repression on the synthesis of endogenous $\alpha$-tubulin polypeptide was found to be directly proportional to the expression of HA$\alpha$1-tubulin indicating the existence of an autoregulatory loop, where $\alpha$-tubulin inhibits its own synthesis. To determine whether overproduction of HA$\alpha$1-tubulin affected the transcription, message stability or translation of endogenous $\alpha$-tubulin, the steady state levels of $\alpha$-tubulin mRNA were analyzed by ribonuclease protection assays. The results showed that the steady state level of $\alpha$-tubulin mRNA is not affected by the overexpression of HA$\alpha$1-tubulin, indicating that the repression is translational. The results are compatible with a model in which $\beta$-tubulin synthesis is largely unperturbed by overexpression of other tubulin subunits, and excess $\beta$-tubulin subunits are rapidly degraded to maintain coordinate $\alpha$- and $\beta$-tubulin levels at steady state. In contrast, free $\alpha$-tubulin represses its own synthesis at the translational level, suggesting that its level of production may be controlled by the amount of $\beta$-tubulin available for heterodimer formation. ^

Localization and production of peptide endocannabinoids in the rodent CNS and adrenal medulla.

The endocannabinoid system (ECS) comprises the cannabinoid receptors CB1 and CB2 and their endogenous arachidonic acid-derived agonists 2-arachidonoyl glycerol and anandamide, which play important neuromodulatory roles. Recently, a novel class of negative allosteric CB1 receptor peptide ligands, hemopressin-like peptides derived from alpha hemoglobin, has been described, with yet unknown origin and function in the CNS. Using monoclonal antibodies we now identified the localization of RVD-hemopressin (pepcan-12) and N-terminally extended peptide endocannabinoids (pepcans) in the CNS and determined their neuronal origin. Immunohistochemical analyses in rodents revealed distinctive and specific staining in major groups of noradrenergic neurons, including the locus coeruleus (LC), A1, A5 and A7 neurons, which appear to be major sites of production/release in the CNS. No staining was detected in dopaminergic neurons. Peptidergic axons were seen throughout the brain (notably hippocampus and cerebral cortex) and spinal cord, indicative of anterograde axonal transport of pepcans. Intriguingly, the chromaffin cells in the adrenal medulla were also strongly stained for pepcans. We found specific co-expression of pepcans with galanin, both in the LC and adrenal gland. Using LC-MS/MS, pepcan-12 was only detected in non-perfused brain (∼40 pmol/g), suggesting that in the CNS it is secreted and present in extracellular compartments. In adrenal glands, significantly more pepcan-12 (400-700 pmol/g) was measured in both non-perfused and perfused tissue. Thus, chromaffin cells may be a major production site of pepcan-12 found in blood. These data uncover important areas of peptide endocannabinoid occurrence with exclusive noradrenergic immunohistochemical staining, opening new doors to investigate their potential physiological function in the ECS. This article is part of a Special Issue entitled 'Fluorescent Neuro-Ligands'.

AN EMPIRICAL ESTIMATION OF MEDICAL AND NON-MEDICAL INPUTS IN THE PRODUCTION OF CARDIO-RESPIRATORY PHYSICAL HEALTH STATUS

The purpose of this study was to examine, in the context of an economic model of health production, the relationship between inputs (health influencing activities) and fitness.^ Primary data were collected from 204 employees of a large insurance company at the time of their enrollment in an industrially-based health promotion program. The inputs of production included medical care use, exercise, smoking, drinking, eating, coronary disease history, and obesity. The variables of age, gender and education known to affect the production process were also examined. Two estimates of fitness were used; self-report and a physiologic estimate based on exercise treadmill performance. Ordinary least squares and two-stage least squares regression analyses were used to estimate the fitness production functions.^ In the production of self-reported fitness status the coefficients for the exercise, smoking, eating, and drinking production inputs, and the control variable of gender were statistically significant and possessed theoretically correct signs. In the production of physiologic fitness exercise, smoking and gender were statistically significant. Exercise and gender were theoretically consistent while smoking was not. Results are compared with previous analyses of health production. ^

Seasonal production patterns of planktonic foraminifera in the NE Atlantic Ocean

Sediment trap samples from OMEX 2 (49°N, 13°W) provide a continuous record of the seasonal succession of planktonic foraminifera in the midlatitude North Atlantic and reveal a complex relationship between periods of production and specific hydrographic conditions. Neogloboquadrina pachyderma dextral coiling (d.), Globigerina bulloides, and Globorotalia inflata are found in great numbers during both the spring and summer seasons, whereas Globigerina quinqueloba, Globorotalia hirsuta, Globorotalia scitula, and Globigerinita glutinata are associated predominantly with the increase in productivity during the spring bloom. Globigerinella aequilateralis, Orbulina universa, and Globigerinoides sacculifer are restricted to late summer conditions following the establishment of a warm, well-stratified surface ocean. An annually integrated fauna from the sediment trap, comprising ~13,000 individuals, is used to evaluate the accuracy of five faunal-based statistical methods of paleotemperature estimation. All of the temperature reconstruction techniques produce estimates of ~16°C and ~11°C for summer and winter surface temperature, respectively, which are in excellent agreement with regional hydrographic data and suggest that the sediment trap assemblage is well represented in the core top faunas. Analysis of the key species that dominate the OMEX 2 sediment trap fauna, G. bulloides, G. inflata, and N. pachyderma d., based on d18O derived temperatures from North Atlantic core top samples, suggests that seasonal variations in planktonic foraminiferal production are nonuniform across the midlatitudes and that this is likely to complicate reconstructing past seasonal hydrographic dynamics using these taxa.

(Table 2) Production parameters of phytoplankton and some associated parameters in the area of the Titanic Polygon

Studies were carried out mostly in the area of RMS Titanic wreck site (41°44'N, 49°57'W) located above the continental slope and the south of the Grand Banks of Newfoundland. In a period from 18.06 to 24.09.2001 five surveys of production characteristics of surface phytoplankton were conducted over 5-9 days. Mean values of these characteristics obtained during the surveys were 9.2-11.7 mg C/m**3 per day for primary production (C_phs), 0.102-0.188 mg/m**3 for chlorophyll a (C_chls), and 4.44-7.42 mg C/mg chl. a per hour for assimilation number (AN). The main reason for low C_phs variability was a significant inverse relationship (R=-0.66) between AN and C_chls found over the research area. When cold shelf waters dominated in the area (27.07 to 19.08.2001), C_chls values for the slope region (0.125+/-0.031 µg/l) and for the outer shelf (0.130+/-0.040 µg/l) were similar. During strengthening of influence of warmer slope waters within area (from 29.08 to 13.09.2001), C_chls concentration within surface waters of the outer shelf was 0.152+/-0.039 µg/l and exceeded one for the slope region (0.094+/-0.004 µg/l) by factor 1.6. Against the background of low Cchls values, the High values of integral primary production in the water column (510-1010 mg C/m**2 per day) at low C_chls values measured within the area were determined both by high assimilation activity of phytoplankton and by the deep (30-40 m) maximum of primary production. Main reasons for formation of such a maximum were high chlorophyll concentration within the layer of the deep chlorophyll maximum (up to 0.5-2.5 µg/l) and in the relatively high solar irradiance within this layer varying from 1.4 to 8.6% of subsurface PAR.

Expansion of Asparagus Production and Exports in Peru

Peru is the one of the most important exporters of asparagus in the world. Its export volume of fresh asparagus is ranked number one, and its export volume of preserved asparagus number two, globally. The objective of this paper is to provide an overview of the recent trends in asparagus production and exports around the world and to analyze factors in the development of the Peruvian asparagus industry. The production of asparagus has spread geographically. The center of its production used to be in the principal consuming countries, such as France, Germany and the United States. Afterward, it spread to neighboring countries such as Spain and Mexico where production factors such as climate and labor costs are favorable. After the rise and fall of Taiwan as a major preserved white asparagus exporter, China and Peru replaced its position. Finally, in recent years, Peru expanded its fresh green asparagus exports to the U.S. market by taking advantage of the increasing demand for fresh vegetables and supplying produce in seasons when neither U.S. nor Mexican producers can harvest. In addition to the changing factors in the international market, there are several factors in the development of the industry: high yields of produce due to favorable climatic and soil conditions; the introduction of the drip irrigation system, which enabled desert cultivation; the integration of production and exports, which is indispensable for fresh produce exports; and the collective efforts of the industry with help from the public sector.

A New Measurement for International Fragmentation of the Production Process: An International Input-Output Approach

The paper investigates the possibility of constructing a new measurement for analysing international fragmentation of the production process. It asserts that the current usage of relevant data, whether the trade shares of parts and components or the index of Vertical Specialisation, is quite unsatisfactory for measuring the phenomenon, since they critically lack the overall perspective of the entire structure of production chains. 　The new measurement is formulated such that it captures every aspect of the vertical sequence of production linkages. It is based on the input-output model of Average Propagation Lengths, recently developed by Eric Dietzenbacher and others, which show the average number of production stages that are passed through for an exogenous change in one industry to affect another. By applying this model to the data of the Asian International Input-Output Tables, the index is able to measure the international dimension of production sharing and division of labour in East Asia.

Production Networks and Spatial Economic Interdependence: An International Input-Output Analysis of the Asia-Pacific Region

The Asia-Pacific Region has enjoyed remarkable economic growth in the last three decades. This rapid economic growth can be partially attributed to the global spread of production networks, which has brought about major changes in spatial interdependence among economies within the region. By applying an Input-Output based spatial decomposition technique to the Asian International Input-Output Tables for 1985 and 2000, this paper not only analyzes the intrinsic mechanism of spatial economic interdependence, but also shows how value added, employment and CO2 emissions induced are distributed within the international production networks.

The Iron and Steel Industry in Asia: Development and Restructuring

The paper examines the development and restructuring of the iron and steel industry in Asian countries. Studying countries that have integrated steelworks with large blast furnaces (South Korea, Taiwan, China and India) and countries without (Thailand, Indonesia and Malaysia), the paper shows the difference in the development processes across the countries and across time, and points to the diversity of the development experience of these countries. The paper argues that significant differences in steel production technologies in terms of initial investment and minimum-efficient scale, the changing role of the state, and shifting demand structures in the domestic steel markets of each country have been the important factors that led to the differences in the development path of the steel industry in each country.